Intrathecal Injection of Newborn Mouse for Genome Editing and Drug Delivery.

Intrathecal injection is a commonly employed procedure in both pediatric and adult clinics, serving as an effective means to administer medications and treatments. By directly delivering medications and treatments into the cerebrospinal fluid of the central nervous system, this method achieves higher localized drug concentrations while reducing systemic side-effects compared to other routes such as intravenous, subcutaneous, or intramuscular injections. Its importance extends beyond clinical settings, as intrathecal injection plays a vital role in preclinical studies focused on treating neurogenetic disorders in rodents and other large animals, including non-human primates. However, despite its widespread application, intrathecal injection in young, particularly neonatal pups, poses significant technical challenges due to their small size and fragile nature. Successful and reliable administration of intrathecal injections in newborn mice requires meticulous attention to detail and careful consideration of various factors. Thus, there is a crucial need for a standardized protocol that not only provides instructions but also highlights key technical considerations and good laboratory practices to ensure procedural consistency, as well as the safety and welfare of the animals. To address this unmet need, we present a detailed and comprehensive protocol for performing intrathecal injections specifically in newborn pups on postnatal day 1 (P1). By following the step-by-step instructions, researchers can confidently perform intrathecal injections in neonatal pups, enabling the accurate delivery of drugs, antisense oligos, and viruses for gene replacement or genome editing-based treatments. Furthermore, the importance of adhering to good laboratory practices is emphasized to maintain the well-being of animals and ensure reliable experimental outcomes. This protocol aims to address the technical challenges associated with intrathecal injections in neonatal mice, ultimately facilitating advances in the field of neurogenetic research that aims to develop potential therapeutic interventions.

Refinement of intrathecal catheter design to enhance neuraxial distribution.

BACKGROUND: Delivery of therapeutics via indwelling intrathecal catheters is highly efficacious for targeting of pain, spasticity, neuraxial cancer and neurodegenerative disorders. However, current catheter designs have some major limitations. Given limited CSF flow, fixed intrathecal volume and the large distance of the rostro-caudal spinal axis, current intrathecal delivery routes fail to achieve adequate drug distribution. Additionally open catheter systems are plagued with cellular ingrowth and debris accumulation if used intermittently. NEW METHOD: RESULTS/COMPARISON WITH EXISTING METHOD(S): High speed imaging showed micro-valve catheters greatly increase fluid exit velocities compared to typical open-ended catheters, which prevents pooling of injectate proximal to the opening. When implanted intrathecally in rats, small injection volumes (7.5 µL) of dye or AAV9-RFP, resulted in an even rostro-caudal distribution along the spinal axis and robust transfection of neurons from cervical to lumbar dorsal root ganglia. In contrast, such injections with an open-ended catheter resulted in localized distribution and transfection proximal to the delivery site. Our poly micro-valve catheter design resulted in equivalent transfection rates of cervical DRG neurons using 100x lower titer of AAV9-RFP. Unlike open port catheters, no debris accumulation was observed in the lumen of implanted catheters, showing potential for long-term intermittent use. CONCLUSIONS: This catheter platform, suitable for small animal models is easily scalable for human use and addresses many of the problems observed with common catheter systems.

Expandable Sendai-Virus-Reprogrammed Human iPSC-Neuronal Precursors: In Vivo Post-Grafting Safety Characterization in Rats and Adult Pig.

One of the challenges in clinical translation of cell-replacement therapies is the definition of optimal cell generation and storage/recovery protocols which would permit a rapid preparation of cell-treatment products for patient administration. Besides, the availability of injection devices that are simple to use is critical for potential future dissemination of any spinally targeted cell-replacement therapy into general medical practice. Here, we compared the engraftment properties of established human-induced pluripotent stem cells (hiPSCs)-derived neural precursor cell (NPCs) line once cells were harvested fresh from the cell culture or previously frozen and then grafted into striata or spinal cord of the immunodeficient rat. A newly developed human spinal injection device equipped with a spinal cord pulsation-cancelation magnetic needle was also tested for its safety in an adult immunosuppressed pig. Previously frozen NPCs showed similar post-grafting survival and differentiation profile as was seen for freshly harvested cells. Testing of human injection device showed acceptable safety with no detectable surgical procedure or spinal NPCs injection-related side effects.

