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Nervous system growth factors are natural proteins of the brain that influence neuronal survival and function throughout life, from embryonic development to old age. In animal models of Alzheimer's disease (AD), the growth factor brain derived neurotrophic factor (BDNF) prevents neuronal death, activates neuronal function, builds new synapses and improves learning and memory. Accordingly, we are determining whether gene delivery of BDNF in patients with AD will slow disease progression and improve memory. In a previous clinical trial of nerve growth factor (NGF) gene therapy in AD patients (NCT00017940, June 2001), we learned that growth factors can unequivocally elicit classic trophic responses from degenerating neurons in AD. Experience gained from the earlier NGF gene therapy trial is guiding our effort to optimize gene delivery of BDNF in our present clinical program (NCT05040217, June 2021). [ABSTRACT FROM AUTHOR]

Background: Finding the balance of good postoperative analgesia while facilitiating mobility is important for a safe and satisfactory patient experience during Total Knee Arthroplasty (TKA). This study aimed to compare the efficacy of intrathecal morphine, adductor canal block, and their combination in optimizing pain management and postoperative recovery in TKA patients. This retrospective analysis of prospectively collected data evaluated postoperative pain scores, time to mobilisation, and length of hospital stay. Methods: 1006 consecutive patients undergoing elective TKA across two large tertiary centres were included over six years. They were divided into one of four groups according to the type of analgesia received: Group N patients received no neuraxial morphine or regional block. Group B patients received adductor canal block (ACB) only. Group M patients received intrathecal morphine (ITM) but no regional block. Group BM patients received both ACB and ITM. Results: Patients who received an ACB had faster postoperative mobilization compared to those without (p < 0.001). Patients in Group BM had the lowest pain scores at rest (Visual Analogue Scale (VAS) 2.9) and with movement (VAS 5.3), while Group B patients experienced the highest pain scores at rest (VAS 3.7) and on movement (VAS 6.5) (p = 0.005). Patients who received ITM had the lowest opioid requirements (p < 0.001). There was no significant differences between groups in requirement for rescue pain management strategies (p = 0.06). Conclusions: The combination of ITM and ACB in patients undergoing TKA provides improved postoperative analgesia with lower postoperative opioid requirement and earlier mobilization compared with ACB or ITM alone. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Patients with intrathecal catheters for pain medication infusion should be aware of the possible complication of acute flaccid paralysis. While exceedingly rare, it should prompt immediate medical attention to rule out compressive pathology requiring intervention. [ABSTRACT FROM AUTHOR]

Highly efficient adeno associated viruses (AAVs) targeting the central nervous system (CNS) are needed to deliver safe and effective therapies for inherited neurological disorders. The goal of this study was to compare the organ-specific transduction efficiencies of two AAV capsids across three different delivery routes. We compared AAV9-CBA-fLucYFP to AAV-DJ-CBA-fLucYFP using the following delivery routes in mice: intracerebroventricular (ICV) 1 × 1012 vg/kg, intrathecal (IT) 1 × 1012 vg/kg, and intravenous (IV) 1 × 1013 vg/kg body weight. Our evaluations revealed that following ICV and IT administrations, AAV-DJ demonstrated significantly increased vector genome (vg) uptake throughout the CNS as compared to AAV9. Through the IV route, AAV9 demonstrated significantly increased vg uptake in the CNS. However, significantly fewer vgs were detected in the off-target organs (kidney and liver) following administration of AAV-DJ using the IT and IV delivery routes as compared to AAV9. Distributions of vgs correlate well with transgene transcript levels, luciferase enzyme activities, and immunofluorescence detection of YFP. Overall, between the two vectors, AAV-DJ resulted in better targeting and expression in CNS tissues paired with de-targeting and reduced expression in liver and kidneys. Our findings support further examination of AAV-DJ as a gene therapy capsid for the treatment of neurological disorders. [ABSTRACT FROM AUTHOR]

Abstract Background Finding the balance of good postoperative analgesia while facilitiating mobility is important for a safe and satisfactory patient experience during Total Knee Arthroplasty (TKA). This study aimed to compare the efficacy of intrathecal morphine, adductor canal block, and their combination in optimizing pain management and postoperative recovery in TKA patients. This retrospective analysis of prospectively collected data evaluated postoperative pain scores, time to mobilisation, and length of hospital stay. Methods 1006 consecutive patients undergoing elective TKA across two large tertiary centres were included over six years. They were divided into one of four groups according to the type of analgesia received: Group N patients received no neuraxial morphine or regional block. Group B patients received adductor canal block (ACB) only. Group M patients received intrathecal morphine (ITM) but no regional block. Group BM patients received both ACB and ITM. Results Patients who received an ACB had faster postoperative mobilization compared to those without (p

Abstract Highly efficient adeno associated viruses (AAVs) targeting the central nervous system (CNS) are needed to deliver safe and effective therapies for inherited neurological disorders. The goal of this study was to compare the organ-specific transduction efficiencies of two AAV capsids across three different delivery routes. We compared AAV9-CBA-fLucYFP to AAV-DJ-CBA-fLucYFP using the following delivery routes in mice: intracerebroventricular (ICV) 1 × 1012 vg/kg, intrathecal (IT) 1 × 1012 vg/kg, and intravenous (IV) 1 × 1013 vg/kg body weight. Our evaluations revealed that following ICV and IT administrations, AAV-DJ demonstrated significantly increased vector genome (vg) uptake throughout the CNS as compared to AAV9. Through the IV route, AAV9 demonstrated significantly increased vg uptake in the CNS. However, significantly fewer vgs were detected in the off-target organs (kidney and liver) following administration of AAV-DJ using the IT and IV delivery routes as compared to AAV9. Distributions of vgs correlate well with transgene transcript levels, luciferase enzyme activities, and immunofluorescence detection of YFP. Overall, between the two vectors, AAV-DJ resulted in better targeting and expression in CNS tissues paired with de-targeting and reduced expression in liver and kidneys. Our findings support further examination of AAV-DJ as a gene therapy capsid for the treatment of neurological disorders.

Background and Aims: The use of intrathecal opioids is associated with high risk of pruritis and this may be decreased by adding a low dose of naloxone. This study evaluated the effect of the addition of 20 μg of naloxone to fentanyl–bupivacaine mixture on the incidence of pruritis in pregnant females scheduled for cesarean section (CS). Material and Methods: Eighty pregnant patients scheduled for CS under spinal anesthesia were randomized to receive either 10 mg of 0.5% hyperbaric bupivacaine (2 ml) plus 25 μg fentanyl (group F) or 10 mg of 0.5% hyperbaric bupivacaine (2 ml) plus 25 μg fentanyl and 20 μg naloxone (group FN). The incidence, onset, duration, site, and severity of pruritis were measured. Furthermore, the postoperative numerical rating scale (NRS) score, the total tramadol rescue analgesia, and the time for the first request of rescue analgesia were recorded. Results: Compared to the F group, the FN group showed a significant decrease in the incidence of pruritis (P = 0.022), prolongation of the onset of pruritis (P = 0.006), shortening of the duration of pruritis (P = 0.029), and decrease in the severity of pruritis (P = 0.039). Furthermore, the postoperative pain score, the rescue analgesic consumption, and the time for the first request of rescue analgesia were comparable between the two groups (P > 0.05). Conclusions: The addition of an ultra-low dose of naloxone (20 μg) to fentanyl–bupivacaine mixture in spinal anesthesia for pregnant females scheduled for CS significantly reduced the incidence of pruritis without having a significant effect on the postoperative analgesia.