Efficacy and Safety of Low-Dose versus High-Dose Postoperative Intrathecal Morphine in 62 Women Undergoing Elective Cesarean Section Delivery at Full Term.

BACKGROUND Adequate pain control is desired in women undergoing cesarean section. This study aimed to compare the efficacy and safety of low- and high-dose postoperative intrathecal morphine in 62 women undergoing elective cesarean section delivery at full term. MATERIAL AND METHODS We performed a prospective, randomized, controlled, multicenter clinical study from April to November 2022. Full-term, 22-38-year-old pregnant women who were singleton pregnancies, weighing 55-80 kg, scheduled for elective cesarean section, were enrolled. A total of 62 patients were randomly assigned into either the low-dose (60 µg morphine, N=32) or high-dose (100 µg morphine, N=30) group. Post-cesarean pain intensity was recorded at 4, 12, and 24 hours. Patients requiring additional rescue analgesics or with adverse effects were documented. RESULTS There were no differences in age, weight, height, gestational age, or operating time between the 2 groups (all P>0.05). The 2 groups also had no statistically significant differences in the resting and exercise pain intensities at 4, 12, and 24 hours after cesarean section (P>0.05). Most patients (53 patients) did not require additional analgesics, suggesting an overall successful analgesic rate of 85.5%. The low-dose group had a lower incidence of pruritus than the high-dose group (13% vs 40%, P=0.029). The 2 groups had no differences in the other adverse effects. CONCLUSIONS A single dose of intrathecal 60 µg morphine could provide adequate analgesia comparable with 100 µg morphine, with a lower incidence of pruritus, in Chinese women after cesarean delivery.

Use of intraoperative topical antibiotics to reduce intrathecal baclofen pump surgical site infections: a single institution's experience over 24 years.

OBJECTIVE: Patients requiring intrathecal baclofen (ITB) therapy are at high risk for surgical site infections (SSIs) given their poor functional status. After years of a nominal infection rate, there was an inexplicable increase in ITB pump infections at the authors' institution and multiple investigations offered no solution. Use of intraoperative topical antibiotics is well-documented in the orthopedic literature and was considered for ITB pump insertion. In this study, the authors investigated whether intraoperative vancomycin and tobramycin powder at the ITB pump site could reduce SSIs. METHODS: Operative and infection data were collected and analyzed retrospectively to determine the efficacy of this change. Patients were stratified into three cohorts (1998-2009, 2010-2012, and 2013-2021) to better understand the trends before and after implementation of intraoperative topical antibiotics. Each cohort had similar demographics. RESULTS: One hundred fifty-four patients underwent 272 ITB pump procedures between 1998 and 2021 (131 in 1998-2009, 49 in 2010-2012, and 92 in 2013-2021) for cerebral palsy (69.5%), spastic quadriparesis due to traumatic brain injury (7.1%), anoxic brain injury (6.5%), and other causes (16.9%). Infection rates were reduced from a high of 32% in 2010-2011 to 3.8% over the last 2.5 years (p = 0.0094). There were no adverse effects from the use of topical antibiotics. CONCLUSIONS: In the setting of an intractable rise in ITB pump infections, the addition of intraoperative topical antibiotics significantly reduced postoperative infections in a high-risk population. One could appreciate a significant drop each year in the rate of infections after the institution of intraoperative topical antibiotics. The reduction in SSIs significantly improved the long-term outcomes for these patients.

Assessment of Health Care Costs and Total Baclofen Use Associated With Targeted Drug Delivery for Spasticity.

BACKGROUND: Chronic spasticity causes significant impairment and financial burden. Oral baclofen, the first-line therapy, can have intolerable, dose-dependent side effects. Targeted drug delivery (TDD) through intrathecal baclofen delivers smaller amounts of baclofen into the thecal sac via an implanted infusion system. However, the health care resource utilization of patients with spasticity receiving TDD has not been studied extensively. MATERIALS AND METHODS: Adult patients who received TDD for spasticity between 2009 and 2017 were identified using the IBM MarketScan® data bases. Patients' use of oral baclofen and health care costs were examined at baseline (one year before implantation) and three years after implantation. A multivariable regression model using the generalized estimating equations method and a log link function was used to compare postimplantation costs with those at baseline. RESULTS: The study identified 771 patients with TDD for medication analysis and 576 for cost analysis. At baseline, the median costs were $39,326 (interquartile range [IQR]: $19,526-$80,679), which increased to $75,728 (IQR: $44,199-$122,676) in year 1, decreased to $27,160 (IQR: $11,896-$62,427) in year 2, and increased slightly to $28,008 (IQR: $11,771-$61,885) in year 3. In multivariable analysis, the cost was 47% higher than at baseline (cost ratio [CR] 1.47, 95% CI: 1.32-1.63) in year 1 but was 25% lower (CR 0.75, 95% CI: 0.66-0.86) in year 2 and 32% lower (CR 0.68, 95% CI: 0.59-0.79) in year 3. Before implant, 58% of patients took oral baclofen, which decreased to 24% by year 3. The median daily baclofen dose decreased from 61.8 mg (IQR: 40-86.4) before TDD to 32.8 mg (IQR: 30-65.7) three years later. CONCLUSIONS: Our findings indicate that patients who undergo TDD use less oral baclofen, potentially reducing the risk of side effects. Although total health care costs increased immediately after TDD, most likely owing to device and implantation costs, they decreased below baseline after one year. The costs of TDD reach cost neutrality approximately three years after implant, indicating its potential for long-term cost savings.

A multicenter initiative to reduce intrathecal baclofen pump surgical site infection: a Cerebral Palsy Research Network quality improvement project.

OBJECTIVE: Intrathecal baclofen (ITB) therapy is an effective treatment for spasticity and dystonia in children with cerebral palsy (CP). However, ITB pump surgery is associated with one of the highest rates of surgical site infection (SSI) in medicine, leading to significant morbidity and expense. Surgical protocols have reduced the rate of SSI in children with other CNS implants, and single-center protocols have been effective in ITB surgery in pediatrics. The authors describe the first multicenter quality improvement (QI)-driven standardized protocol for ITB pump surgery in children with CP across the Cerebral Palsy Research Network (CPRN), implemented with the aim of reducing ITB-associated SSI. METHODS: SSI was defined as a culture-positive infection, ITB pump system removal for suspected infection, or wound dehiscence with exposed hardware. Each center reported historical infection rates for at least 3 years before initiating the SSI protocol (preintervention phase). After initiation of a 13-step surgical protocol, a consecutive series of 130 patients undergoing 149 surgical procedures for ITB at four CPRN tertiary pediatric neurosurgery centers were prospectively enrolled at surgery during a 2-year study period (intervention phase). QI methodology was used, including development of a key driver diagram and tracking performance using run and control charts. The primary process measure goal was documented compliance with 80% of the protocol steps, and the primary outcome measure goal was a 20% reduction in 90-day infection rate. Patient characteristics were collected from the CPRN Research Electronic Data Capture registry, including age at surgery, BMI, Gross Motor Function Classification System level, and pattern of spasticity. RESULTS: The aggregated preintervention 90-day ITB SSI rate was 4.9% (223 procedures) between 2014 and 2017. During the intervention phase, 136 of 149 ITB surgeries performed met inclusion criteria for analysis. The mean documented compliance rate with protocol steps was 75%, and the 90-day infection rate was 4.4%, with an average of 42 days from index surgery to infection. CONCLUSIONS: This is the first multicenter QI initiative designed to reduce SSI in ITB surgery in children with CP. Ongoing enrollment and expansion of the protocol to other CPRN centers will facilitate identification of patient- and procedure-specific risk factors for SSI, and iterative plan-do-study-act cycles incorporating these data will further decrease the risk of SSI for ITB surgery in children.

Attainment of personal goals in the first year of intrathecal baclofen treatment in dyskinetic cerebral palsy: a prospective cohort study.