Purpose: The impact of central nervous system (CNS) prophylaxis in diffuse large B-cell lymphoma (DLBCL) is contentious. The CNS International Prognostic Index (IPI) calculator offers prognostic guidance in identifying those patients who may be at highest risk of disease progression or relapse to the CNS. However, it is unclear whether this tool has guided clinician decision-making in a real-world setting. Studies have suggested that CNS prophylaxis may not offer clinically significant benefit in terms of preventing CNS disease progression. Given this, we investigated the utilization of CNS prophylaxis within our own population and documentation of the CNS-IPI score. Methods: We retrospectively evaluated patients with newly diagnosed DLBCL between January 1, 2014, and December 31, 2017. Patients were assessed for receipt of CNS prophylaxis in the form of intrathecal (IT) chemotherapy and/or high-dose intravenous (IV) methotrexate. CNS-IPI scores were calculated for all patients who received CNS prophylaxis or those who experienced CNS disease. Long-term outcomes at five years from diagnosis included CNS progression/relapse and survival. Results: Of 234 patients who met criteria, 20 (8.6%) received either IV methotrexate or IT chemotherapy; most received IT methotrexate. No patients in the IT prophylaxis group developed CNS disease, while two of eight IV methotrexate patients experienced CNS disease involvement. The incidence of CNS progression was 3.7% in the no prophylaxis group and 10% in those who received prophylaxis. Conclusions: This study revealed low utilization of CNS prophylaxis and CNS-IPI documentation in a community hospital system. Given large differences between groups, claims of CNS prophylaxis efficacy are unable to be made. CNS relapse rates were consistent with existing literature and promote continued evaluation of the utility of current CNS prophylaxis approaches in DLBCL. New unambiguously effective therapeutic approaches are needed and may encourage a higher rate of standardized use.

Introduction: Opioids are commonly added to local anaesthetic for subarachnoid block for caesarean section due to their synergistic effects. The physiochemical characteristics of opioids suggest premixing with hyperbaric bupivacaine may limit their distribution within the CSF. We studied the effect of a separate injection with a combination of bupivacaine, morphine and fentanyl on block characteristics, haemodynamic changes, postoperative pain and patient satisfaction. Method: Following ethical approval and informed consent, a prospective double-blinded randomised controlled trial was performed in a university hospital. A total of 126 patients undergoing caesarean section were randomised to two groups. In group M, the premixed group, patients received 12 mg of hyperbaric bupivacaine, 20 mcg of fentanyl and 100 mcg of morphine injected as a single mixture. In group S, the separate injection group, patients received the same drugs in separate injections. Measurements included haemodynamics, block distribution, intra- and postoperative pain, as well as patient satisfaction. Results: Patients in both groups had similar block height, time to maximum sensory block, time to block regression and motor block. However, haemodynamics were different between the groups. The proportion of systolic hypotension episodes was greater in group S [159/1320 (12.05%)] than group M [113/1452 (7.78%)], with P = 0.0002. Moreover, a greater amount of ephedrine was administered in group S than group M, with values 12.09 (8.1) and 9.09 (8.5) mg respectively (P = 0.001). Additionally, postoperative pain, as measured by the Visual Analogue Scale (VAS), was greater in group M, with a VAS of 4.6 (1.7), vs. group S, which recorded a VAS of 3.8 (2.0) (P = 0.017). Conclusion: Sequential injection of intrathecal opioids and hyperbaric bupivacaine resulted in greater early haemodynamic instability and slightly better postoperative analgesia without any difference in block height or patient satisfaction. Clinical trial registration: NCT04403724. [ABSTRACT FROM AUTHOR]

Management of refractory spasticity symptoms remains a challenging task for clinicians. Intrathecal baclofen (ITB) therapy has emerged as a promising option for treating this condition. This study evaluates the effectiveness of ITB therapy in managing refractory spasticity symptoms. A retrospective chart review was conducted on 34 patients with refractory spasticity symptoms who underwent ITB therapy at a single institution. The patients' demographics, clinical characteristics, and dosages were recorded. The primary outcome measures were the reduction in pain, improvement in mobility, decrease in spasm frequency, and alleviation of spasticity. ITB therapy successfully reduced pain, improved mobility, decreased spasm frequency, and alleviated spasticity. The mean daily administered dose was 245 μg (range: 88–510 μg, standard deviation:104). However, it was observed that the appropriate dosage of ITB therapy was patient-specific and time-sensitive. Moreover, side effects were observed when an incorrect dose was administered. ITB therapy is an effective and safe option for managing refractory spasticity symptoms. However, the appropriate dosage should be individualized and monitored closely to avoid side effects. This study highlights the importance of carefully considering the potential risks and benefits of ITB therapy for each patient. [ABSTRACT FROM AUTHOR]

Background: Spinal anesthesia is the most popular regional anesthesia technique for lower limb and lower abdominal surgery. Bupivacaine 0.5% heavy is commonly used for intrathecal use. New long-acting local anesthetic agents such as ropivacaine have claimed benefits of reduced cardiac toxicity on overdose and more specific effects on sensory rather than motor nerve fibers. The use of intrathecal hyperbaric ropivacaine is not much studied. With this background, we studied intrathecal ropivacaine hyperbaric 0.75% against intrathecal bupivacaine hyperbaric 0.5% for lower abdominal and lower limb surgery. Aims and Objectives: To note the effectiveness of intrathecal ropivacaine and bupivacaine on characteristics of subarachnoid block such as sensory block, motor block, hemodynamic parameters, and complications if any. Materials and Methods: We randomized patients undergoing lower abdominal surgeries and lower limb orthopedic surgeries under spinal anesthesia into two groups so as to receive intrathecal either ropivacaine 0.75% hyperbaric (3 mL) or bupivacaine 0.5% hyperbaric (3mL) and noted study parameters. Results: Time of sensory block onset (P=0.0005), peak sensory level (P=0.0029), and onset of L1 bromage-3 motor block (P=1.27E--08) was significantly delayed in the ropivacaine group as compared to bupivacaine group. However, maximum sensory level achieved (T6), time required for two-segment sensory regressions (P=0.1162), and time of onset of pain (P=0.1162) were comparable in both groups. Conclusion: Intrathecal ropivacaine 0.75% hyperbaric produced slow onset sensory and motor block than 0.5% hyperbaric bupivacaine with comparable cephalic spread and duration of sensory block. [ABSTRACT FROM AUTHOR]

Background There is little literature about the intrathecal use of dexmedetomidine with local anaesthetics in humans. Also, levobupivacaine is known to have lesser CNS and CVS side-effects than its racemic isomer. Fentanyl is a commonly used intrathecal adjuvant. Aims To compare and evaluate the efficacy of levobupivacaine alone, with dexmedetomidine and with fentanyl as adjuvants in spinal anaesthesia for providing adequate analgesia, hemodynamic stability and minimal sedation after infra-umbilical surgeries. Methods A total of 60 patients of ASA I-II of both sexes aged between 20 and 60 years were randomly allocated into three equal groups of 20 patients each. Group L received isobaric levobupivacaine 15 mg with normal saline as control; group LD received levobupivacaine 15 mg with 5 µg dexmedetomidine and group LF received 15 mg of levobupivacaine with 25 mcg of fentanyl, all made up to 4 ml after diluting with normal saline. Results The demographic profiles were comparable among the three groups. Dexmedetomidine showed early appearance of peak sensory level (5.72±1.05) and motor blockade (2.01±0.685), and early reach T10 segments (2.253±0.69). S1 and Bromage 0 regression times were prolonged with dexmedetomidine (225.87±6.65, 194.75±4.17). Analgesic duration was also significantly prolonged with dexmedetomidine (250.33±8.92). Conclusion Adding dexmedetomidine as an adjuvant to levobupivacaine improves the duration of block and analgesia, resulting in early block achievement with minimal side effects. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effect of intrathecal (IT) recombinant human arylsulfatase A (rhASA) on magnetic resonance imaging (MRI)‐assessed brain tissue changes in children with metachromatic leukodystrophy (MLD). In total, 510 MRI scans were collected from 12 intravenous (IV) rhASA‐treated children with MLD, 24 IT rhASA‐treated children with MLD, 32 children with untreated MLD, and 156 normally developing children. Linear mixed models were fitted to analyze the time courses of gray matter (GM) volume and fractional anisotropy (FA) in the posterior limb of the internal capsule. Time courses for demyelination load and FA in the centrum semiovale were visualized using locally estimated scatterplot smoothing regression curves. All assessed imaging parameters demonstrated structural evidence of neurological deterioration in children with MLD. GM volume was significantly lower at follow‐up (median duration, 104 weeks) in IV rhASA‐treated versus IT rhASA‐treated children. GM volume decline over time was steeper in children receiving low‐dose (10 or 30 mg) versus high‐dose (100 mg) IT rhASA. Similar effects were observed for demyelination. FA in the posterior limb of the internal capsule showed a higher trend over time in IT rhASA‐treated versus children with untreated MLD, but FA parameters were not different between children receiving the low doses versus those receiving the high dose. GM volume in IT rhASA‐treated children showed a strong positive correlation with 88‐item Gross Motor Function Measure score over time. In some children with MLD, IT administration of high‐dose rhASA may delay neurological deterioration (assessed using MRI), offering potential therapeutic benefit. [ABSTRACT FROM AUTHOR]

Key Clinical Message Patients with intrathecal catheters for pain medication infusion should be aware of the possible complication of acute flaccid paralysis. While exceedingly rare, it should prompt immediate medical attention to rule out compressive pathology requiring intervention.

Abstract Background Mesenchymal stem cell-neural progenitors (MSC-NPs) are a bone marrow mesenchymal stem cell (MSC)-derived ex vivo manipulated cell product with therapeutic potential in multiple sclerosis (MS). The objective of this study was to determine efficacy of intrathecal (IT) MSC-NP treatment in patients with progressive MS. Methods The study is a phase II randomized, double-blind, placebo-controlled clinical trial with a compassionate crossover design conducted at a single site. Subjects were stratified according to baseline Expanded Disability Status Scale (EDSS) (3.0-6.5) and disease subtype (secondary or primary progressive MS) and randomized into either treatment or placebo group to receive six IT injections of autologous MSC-NPs or saline every two months. The primary outcome was EDSS Plus, defined by improvement in EDSS, timed 25-foot walk (T25FW) or nine-hole peg test. Secondary outcomes included the individual components of EDSS Plus, the six-minute walk test (6MWT), urodynamics testing, and brain atrophy measurement. Results Subjects were randomized into MSC-NP (n = 27) or saline (n = 27) groups. There was no difference in EDSS Plus improvement between the MSC-NP (33%) and saline (37%) groups. Exploratory subgroup analysis demonstrated that in subjects who require assistance for ambulation (EDSS 6.0-6.5) there was a significantly higher percentage of improvement in T25FW and 6MWT in the MSC-NP group (3.7% ± 23.1% and − 9.2% ± 18.2%) compared to the saline group (-54.4% ± 70.5% and − 32.1% ± 30.0%), (p = 0.030 and p = 0.036, respectively). IT-MSC-NP treatment was also associated with improved bladder function and reduced rate of grey matter atrophy on brain MRI. Biomarker analysis demonstrated increased MMP9 and decreased CCL2 levels in the cerebrospinal fluid following treatment. Conclusion Results from exploratory outcomes suggest that IT-MSC-NP treatment may be associated with a therapeutic response in a subgroup of MS patients. Trial Registration ClinicalTrials.gov NCT03355365, registered November 14, 2017, https://clinicaltrials.gov/study/NCT03355365?term=NCT03355365&rank=1 .

Introduction: The diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) and, despite all the progress in this field, central nervous system infiltration (CNSi) still occurs at an incidence of 2–10%. The objective of the present study was to evaluate the Central Nervous System International Prognostic Index (CNS-IPI) score in daily practice regarding the reproducibility in a heterogeneous cohort apart from a clinical trial. Methods: Primary DLBCL patients were eligible for this study, between January 2007 and January 2017. All patients were treated with rituximab-based chemotherapy, mostly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). The CNSi was diagnosed by liquor (positive cytology and/or immunophenotype), computerized tomography, magnetic resonance image and/or fluorodeoxy-glucose-positron emission tomography, requested only in symptomatic patients when the CNSi was clinically suspected. The CNS-IPI was assessed by graphical comparison and calibration. Results: After applying the inclusion/exclusion criteria, 322 patients were available for the analysis. The median follow-up was 60 months and the median age was 58 years. Seven patients experienced CNSi, characterizing an incidence of 2.17% (7/322). Comparing groups of patients with and without CNSi, we observed that the lactate dehydrogenase (LDH), number of extranodal sites, IPI, kidney/adrenal and absence of complete response were statistically different. The CNS-IPI model stratified patients in a three-risk group model as low-, intermediate- and high-risk. In our cohort, using the same stratification, we obtained an equivalent the 2-year rate of CNS relapse of 0.0%, 0.8% and 13.8%, respectively. Conclusion: Our study reinforces the reproducibility of the CNS-IPI, specifically apart from clinical trials, and suggests the CNS-IPI score as a tool to guide therapy.

Abstract Background Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by iduronate-2-sulfatase gene (IDS) deficiency and downstream glycosaminoglycan accumulation. Two-thirds of patients present with neuronopathic disease and evaluating cognitive function in these patients is challenging owing to limitations of currently available tests. During the clinical development of intrathecal idursulfase (idursulfase-IT), regulatory authorities requested qualitative data to further understand the neurocognitive changes observed by the investigators through the clinical trials. Results This qualitative study consisted of semi-structured interviews with all nine of the principal investigators who participated in the idursulfase-IT phase 2/3 (NCT02055118) and extension (NCT02412787) trials. These investigators enrolled the 56 patients with neuronopathic MPS II who qualified for the extension phase of the trial. The investigators were asked to rate the disease status of their patients. Of the 56 patients, 49 (88%) were rated as having disease that was improved/improving, stabilized or slowing progression compared with the expected outcomes with no treatment. Three patients were rated as worsening, while the remaining four patients were considered to have slowing progression or worsening disease. Similar results were demonstrated for patients aged from 3 to under 6 years at baseline, with 33 of 39 patients (85%) rated as having disease that was improved/improving, stabilized or slowing progression. Of the seven patients rated with slowing progression/worsening or worsening disease, five of them had an IDS variant other than missense, while two had a missense class variant. All the assigned improved/improving ratings were in patients receiving idursulfase-IT from the start of the phase 2/3 trial. Moreover, patients under 3 years of age at baseline were all rated as either improved/improving or stabilized disease. In a blinded review of patient profiles, investigators were requested to assign a disease status rating to 18 patients with large IDS deletions; 67% of these patients were rated as improved/improving or stabilized disease. Conclusions This qualitative analysis provides a snapshot of clinicians’ considerations when evaluating treatment in patients with neuronopathic MPS II, compared with the expected decline in cognitive function in the absence of treatment. The results highlight the importance of robust assessment tools in treatment evaluation.

Background: The use of a higher volume of 0.5% bupivacaine, however, is associated with hemodynamic instability. Adjuvants such as morphine and other opioids are added in with the local anesthetic to reduce this adverse effect and extend the duration of sensory block, hence extending the length of analgesia. However, opiates are associated with a high risk of respiratory depression and other side effects. Nalbuphine has been used to counteract these adverse effects. Thus, we decided to compare the analgesic effect of intrathecal (IT) nalbuphine with IT morphine. Aims and Objectives: The aim of the study was to compare IT morphine with nalbuphine as adjuvant to a spinal anesthetic agent. The primary objective was to compare between the time of onset of sensory and motor blockade and the post-operative analgesic duration between the two adjuvants, while hemodynamic variables and side effects were studied as secondary variables. Materials and Methods: This randomized controlled study was conducted after Ethical Committee approval for a period of 1 year on 100 patients who fulfilled the inclusion criteria. They were randomized into two groups to receive sub-arachnoid block: Group A: 3 mL of 0.5% Hyperbaric Bupivacaine and 0.2 mg morphine and Group B:3 mL of 0.5% Hyperbaric Bupivacaine and 0.5 mg nalbuphine. The following parameters were monitored – Height, Weight, blood pressure, American Society of Anesthesiologists grading, time of onset, maximum duration and regression of Motor and sensory blocks, and total duration of analgesia. Results: The onset of sensory blockade was comparable in both groups while the onset of motor blockade was significantly longer in the morphine group (P≤0.001). The duration of analgesia in the morphine group was longer as compared to nalbuphine group and was statistically significant (P