PURPOSE: To assess attainment of individual treatment goals one year after intrathecal baclofen (ITB) pump implantation in individuals with dyskinetic cerebral palsy (CP). MATERIALS AND METHODS: A multi-center prospective cohort study was conducted including 34 non-walking individuals with severe dyskinetic CP, classified as Gross Motor Function Classification System (GMFCS) IV/V, aged 4-24 years, 12 months after pump implantation. The main outcome measure was Goal Attainment Scaling (GAS). Predictors of GAS results were analyzed. Complications were registered systematically. RESULTS: Seventy-one percent of individuals with dyskinetic CP fully achieved one or more treatment goals. One or more treatment goals were partially achieved in 97% of individuals. Two factors were found to be associated with attainment of goals: Dyskinesia Impairment Scale (DIS) score at baseline and the difference in pain score between baseline and follow-up. These two variables explain 30% of the variance in the outcome. CONCLUSIONS: Intrathecal baclofen is effective in achieving individual treatment goals in children and young adults with dyskinetic CP after nine to 12 months of ITB treatment. A positive outcome on treatment goals is, for a small part, associated with higher severity of dystonia at baseline and with improvement of pain during treatment. CLINICAL TRIAL REGISTRATION NUMBER: Dutch Trial Register, number NTR3642.Implications for rehabilitationIntrathecal baclofen treatment is effective in attainment of personal treatment goals, one year after pump implantation in patients with dyskinetic cerebral palsy.A positive outcome on treatment goals is, for a small part, related to higher severity of dystonia at the start and on improvement of pain during treatment.

Inflammatory markers in cerebrospinal fluid of paediatric spinal muscular atrophy patients receiving nusinersen treatment.

Spinal muscular atrophy (SMA) is a progressive motor neuron disease with onset during infancy or early childhood. Recent therapeutic advances targeting the genetic defect that underlies SMA improved survival in patients with infantile onset SMA (type 1) and improved motor function in SMA type 1-3. The most commonly used therapy for SMA, the antisense oligonucleotide nusinersen, is delivered by repeated intrathecal injections. The long-term safety effects of this procedure, however, have not yet been investigated in detail. We here present case reports of three children with SMA in which routine laboratory investigation revealed increased leukocyte counts in cerebrospinal fluid (CSF) collected during the course of nusinersen treatment. To further characterize this observation, we used a multiplex method to analyse a broad spectrum of inflammatory markers in the CSF of these patients. We found that interleukin-10 (IL10) was consistently elevated in CSF with increased leukocyte counts, but other inflammatory markers were not. Based on this analysis we selected 7 markers for further analysis in a cohort of 38 children with SMA and determined their expression during the course of nusinersen therapy. No consistent association was found between levels of inflammatory markers and the duration of nusinersen therapy in individual patients. However, monocyte chemoactive protein 1 (MCP1/CCL2) -a neuroprotective protein secreted by astrocytes and previously associated with SMA- levels increased over the course of nusinersen treatment, indicating a possible neuroprotective mechanism associated with nusinersen therapy. In summary, our findings confirm that repeated intrathecal injections are safe and do not trigger unwanted immune responses.

Prepontine cisternal routine for intrathecal targeted drug delivery in craniofacial cancer pain treatment: technical note.

Intrathecal targeted drug delivery provides effective relief for cancer-related pain. However, its validation in management of craniofacial pain remains much less widely practiced, mainly due to the localized diffusion of analgesic agent with current approach. Here, we report our experience of prepontine cisternal routine for placement and implantation of intrathecal targeted drug delivery in two cases of cancer-related craniofacial pain. Lumbar cannulation was applied and the intrathecal catheter tip was positioned at the prepontine cistern under fluoroscopic guidance during the surgical implantation. Postoperative imaging confirmed that the catheter tip was successfully placed in the prepontine cisternal space. Satisfactory control of pain was achieved after intrathecal therapy, with significant reduction of background and breakthrough cancer pain. None obvious complications were observed in this study. Thus, our novel intrathecal routine may provide an alternative option for craniofacial pain caused by tumor, who were insufficiently treated by oral analgesic agents.

Ultrasound-guided transforaminal approach for nusinersen delivery in adult spinal muscle atrophy patients with challenging access.