Abstract Background Approximately two-thirds of patients with mucopolysaccharidosis II (MPS II) have a severe, neuronopathic phenotype, characterized by somatic, cognitive, and behavioral issues. Current standard of care for the treatment of MPS II is enzyme replacement therapy with intravenous recombinant human iduronate-2-sulfatase (idursulfase). To target cognitive manifestations of MPS II, idursulfase has been formulated for intrathecal administration into the cerebrospinal fluid (idursulfase-IT). In accordance with recommendations for patient-focused drug development, semi-structured interviews were conducted to assess caregiver experiences and observations in a 52-week phase 2/3 trial of idursulfase-IT, in addition to intravenous idursulfase in pediatric patients with neuronopathic MPS II, or a substudy which enrolled patients younger than 3 years old, all of whom received idursulfase-IT. Results Overall, 46 caregivers providing care for 50 children (mean [range] age 7.9 [3–17] years at interview) took part in a single 60-min exit interview; six of these children had participated in the substudy. Qualitative and quantitative data were obtained demonstrating the burden of MPS II experienced by caregivers and their families. Following participation in the trials, 39 (78%) of the children were reported by their caregivers to have experienced improvements in the symptoms and impact of disease. Of those with improvements, 37 (95%) experienced cognitive improvements and 26 (67%) experienced emotional/behavioral improvements. Overall, 43 children (86%) were rated by caregivers as having moderate or severe symptoms before the trials; after the trials, 28 children (56%) were considered to have mild or no symptoms. For the six children who participated in the substudy, these proportions were 83% and 100%, respectively. Caregivers’ qualitative descriptions of trial experiences suggested improvements in children’s verbal and non-verbal functioning and spatial and motor skills, as well as a positive impact on family life. Conclusions This study revealed caregiver-reported improvements in children’s MPS II symptoms and the impact of the disease on patients and their families. There was a trend for cognitive improvement and a reduction in severity of MPS II symptoms. After many years of extensive review and regulatory discussions of idursulfase-IT, the clinical trial data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Introduction Generalized tetanus from Clostridium tetani infections is rare in the United States due to widespread use of tetanus toxoid-containing vaccines, and management of these critically ill patients can be challenging. We report a case of generalized tetanus in a pediatric patient treated with multiple sedatives and paralytics whose stabilization was associated with initiation of intrathecal baclofen.Case A 16-year-old unvaccinated male suffered a puncture wound to his left heel and presented with trismus, difficulty swallowing, diaphoresis, hypertension at 153/86 mmHg, and tachycardia at 120 bpm one week after sustaining the injury. The patient was intubated, received wound debridement, antibiotics, tetanus immune globulin, and a Tdap (tetanus, diphtheria, acellular, pertussis) vaccine. His tetany and autonomic stability worsened. He received norepinephrine, esmolol, midazolam, magnesium, morphine, propofol, vecuronium, dexmedetomidine, dantrolene, and oral baclofen without improvement. Intrathecal baclofen was started on hospital day 18, and within a day vecuronium was discontinued, and multiple sedatives were titrated down. He received intrathecal baclofen until hospital day 35 and was discharged on hospital day 40.Discussion Intrathecal baclofen is a potential treatment for generalized tetanus which may allow for reduction in paralytic and sedative use, and possibly shorter duration of mechanical ventilation and inpatient time.

Background: Mesenchymal stem cell-neural progenitors (MSC-NPs) are a bone marrow mesenchymal stem cell (MSC)-derived ex vivo manipulated cell product with therapeutic potential in multiple sclerosis (MS). The objective of this study was to determine efficacy of intrathecal (IT) MSC-NP treatment in patients with progressive MS. Methods: The study is a phase II randomized, double-blind, placebo-controlled clinical trial with a compassionate crossover design conducted at a single site. Subjects were stratified according to baseline Expanded Disability Status Scale (EDSS) (3.0-6.5) and disease subtype (secondary or primary progressive MS) and randomized into either treatment or placebo group to receive six IT injections of autologous MSC-NPs or saline every two months. The primary outcome was EDSS Plus, defined by improvement in EDSS, timed 25-foot walk (T25FW) or nine-hole peg test. Secondary outcomes included the individual components of EDSS Plus, the six-minute walk test (6MWT), urodynamics testing, and brain atrophy measurement. Results: Subjects were randomized into MSC-NP (n = 27) or saline (n = 27) groups. There was no difference in EDSS Plus improvement between the MSC-NP (33%) and saline (37%) groups. Exploratory subgroup analysis demonstrated that in subjects who require assistance for ambulation (EDSS 6.0-6.5) there was a significantly higher percentage of improvement in T25FW and 6MWT in the MSC-NP group (3.7% ± 23.1% and − 9.2% ± 18.2%) compared to the saline group (-54.4% ± 70.5% and − 32.1% ± 30.0%), (p = 0.030 and p = 0.036, respectively). IT-MSC-NP treatment was also associated with improved bladder function and reduced rate of grey matter atrophy on brain MRI. Biomarker analysis demonstrated increased MMP9 and decreased CCL2 levels in the cerebrospinal fluid following treatment. Conclusion: Results from exploratory outcomes suggest that IT-MSC-NP treatment may be associated with a therapeutic response in a subgroup of MS patients. Trial Registration: ClinicalTrials.gov NCT03355365, registered November 14, 2017, https://clinicaltrials.gov/study/NCT03355365?term=NCT03355365&rank=1. [ABSTRACT FROM AUTHOR]

This article compares the effects of adding dexmedetomidine or fentanyl to ropivacaine in intrathecal anesthesia for lower limb surgeries. The study found that adding dexmedetomidine resulted in a faster onset of sensory and motor blockade, as well as a longer duration of motor and sensory block, compared to fentanyl. Dexmedetomidine also provided longer post-operative analgesia and higher sedation levels. The study concludes that dexmedetomidine is a safe and effective adjuvant to ropivacaine for intrathecal anesthesia. [Extracted from the article]

Background: Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by iduronate-2-sulfatase gene (IDS) deficiency and downstream glycosaminoglycan accumulation. Two-thirds of patients present with neuronopathic disease and evaluating cognitive function in these patients is challenging owing to limitations of currently available tests. During the clinical development of intrathecal idursulfase (idursulfase-IT), regulatory authorities requested qualitative data to further understand the neurocognitive changes observed by the investigators through the clinical trials. Results: This qualitative study consisted of semi-structured interviews with all nine of the principal investigators who participated in the idursulfase-IT phase 2/3 (NCT02055118) and extension (NCT02412787) trials. These investigators enrolled the 56 patients with neuronopathic MPS II who qualified for the extension phase of the trial. The investigators were asked to rate the disease status of their patients. Of the 56 patients, 49 (88%) were rated as having disease that was improved/improving, stabilized or slowing progression compared with the expected outcomes with no treatment. Three patients were rated as worsening, while the remaining four patients were considered to have slowing progression or worsening disease. Similar results were demonstrated for patients aged from 3 to under 6 years at baseline, with 33 of 39 patients (85%) rated as having disease that was improved/improving, stabilized or slowing progression. Of the seven patients rated with slowing progression/worsening or worsening disease, five of them had an IDS variant other than missense, while two had a missense class variant. All the assigned improved/improving ratings were in patients receiving idursulfase-IT from the start of the phase 2/3 trial. Moreover, patients under 3 years of age at baseline were all rated as either improved/improving or stabilized disease. In a blinded review of patient profiles, investigators were requested to assign a disease status rating to 18 patients with large IDS deletions; 67% of these patients were rated as improved/improving or stabilized disease. Conclusions: This qualitative analysis provides a snapshot of clinicians' considerations when evaluating treatment in patients with neuronopathic MPS II, compared with the expected decline in cognitive function in the absence of treatment. The results highlight the importance of robust assessment tools in treatment evaluation. [ABSTRACT FROM AUTHOR]

Tuberculous meningitis (TBM) presents a critical neurologic emergency characterized by high mortality and morbidity rates, necessitating immediate therapeutic intervention, often ahead of definitive microbiological and molecular diagnoses. The primary hurdle in effective TBM treatment is the blood–brain barrier (BBB), which significantly restricts the delivery of anti-tuberculous medications to the central nervous system (CNS), leading to subtherapeutic drug levels and poor treatment outcomes. The standard regimen for initial TBM treatment frequently falls short, followed by adverse side effects, vasculitis, and hydrocephalus, driving the condition toward a refractory state. To overcome this obstacle, intrathecal (IT) sustained release of anti-TB medication emerges as a promising approach. This method enables a steady, uninterrupted, and prolonged release of medication directly into the cerebrospinal fluid (CSF), thus preventing systemic side effects by limiting drug exposure to the rest of the body. Our review diligently investigates the existing literature and treatment methodologies, aiming to highlight their shortcomings. As part of our enhanced strategy for sustained IT anti-TB delivery, we particularly seek to explore the utilization of nanoparticle-infused hydrogels containing isoniazid (INH) and rifampicin (RIF), alongside osmotic pump usage, as innovative treatments for TBM. This comprehensive review delineates an optimized framework for the management of TBM, including an integrated approach that combines pharmacokinetic insights, concomitant drug administration strategies, and the latest advancements in IT and intraventricular (IVT) therapy for CNS infections. By proposing a multifaceted treatment strategy, this analysis aims to enhance the clinical outcomes for TBM patients, highlighting the critical role of targeted drug delivery in overcoming the formidable challenges presented by the blood–brain barrier and the complex pathophysiology of TBM. [ABSTRACT FROM AUTHOR]

Background: The use of a higher volume of 0.5% bupivacaine, however, is associated with hemodynamic instability. Adjuvants such as morphine and other opioids are added in with the local anesthetic to reduce this adverse effect and extend the duration of sensory block, hence extending the length of analgesia. However, opiates are associated with a high risk of respiratory depression and other side effects. Nalbuphine has been used to counteract these adverse effects. Thus, we decided to compare the analgesic effect of intrathecal (IT) nalbuphine with IT morphine. Aims and Objectives: The aim of the study was to compare IT morphine with nalbuphine as adjuvant to a spinal anesthetic agent. The primary objective was to compare between the time of onset of sensory and motor blockade and the post-operative analgesic duration between the two adjuvants, while hemodynamic variables and side effects were studied as secondary variables. Materials and Methods: This randomized controlled study was conducted after Ethical Committee approval for a period of 1 year on 100 patients who fulfilled the inclusion criteria. They were randomized into two groups to receive sub-arachnoid block: Group A: 3 mL of 0.5% Hyperbaric Bupivacaine and 0.2 mg morphine and Group B:3 mL of 0.5% Hyperbaric Bupivacaine and 0.5 mg nalbuphine. The following parameters were monitored -- Height, Weight, blood pressure, American Society of Anesthesiologists grading, time of onset, maximum duration and regression of Motor and sensory blocks, and total duration of analgesia. Results: The onset of sensory blockade was comparable in both groups while the onset of motor blockade was significantly longer in the morphine group (P≤0.001). The duration of analgesia in the morphine group was longer as compared to nalbuphine group and was statistically significant (P<0.05). The incidence of side effects was 26% in the morphine group and 6% in the nalbuphine group, which was statistically significant (P<0.05). Fourteen patients in the morphine group had pruritus and four patients in the nalbuphine group experienced nausea. Conclusion: IT nalbuphine with 0.5% bupivacaine produces rapid onset of anesthesia and early post-operative analgesia with minimal side effects, but the total analgesic duration was more with IT morphine. [ABSTRACT FROM AUTHOR]

Background: Approximately two-thirds of patients with mucopolysaccharidosis II (MPS II) have a severe, neuronopathic phenotype, characterized by somatic, cognitive, and behavioral issues. Current standard of care for the treatment of MPS II is enzyme replacement therapy with intravenous recombinant human iduronate-2-sulfatase (idursulfase). To target cognitive manifestations of MPS II, idursulfase has been formulated for intrathecal administration into the cerebrospinal fluid (idursulfase-IT). In accordance with recommendations for patient-focused drug development, semi-structured interviews were conducted to assess caregiver experiences and observations in a 52-week phase 2/3 trial of idursulfase-IT, in addition to intravenous idursulfase in pediatric patients with neuronopathic MPS II, or a substudy which enrolled patients younger than 3 years old, all of whom received idursulfase-IT. Results: Overall, 46 caregivers providing care for 50 children (mean [range] age 7.9 [3–17] years at interview) took part in a single 60-min exit interview; six of these children had participated in the substudy. Qualitative and quantitative data were obtained demonstrating the burden of MPS II experienced by caregivers and their families. Following participation in the trials, 39 (78%) of the children were reported by their caregivers to have experienced improvements in the symptoms and impact of disease. Of those with improvements, 37 (95%) experienced cognitive improvements and 26 (67%) experienced emotional/behavioral improvements. Overall, 43 children (86%) were rated by caregivers as having moderate or severe symptoms before the trials; after the trials, 28 children (56%) were considered to have mild or no symptoms. For the six children who participated in the substudy, these proportions were 83% and 100%, respectively. Caregivers' qualitative descriptions of trial experiences suggested improvements in children's verbal and non-verbal functioning and spatial and motor skills, as well as a positive impact on family life. Conclusions: This study revealed caregiver-reported improvements in children's MPS II symptoms and the impact of the disease on patients and their families. There was a trend for cognitive improvement and a reduction in severity of MPS II symptoms. After many years of extensive review and regulatory discussions of idursulfase-IT, the clinical trial data were found to be insufficient to meet the evidentiary standard to support regulatory filings. [ABSTRACT FROM AUTHOR]

Objective: The primary objective was to elucidate the epidemiologic characteristics, risk determinants, and clinical outcomes associated with Pseudomonas aeruginosa –induced meningitis. Methods: All cases of meningitis caused by Pseudomonas aeruginosa that were treated at the hospital between 2012 and 2022 were retrospectively analyzed and detailed. Results: During a 10-year period, only 10 patients satisfied the inclusion criteria. Three patients had previously undergone neurosurgical procedures and 4 patients had leukemia. Conclusions: Although Pseudomonas aeruginosa meningitis possesses a low incidence rate, the rate of mortality is high. Patients with leukemia or those who have undergone neurosurgery are the most susceptible to diagnosis. Cases of severe neutropenia present only mild or no cerebrospinal fluid pleocytosis. In patients with sensitive Pseudomonas aeruginosa meningitis, the timely use of anti- Pseudomonas carbapenems for intravenous treatment is highly effective. For drug-resistant Pseudomonas aeruginosa meningitis, intrathecal polymyxins administration can be an effective treatment option. [ABSTRACT FROM AUTHOR]

Dexmedetomidine can be used as an adjuvant in epidurals with local anesthetic sparing effects. Its use during nerve blocks results in reduced postoperative pain. Also, local infiltration of IV dexmedetomidine is associated with earlier discharge from PACU. Similarly, magnesium the blockade of N-methyl-D-aspartate (NMDA) receptor and calcium channel has an important meaning to anesthesia. However, side effects could be cardiac or respiratory complications. Therefore, we compared the intrathecal dexmedetomidine and magnesium sulphate for post-operative analgesia requirement reduction in patients undergoing spinal anaesthesia and analysing hemodynamic changes. All three drugs (dexmedetomidine, magnesium sulphate and hyperbaric bupivacaine) proved to be haemodynamically stable as clinically significant bradycardia and hypotension were not observed in any of the groups. The incidences of side effects were negligible in all the three groups. In conclusion, although longer duration of effect can be obtained by the addition of either dexmedetomidine or magnesium to intrathecal hyperbaric bupivacaine, dexmedetomidine showed a significantly prolonged effect and a faster onset with fewer side effects. [ABSTRACT FROM AUTHOR]