INTRODUCTION/AIMS: Previous papers on ultrasound (US)-guided delivery of nusinersen in patients with spinal muscle atrophy (SMA) described good results with translaminar approach. However, this approach is not possible in patients with spinal fusion and no visible interlaminar space on pre-procedural computed tomography (CT). US-guided transforaminal nusinersen delivery is a potential option that warrants investigation. METHODS: Twenty adult SMA patients with challenging access were treated in our institution under cone beam CT (CBCT) guidance. The patients were already in the maintenance phase of the dosing protocol and were prospectively evaluated for US-guided transforaminal approach. After they completed one injection via US-guided transforaminal approach, success and safety of the approach were analyzed. Patients shared their experience on US-guided in comparison to CBCT-guided injections. RESULTS: US-guided transforaminal puncture was possible in 14 (70.0%) patients, although 2 of them required needle repositioning under fluoroscopy due to inadvertent access of a prominent vein. US-guided transforaminal approach was therefore successful in 60% of patients. Mild adverse events were recorded in four patients. The survey on patients' experience showed that seven reported no difference in the two approaches, six preferred the US-guided procedure, and one preferred the CBCT-guided procedure. DISCUSSION: US-guided transforaminal lumbar approach is an effective and safe method of intrathecal nusinersen delivery in adult SMA patients with challenging spinal access and could be considered the first option in appropriately selected adult SMA patients requiring transforaminal nusinersen delivery.

Intrathecal Delivery of Therapeutic Oligonucleotides for Potent Modulation of Gene Expression in the Central Nervous System.

Therapeutic oligonucleotides hold tremendous potential for treating central nervous system (CNS) disorders. The route of administration of oligonucleotides significantly impacts both distribution and silencing efficiency. Here, we describe a technically simple, clinically relevant method to administer oligonucleotide compounds into the CNS via direct intrathecal injections. This method achieves distribution throughout the CNS rapidly and permits high-throughput testing of oligonucleotide efficacy and potency in mammals.

Restoration of Nusinersen Levels Following Treatment Interruption in People With Spinal Muscular Atrophy: Simulations Based on a Population Pharmacokinetic Model.

BACKGROUND: Nusinersen is approved for the treatment of spinal muscular atrophy. The most common approved dosing regimen is four intrathecal loading doses of nusinersen 12 mg; the first three are administered at 14-day intervals followed by a fourth dose 30 days later, and then 12-mg maintenance doses are administered every 4 months thereafter. Interruption of nusinersen treatment in the maintenance dosing phase might occur for a number of clinical reasons. OBJECTIVE: The objective of this report is to describe dosing regimens that allow for the most rapid restoration of steady-state concentrations of nusinersen in the cerebrospinal fluid (CSF) following a treatment interruption during maintenance dosing. METHODS: Population pharmacokinetic models using integrated pharmacokinetic data from ten nusinersen clinical trials that included a broad range of participants with spinal muscular atrophy treated with intrathecal nusinersen were used to investigate different durations of treatment interruptions during maintenance treatment. Potential dosing regimens for re-initiation of nusinersen were evaluated, with the goal of achieving the quickest restoration of steady-state nusinersen CSF concentrations without exceeding maximal CSF exposures observed during the initial loading period. RESULTS: Our pharmacokinetic modeling indicates the following regimen will lead to optimal restoration of nusinersen CSF levels after treatment interruption: two doses of nusinersen should be administered at 14-day intervals following treatment interruptions of ≥ 8 to < 16 months since the last dose, and three doses of nusinersen at 14-day intervals for treatment interruptions of ≥ 16 to < 40 months since the last maintenance dose, with subsequent maintenance dosing every 4 months in both instances. After treatment interruptions of ≥ 40 months, the full loading regimen will rapidly restore nusinersen CSF levels. CONCLUSIONS: Prolonged treatment interruptions lead to suboptimal CSF levels of nusinersen. The optimal regimen to restore nusinersen CSF levels depends on the interval since the last maintenance dose was administered.