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Background: This study compared rapid and slow intrathecal fentanyl injection followed by a slow injection of bupivacaine to estimate the duration of postoperative analgesia in lower-segment caesarean sections (LSCS). Methods: The study was performed on 60 parturient aged 18-35 years undergoing LSCS and was divided equally into two groups. Group A (Normal Sequential) received slow sequential intrathecal injections of fentanyl and hyperbaric bupivacaine and Group B (Rapid Sequential) received a rapid intrathecal injection of fentanyl followed by a slow injection of hyperbaric bupivacaine. We compared the duration of postoperative analgesia, time of onset of sensory and motor block attained, the highest level of sensory block attained, duration of motor block, Visual Analogue Scale (VAS) scores, spinal anaesthesia-related complications and haemodynamic parameters between both the groups. Results: The duration of postoperative analgesia was longer (P < 0.001) in group B (3.22 ± 0.66 hrs) as compared to group A (2.53 ± 0.41 hrs.) The onset of sensory block was faster (P < 0.001) in group B (1.01 ± 0.29 min) as compared to group A (1.32 ± 0.08 min). More patients in group B achieved higher levels of sensory blockade as compared to group A (5 patients in group A and 12 patients ofgroup B achieved a sensory block up to the T2 dermatome). VAS scores and the requirement of rescue analgesia were significantly lower (10 in group B and 19 in group A). Conclusion: Rapid sequential intrathecal injection of fentanyl and hyperbaric bupivacaine provided better anaesthesia and postoperative analgesia than the normal group.

Background Effective post-operative pain management is crucial for patient comfort and recovery following lower abdominal gynaecological surgeries. This study protocol outlines a randomised control trial designed to compare the efficacy and safety of two intrathecal adjuvants, nalbuphine and fentanyl, in conjunction with hyperbaric levobupivacaine for postoperative analgesia. Methods The study will be conducted at the Department of Anaesthesiology, Jawaharlal Nehru Medical College, DMIMS (DU), and affiliated institutions. Sixty eligible patients aged 35-75 years undergoing lower abdominal gynaecological surgeries under subarachnoid block will be randomly assigned to one of two groups. Group A will receive nalbuphine with levobupivacaine, while Group B will receive fentanyl with levobupivacaine. Patients will be monitored for the duration of post-operative analgesia, onset of sensory and motor block, hemodynamic effects, and side effects. Outcomes The primary outcome is the comparison of post-operative analgesia duration between nalbuphine and fentanyl. Secondary outcomes include assessing sensory and motor block onset, hemodynamic changes, ephedrine usage, and side effects. Aim To evaluate the efficacy and safety of intrathecal nalbuphine and fentanyl as adjuvants with hyperbaric levobupivacaine for postoperative analgesia in lower abdominal gynaecological surgeries.

Agmatine, a decarboxylated form of L-arginine, prevents opioid analgesic tolerance, dependence, and self-administration when given by both central and systemic routes of administration. Endogenous agmatine has been previously detected in the central nervous system. The presence of a biochemical pathway for agmatine synthesis offers the opportunity for sitespecific overexpression of the presumptive synthetic enzyme for local therapeutic effects. In the present study, we evaluated the development of opioid analgesic tolerance in ICR-CD1 mice pre-treated with either vehicle control or intrathecally delivered adeno-associated viral vectors (AAV) carrying the gene for human arginine decarboxylase (hADC). Vehicle-treated or AAVhADC-treated mice were each further divided into two groups which received repeated delivery over three days of either saline or systemically-delivered morphine intended to induce opioid analgesic tolerance. Morphine analgesic dose-response curves were constructed in all subjects on day four using the warm water tail flick assay as the dependent measure. We observed that pretreatment with AAV-hADC prevented the development of analgesic tolerance to morphine. Peripheral and central nervous system tissues were collected and analyzed for presence of hADC mRNA. In a similar experiment, AAV-hADC pre-treatment prevented the development of analgesic tolerance to a high dose of the opioid neuropeptide endomorphin-2. Intrathecal delivery of antiagmatine IgG (but not normal IgG) reversed the inhibition of endomorphin-2 analgesic tolerance in AAV-hADC-treated mice. To summarize, we report here the effects of AAV-mediated gene transfer of human ADC (hADC) in models of opioid-induced analgesic tolerance. This study suggests that gene therapy may contribute to reducing opioid analgesic tolerance. [ABSTRACT FROM AUTHOR]

Background and Aims: Intrathecal bupivacaine is used for anaesthesia and analgesia but is associated with hypotension. Ropivacaine is an alternative drug that may have fewer cardiotoxic and neurotoxic events. This meta-analysis investigated whether intrathecal ropivacaine is associated with reduced hypotension as compared to bupivacaine. Methods: The meta-analysis is registered in the International Prospective Register of Systematic Reviews (PROSPERO). The databases PubMed, Cinahl Plus, Google Scholar, and Scopus were searched, and papers from January 1980 to January 2023 were deemed eligible and filtered using predetermined inclusion and exclusion criteria. The primary outcome was the incidence of hypotension. Secondary outcomes were the duration of sensory block, duration of motor block, incidence of bradycardia, ephedrine usage, and duration of analgesia. Jadad scores were used to evaluate the quality of the papers. RevMan statistical software® utilised inverse variance and a random effect model to calculate the standardised mean difference with 95% confidence intervals for continuous variables and the Mantel--Haenszel test and the random effect model to calculate the odds ratio for dichotomous variables. Results: Thirty-three papers, including 2475 patients in total, were included. The Jadad score was between 1 and 5. The incidence of hypotension was significantly higher with intrathecal bupivacaine than with ropivacaine (P = 0.02). The duration of sensory block (P < 0.001) and motor block (P < 0.001) was prolonged with intrathecal bupivacaine. The duration of analgesia favoured intrathecal bupivacaine (P = 0.003). Conclusion: Intrathecal ropivacaine has a reduced incidence of hypotension and a reduced duration of sensory block compared to bupivacaine. [ABSTRACT FROM AUTHOR]

Background: prilocaine is an intermediate acting local anesthetic that can be used for spinal anesthesia in short duration surgeries. This might help reducing the traffic in postoperative care units (PACU) and reduce the duration of hospital stay. The aim of the study is to compare regression time of spinal anesthesia induced by hyperbaric prilocaine 2% with 20µ fentanyl versus hyperbaric bupivacaine 0.5% with 20µ fentanyl in perianal surgeries. Methods: Patients were into 2 groups: Control group (Group C: n=40) were given 1.5 ml (7.5 mg) hyperbaric bupivacaine 0.5%+ 20µ fentanyl while Group P (n=40 patients) were given 1.5 ml (30mg) hyperbaric prilocaine 2%+20µ fentanyl. In both groups, regression of spinal anesthesia (sensory and motor), time to spontaneous micturition, postoperative analgesic behavior, duration of PACU and hospital stay were evaluated. Results: m aximum levels of block in both groups were comparable. Sensory and motor block regression times were statistically shorter in Group P. Time to spontaneous voiding and time to unaided walking were shorter in Group P. There were no significant differences in duration of PACU stay between the two groups. Time till home readiness was significantly shorter in Group P. There were no cases of postoperative urinary retention or transient neurologic symptoms. Conclusion: Both mixtures of 30 mg hyperbaric prilocaine 2% plus 20 µg fentanyl versus 7.5 mg hyperbaric bupivacaine 0.5% plus fentanyl 20 µg are equipotent and safe when used intrathecally in perianal surgeries. Prilocaine is superior to bupivacaine regarding block regression and home readiness. [ABSTRACT FROM AUTHOR]

Background: This study compared rapid and slow intrathecal fentanyl injection followed by a slow injection of bupivacaine to estimate the duration of postoperative analgesia in lower-segment caesarean sections (LSCS). Methods: The study was performed on 60 parturient aged 18-35 years undergoing LSCS and was divided equally into two groups. Group A (Normal Sequential) received slow sequential intrathecal injections of fentanyl and hyperbaric bupivacaine and Group B (Rapid Sequential) received a rapid intrathecal injection of fentanyl followed by a slow injection of hyperbaric bupivacaine. We compared the duration of postoperative analgesia, time of onset of sensory and motor block attained, the highest level of sensory block attained, duration of motor block, Visual Analogue Scale (VAS) scores, spinal anaesthesia-related complications and haemodynamic parameters between both the groups. Results: The duration of postoperative analgesia was longer (P < 0.001) in group B (3.22 ± 0.66 hrs) as compared to group A (2.53 ± 0.41 hrs.) The onset of sensory block was faster (P < 0.001) in group B (1.01 ± 0.29 min) as compared to group A (1.32 ± 0.08 min). More patients in group B achieved higher levels of sensory blockade as compared to group A (5 patients in group A and 12 patients ofgroup B achieved a sensory block up to the T2 dermatome). VAS scores and the requirement of rescue analgesia were significantly lower (10 in group B and 19 in group A). Conclusion: Rapid sequential intrathecal injection of fentanyl and hyperbaric bupivacaine provided better anaesthesia and postoperative analgesia than the normal group. [ABSTRACT FROM AUTHOR]

Background and aim: Many adjuvants have been used with local anesthetics in spinal anesthesia but none has been found ideal. We have conducted this prospective randomized double blind study to evaluate the effect of intrathecal dexmedetomidine when added to ropivacaine in spinal anesthesia. Methods: 50 patients who underwent lower limb surgeries under spinal anesthesia were included in this study and were randomly allocated in to two groups. Group C received intrathecal 3 ml of 0.75% ropivacaine + 0.5 ml normal saline and group D received intrathecal 3 ml of 0.75% ropivacaine + 5 μg dexmedetomidine in 0.5 ml of normal saline. Following intrathecal administration, onset of sensory and motor blockade, maximum dermatomal level achieved, duration of analgesia, hemodynamic parameters and incidence of side effects were observed. Results: Onset of sensory and motor block was earlier in group D compared to group C which was statistically significant. Block regression was significantly delayed with the addition of intrathecal dexmedetomidine (Group D) as compared to ropivacaine alone (Group C). Both, time to two segment regressions and time to regression to S2 were delayed significantly in group D. The duration of analgesia was also significantly prolonged in group D (348.00±23.02 min) as compared to group C.(207.60±17.23min) There were no significant difference in haemodynamic parameters and incidence of side effects in both the groups. Conclusion: The addition of dexmedetomidine(5 μg) to ropivacaine in spinal anesthesia produces significantly longer sensory and motor blockade along with prolonged postoperative analgesia, without any significant side effects. [ABSTRACT FROM AUTHOR]

Aims: Aim of our study is to compare the effects of tramadol and fentanyl as intrathecal adjuvant to hyperbaric Bupivacaine in lower limb surgeries under spinal anaesthesia. Method-100 patients of ASA status I and II posted for lower limb surgery were randomly divided into two groups. Group T was administered Hyperbaric Bupivacaine 15mg + tramadol 25 mg, and group F was administered Hyperbaric Bupivacaine 15mg + Fentanyl 25 μg. Hemodynamic parameters, duration and quality of sensory and motor block and any side effects were assessed. Results: Intrathecal tramadol and intrathecal fentanyl acted synergistically to potentiate bupivacaine induced sensory spinal block. Excellent surgical anaesthesia and an extended analgesia was observed in post-operative period with minimum side effects in both groups. Conclusion- Both intrathecal tramadol and fentanyl as adjuvant to bupivacaine produced comparable hemodynamic changes, post-operative analgesia and sensory blockade. [ABSTRACT FROM AUTHOR]

Aim: Aim of this trial was to compare the analgesic efficacy of intrathecal dexmedetomidine or clonidine as adjuvant with isobaric ropivacaine in gynaecological surgery. Methods: 90 patients of ASA grade I or II, ages between 20-60 years, were randomly allocated to three equal groups, Group R received 3ml of isobaric ropivacaine (0.75%) with normal saline as a placebo, group D received 3ml of isobaric ropivacaine (0.75%) with 5 μg of dexmedetomidine and Group C received 3ml of isobaric ropivacaine (0.75%) with 30 μg of clonidine. All solutions were made up to 3.5 ml with addition of normal saline. The onset and duration of sensory and motor blockade, time to reach peak sensory and motor level and the sensory and motor regression times were recorded. Time to use first rescue analgesia, hemodynamic changes and side effects were recorded. Results: Time to onset of sensory block and motor block was earlier in Group D and Group C as compared to Group R. Duration of sensory and motor blockade was prolonged in Groups C and D compared with Group R. The mean regression time to S1 segment was prolonged in Group D, and in Group C compared to Group B. The time to 1st rescue analgesia was significantly prolonged in Group D compared with Group C and group R. Conclusion: Dexmedetomidine when added to intrathecal ropivacaine prolongs the sensory block and provides prolonged postoperative analgesia compared to clonidine. [ABSTRACT FROM AUTHOR]

The inhibitory function of GABA at the spinal level and its central modulation in the brain are essential for pain perception. However, in post-surgical pain, the exact mechanism and modes of action of GABAergic transmission have been poorly studied. This work aimed to investigate GABA synthesis and uptake in the incisional pain model in a time-dependent manner. Here, we combined assays for mechanical and heat stimuli-induced withdrawal reflexes with videobased assessments and assays for non-evoked (NEP, guarding of affected hind paw) and movement-evoked (MEP, gait pattern) pain-related behaviors in a plantar incision model in male rats to phenotype the effects of the inhibition of the GABA transporter (GAT-1), using a specific antagonist (NO711). Further, we determined the expression profile of spinal dorsal horn GAT-1 and glutamate decarboxylase 65/67 (GAD65/67) by protein expression analyses at four time points post-incision. Four hours after incision, we detected an evoked pain phenotype (mechanical, heat and movement), which transiently ameliorated dose-dependently following spinal inhibition of GAT-1. However, the NEPphenotype was not affected. Four hours after incision, GAT-1 expression was significantly increased, whereas GAD67 expression was significantly reduced. Our data suggest that GAT-1 plays a role in balancing spinal GABAergic signaling in the spinal dorsal horn shortly after incision, resulting in the evoked pain phenotype. Increased GAT-1 expression leads to increased GABA uptake from the synaptic cleft and reduces tonic GABAergic inhibition at the post-synapse. Inhibition of GAT-1 transiently reversed this imbalance and ameliorated the evoked pain phenotype. [ABSTRACT FROM AUTHOR]

Inadvertent dural puncture and post-dural puncture headache are complications of labour epidural analgesia and may result in acute and chronic morbidity. Identification of risk factors may enable pre-emptive management and reduce associated morbidity. In this retrospective cohort study, we aimed to identify factors associated with an inadvertent dural puncture or post-dural puncture headache by identifying parturients who received labour epidural analgesia from January 2017 to December 2021. The primary outcome was any witnessed inadvertent dural puncture, inadvertent placement of an intrathecal catheter, clinical diagnosis of post-dural puncture headache, or headache that was assessed to have characteristic post-dural puncture headache features. A wide range of demographic, obstetric, and anaesthetic factors were analysed using univariate and multivariable analyses to identify independent associations with the primary outcome.Data from 26,395 parturients were analysed, of whom 94 (0.36%) had the primary outcome. Within these 94 parturients, 26 (27.7%) had inadvertent dural puncture, 30 (31.9%) had inadvertent intrathecal catheter, and 38 (40.4%) had post-dural puncture headache without documented inadvertent dural puncture or intrathecal catheter insertion. Increased number of procedure attempts (adjusted odds ratio 1.39, 95% confidence interval 1.19 to 1.63), longer procedure duration adjusted odds ratio 1.03, 95% confidence interval 1.01 to 1.05), increased depth of epidural space (adjusted odds ratio 1.10, 95% confidence interval 1.04 to 1.18), greater post-procedure Bromage score (adjusted odds ratio 7.70, 95% confidence interval 4.22 to 14.05), and breakthrough pain (adjusted odds ratio 3.97, 95% confidence interval 2.59 to 6.08) were independently associated with increased odds of the primary outcome, while the use of standard patient-controlled epidural analgesia (PCEA) regimen (adjusted odds ratio 0.50, 95%confidence interval 0.31 to 0.81), increased concentration of ropivacaine (adjusted odds ratio 0.08 per 0.1%, 95% confidence interval 0.02 to 0.46), and greater satisfaction score (adjusted odds ratio 0.96, 95% confidence interval 0.95 to 0.97) were associated with reduced odds. The area under curve of this multivariable model was 0.83.We identified independent association factors suggesting that greater epidural depth and procedure difficulty may increase the odds of inadvertent dural puncture or post-dural puncture headache.