Nusinersen is a drug used to treat people of all ages who have spinal muscular atrophy. Nusinersen is injected with a thin needle into the lower back, a procedure known as a lumbar puncture. People initially receive three doses of nusinersen 12 mg each 14 days apart. They receive a fourth dose 1 month later, and then injections every 4 months (known as maintenance dosing). This treatment plan allows nusinersen to build up to effective levels in the fluid surrounding the spinal cord and brain. Some people may miss dose(s) or may stop nusinersen treatment at some point during maintenance dosing and then may want to continue treatment. This study used information from ten clinical trials to find out the best way to restart treatment to build up nusinersen to effective levels. People with a treatment break of ≥ 8 to < 16 months since the last dose need two doses of nusinersen at 14-day intervals before receiving maintenance dosing. People with a treatment break of ≥ 16 to < 40 months since the last dose need three doses of nusinersen at 14-day intervals before receiving maintenance dosing. If people stopped treatment for ≥ 40 months, they would need four doses before starting maintenance treatment. Results from this study showed that the number of doses that people needed before starting maintenance treatment depended on how long the treatment break was.

Computed Tomography-Guided Lumbar Puncture: Advantages and Disadvantages.

OBJECTIVE: This study aimed to evaluate the utility of computed tomography (CT) guidance in difficult lumbar puncture (LP) cases, which had a history of at least one unsuccessful blind attempt at LP (no imaging guidance), and to note potential advantages and disadvantages of the use of CT guidance. METHODS: In total, 32 CT-guided LP procedures performed between June 2019 and March 2021 were included. All LP indications were recorded. The procedures where the cerebrospinal fluid flow was provided by a single puncture were evaluated as "primary technical success." "Secondary technical success" corresponded with the procedures in which additional puncture was necessary for the cerebrospinal fluid flow. RESULTS: Intrathecal nusinersen injections due to spinal muscular atrophy constituted the largest procedure group of this study. Among 32 procedures, primary and secondary technical success rates were 78.12% and 28.57%, respectively. There were no major procedural complications. CONCLUSIONS: Computed tomography-guided LP is an effective interventional technique offering an alternative approach in the setting of difficult LP procedures.

Perioperative Opioid Consumption and Clinical Outcomes in Surgical Patients With a Pre-existing Opioid-Based Intrathecal Drug Delivery System.

BACKGROUND: Intrathecal drug delivery systems (IDDS) have been utilized for over 3 decades for management of chronic pain and spasticity. Patients with IDDS may present for surgical procedures unrelated to the IDDS device, although data are limited regarding perioperative outcomes. METHODS: This is a historical matched cohort study conducted between January 1, 2007 and December 31, 2016 of patients with an opioid-based IDDS versus matched control patients undergoing surgery excluding interventional pain procedures. Patients in the IDDS group were matched with up to 2 patients without an IDDS. Multivariable regression analyses were utilized to assess differences in the primary outcome of cumulative perioperative opioid consumption (ie, intraoperative and postanesthesia care unit [PACU] opioid consumption), and opioid consumption during the first 24 and 72 postoperative hours. Postoperative clinical outcomes were also assessed including escalating oxygen requirements, naloxone administration, pain-sedation mismatch, and perioperative pain service consultation. RESULTS: A total of 321 surgeries were included, 112 with IDDS and 209 controls, with median (interquartile range [IQR]) age of 57 (49-64) years. Compared to matched controls, patients with an IDDS had greater perioperative opioid consumption (median [IQR] oral morphine milligram equivalents [OME] of 110 [60-163] vs 93 [IQR, 53-142]; adjusted multiplicative increase 1.28 [95% confidence interval {CI}, 1.03-1.59]; P = .026). IDDS patients also had greater opioid consumption in the first 24 and 72 postoperative hours (multiplicative increases of 2.23 [95% CI, 1.36-3.63], P = .001, and 2.46 [95% CI, 1.41-4.32], P = .002, respectively). There were no significant differences in postoperative oxygen requirements, naloxone administration, or pain-sedation mismatch. Inpatient pain medicine consultation was more frequent in IDDS patients compared to controls (51.8% vs 6.2%; P < .001). CONCLUSIONS: Patients with opioid-based IDDS received more perioperative opioids and were more likely to receive postoperative pain service consultation compared to matched controls. There were no significant differences in clinical safety outcomes, suggesting tolerance for higher opioid doses. Further research is warranted to optimize perioperative outcomes in those with IDDS.

Nusinersen by subcutaneous intrathecal catheter for symptomatic spinal muscular atrophy patients with complex spine anatomy.