Hunter syndrome, or mucopolysaccharidosis (MPS) II, is a rare lysosomal disorder characterized by progressive, multi-system disease. As most symptoms cannot be reversed once established, early detection and treatment prior to the onset of clinical symptoms are critical. However, it is difficult to identify affected individuals early in disease, and therefore the long-term outcomes of initiating treatment during this optimal time period are incompletely described. We report long-term clinical outcomes of treatment when initiated prior to obvious clinical signs by comparing the courses of two siblings with neuronopathic Hunter syndrome (c.1504 T > G[p.W502G]), one who was diagnosed due to clinical disease (Sibling-O, age 3.7 years) and the other who was diagnosed before disease was evident (Sibling-Y, age 12 months), due to his older sibling's findings. The brothers began enzyme replacement therapy within a month of diagnosis. Around the age of 5 years, Sibling-O had a cognitive measurement score in the impaired range of

Background: Spinal anesthesia is the most popular regional anesthesia technique for lower limb and lower abdominal surgery. Bupivacaine 0.5% heavy is commonly used for intrathecal use. New long-acting local anesthetic agents such as ropivacaine have claimed benefits of reduced cardiac toxicity on overdose and more specific effects on sensory rather than motor nerve fibers. The use of intrathecal hyperbaric ropivacaine is not much studied. With this background, we studied intrathecal ropivacaine hyperbaric 0.75% against intrathecal bupivacaine hyperbaric 0.5% for lower abdominal and lower limb surgery. Aims and Objectives: To note the effectiveness of intrathecal ropivacaine and bupivacaine on characteristics of subarachnoid block such as sensory block, motor block, hemodynamic parameters, and complications if any. Materials and Methods: We randomized patients undergoing lower abdominal surgeries and lower limb orthopedic surgeries under spinal anesthesia into two groups so as to receive intrathecal either ropivacaine 0.75% hyperbaric (3 mL) or bupivacaine 0.5% hyperbaric (3mL) and noted study parameters. Results: Time of sensory block onset (P=0.0005), peak sensory level (P=0.0029), and onset of L1 bromage-3 motor block (P=1.27E–08) was significantly delayed in the ropivacaine group as compared to bupivacaine group. However, maximum sensory level achieved (T6), time required for two-segment sensory regressions (P=0.1162), and time of onset of pain (P=0.1162) were comparable in both groups. Conclusion: Intrathecal ropivacaine 0.75% hyperbaric produced slow onset sensory and motor block than 0.5% hyperbaric bupivacaine with comparable cephalic spread and duration of sensory block.

Enzyme replacement therapy with weekly infused intravenous (IV) idursulfase is effective in treating somatic symptoms of mucopolysaccharidosis II (MPS II; Hunter syndrome). A formulation of idursulfase for intrathecal administration (idursulfase-IT) is under investigation for the treatment of neuronopathic MPS II. Here, we report 36-month data from the open-label extension (NCT02412787) of a phase 2/3, randomized, controlled study (HGT-HIT-094; NCT02055118) that assessed the safety and efficacy of monthly idursulfase-IT 10 mg in addition to weekly IV idursulfase on cognitive function in children older than 3 years with MPS II and mild-to-moderate cognitive impairment. Participants were also enrolled in this extension from a linked non-randomized sub-study of children younger than 3 years at the start of idursulfase-IT therapy. The extension safety population comprised 56 patients who received idursulfase-IT 10 mg once a month (or age-adjusted dose for sub-study patients) plus IV idursulfase (0.5 mg/kg) once a week. Idursulfase-IT was generally well tolerated over the cumulative treatment period of up to 36 months. Overall, 25.0% of patients had at least one adverse event (AE) related to idursulfase-IT; most treatment-emergent AEs were mild in severity. Of serious AEs (reported by 76.8% patients), none were considered related to idursulfase-IT treatment. There were no deaths or discontinuations owing to AEs. Secondary efficacy analyses (in patients younger than 6 years at phase 2/3 study baseline; n = 40) indicated a trend for improved Differential Ability Scale-II (DAS-II) General Conceptual Ability (GCA) scores in the early idursulfase-IT versus delayed idursulfase-IT group (treatment difference over 36 months from phase 2/3 study baseline: least-squares mean, 6.8 [90% confidence interval: -2.1, 15.8; p = 0.2064]). Post hoc analyses of DAS-II GCA scores by genotype revealed a clinically meaningful treatment effect in patients younger than 6 years with missense variants of the iduronate-2-sulfatase gene (IDS) (least-squares mean [standard error] treatment difference over 36 months, 12.3 [7.24]). These long-term data further suggest the benefits of idursulfase-IT in the treatment of neurocognitive dysfunction in some patients with MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Two-thirds of patients with mucopolysaccharidosis II (MPS II; Hunter syndrome) have cognitive impairment. This phase 2/3, randomized, controlled, open-label, multicenter study (NCT02055118) investigated the effects of intrathecally administered idursulfase-IT on cognitive function in patients with MPS II. Children older than 3 years with MPS II and mild-to-moderate cognitive impairment (assessed by Differential Ability Scales-II [DAS-II], General Conceptual Ability [GCA] score) who had tolerated intravenous idursulfase for at least 4 months were randomly assigned (2:1) to monthly idursulfase-IT 10 mg (n = 34) via an intrathecal drug delivery device (IDDD; or by lumbar puncture) or no idursulfase-IT treatment (n = 15) for 52 weeks. All patients continued to receive weekly intravenous idursulfase 0.5 mg/kg as standard of care. Of 49 randomized patients, 47 completed the study (two patients receiving idursulfase-IT discontinued). The primary endpoint (change from baseline in DAS-II GCA score at week 52 in a linear mixed-effects model for repeated measures analysis) was not met: although there was a smaller decrease in DAS-II GCA scores with idursulfase-IT than with no idursulfase-IT at week 52, this was not significant (least-squares mean treatment difference [95% confidence interval], 3.0 [-7.3, 13.3]; p = 0.5669). Changes from baseline in Vineland Adaptive Behavioral Scales-II Adaptive Behavior Composite scores at week 52 (key secondary endpoint) were similar in the idursulfase-IT (n = 31) and no idursulfase-IT (n = 14) groups. There were trends towards a potential positive effect of idursulfase-IT across DAS-II composite, cluster, and subtest scores, notably in patients younger than 6 years at baseline. In a post hoc analysis, there was a significant (p = 0.0174), clinically meaningful difference in change from baseline in DAS-II GCA scores at week 52 with idursulfase-IT (n = 13) versus no idursulfase-IT (n = 6) among those younger than 6 years with missense iduronate-2-sulfatase gene variants. Overall, idursulfase-IT reduced cerebrospinal glycosaminoglycan levels from baseline by 72.0% at week 52. Idursulfase-IT was generally well tolerated. These data suggest potential benefits of idursulfase-IT in the treatment of cognitive impairment in some patients with neuronopathic MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.