INTRODUCTION/AIMS: Intrathecal administration of nusinersen is challenging in patients with spinal muscular atrophy (SMA) who have spine deformities or fusions. We prospectively studied the safety and efficacy of nusinersen administration via an indwelling subcutaneous intrathecal catheter (SIC) for SMA patients with advanced disease. METHODS: Seventeen participants commenced nusinersen therapy between 2.7 and 31.5 years of age and received 9 to 12 doses via SIC. Safety was assessed in all participants. A separate efficacy analysis comprised 11 nonambulatory, treatment-naive SMA patients (18.1 ± 6.8 years) with three SMN2 copies and complex spine anatomy. RESULTS: In the safety analysis, 14 treatment-related adverse events (AEs) occurred among 12 (71%) participants; all were related to the SIC and not nusinersen. Device-related AEs interfered with 2.5% of nusinersen doses. Four SICs (24%) required surgical revision due to mechanical malfunction with or without cerebrospinal fluid leak (n = 2), and one (6%) was removed due to Staphylococcus epidermidis meningitis. In the efficacy analysis, mean performance on the nine-hole peg test improved in dominant (15.9%, P = 0.012) and nondominant (19.0%, P = 0.008) hands and grip strength increased by 44.9% (P = 0.031). We observed no significant changes in motor scales, muscle force, pulmonary function, or SMA biomarkers. All participants in the efficacy cohort reported one or more subjective improvement(s) in endurance, purposeful hand use, arm strength, head control, and/or speech. DISCUSSION: For SMA patients with complex spine anatomy, the SIC allows for reliable outpatient administration of nusinersen that results in meaningful improvements in upper limb function, but introduces risks of technical malfunction and iatrogenic infection.

Effect of Monoammonium Glycyrrhizinate on the Development of Hepatotoxicity After Initial Intrathecal Chemotherapy for Leukemia.

BACKGROUND/AIM: Chemotherapy for acute leukemia includes agents known to cause hepatotoxicity. This study evaluated the role of monoammonium glycyrrhizinate for the prevention of hepatotoxicity after the first methotrexate-containing intrathecal chemotherapy (ITC) in children and adolescents with leukemia. PATIENTS AND METHODS: Patients with newly diagnosed acute leukemia (age 0-18 years) who received ITC during the first week of induction therapy at our hospital between April 2016 and March 2021 were enrolled. Intravenous monoammonium glycyrrhizinate (IVMG) was defined as the intravenous administration of monoammonium glycyrrhizinate initiated on the day before or the day of the first ITC. RESULTS: Overall, 39 of 118 patients (33%) developed grade 3-4 hepatotoxicity. The inverse probability of treatment weighting logistic regression model showed that IVMG was not associated with the development of grade 3-4 hepatotoxicity (OR=1.9, 95%CI=0.808-4.468). CONCLUSION: IVMG did not protect against the development of grade 3-4 hepatotoxicity after the first methotrexate-containing ITC for leukemia.

Candida meningitis in an infant after abdominal surgery successfully treated with intrathecal and intravenous amphotericin B: A case report.

RATIONALE: Studies on Candida infections in the central nervous system, especially in infants and young children that did or did not have postoperative surgery, are rarely reported. Thus far, intrathecal (i.t.) amphotericin B (AmB) is not routinely recommended as a therapy for Candida meningitis. We report the first case of Candida meningitis in an infant who underwent abdominal surgery and was successfully treated with i.t. and intravenous (i.v.) AmB in the mainland of China. PATIENT CONCERNS: Candida meningitis was confirmed by culture and immunoserological tests in a 1-day-old girl after surgery. She was treated with fluconazole for 1 month, but the patient's symptoms showed no improvement. DIAGNOSES: After surgery, the infant started having recurrent attacks of fever, and laboratory tests of the cerebrospinal fluid (CSF) revealed antigens of Candida tropicalis. CSF tests revealed a high total protein level and a low glucose level. She was diagnosed with a secondary Candida meningitis. INTERVENTIONS: After azole therapy failure, intrathecal and intravenous AmB therapy were used as rescue therapies. OUTCOMES: After nearly 2 months of AmB treatment, all repeat CSF cultures were negative, the infant was deemed stable and was discharged home, and she continued taking voriconazole orally as an outpatient. LESSONS: The combination of i.t. and i.v. administration of AmB can provide a safe and effective alternative to managing this rare but severe disease.