Intrathecal Gene Therapy for Giant Axonal Neuropathy.

BACKGROUND: Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the gene encoding gigaxonin. METHODS: We conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-complementary adeno-associated virus-based gene therapy containing the GAN transgene) in children with giant axonal neuropathy. Safety was the primary end point. The key secondary clinical end point was at least a 95% posterior probability of slowing the rate of change (i.e., slope) in the 32-item Motor Function Measure total percent score at 1 year after treatment, as compared with the pretreatment slope. RESULTS: One of four intrathecal doses of scAAV9/JeT-GAN was administered to 14 participants - 3.5×1013 total vector genomes (vg) (in 2 participants), 1.2×1014 vg (in 4), 1.8×1014 vg (in 5), and 3.5×1014 vg (in 3). During a median observation period of 68.7 months (range, 8.6 to 90.5), of 48 serious adverse events that had occurred, 1 (fever) was possibly related to treatment; 129 of 682 adverse events were possibly related to treatment. The mean pretreatment slope in the total cohort was -7.17 percentage points per year (95% credible interval, -8.36 to -5.97). At 1 year after treatment, posterior mean changes in slope were -0.54 percentage points (95% credible interval, -7.48 to 6.28) with the 3.5×1013-vg dose, 3.23 percentage points (95% credible interval, -1.27 to 7.65) with the 1.2×1014-vg dose, 5.32 percentage points (95% credible interval, 1.07 to 9.57) with the 1.8×1014-vg dose, and 3.43 percentage points (95% credible interval, -1.89 to 8.82) with the 3.5×1014-vg dose. The corresponding posterior probabilities for slowing the slope were 44% (95% credible interval, 43 to 44); 92% (95% credible interval, 92 to 93); 99% (95% credible interval, 99 to 99), which was above the efficacy threshold; and 90% (95% credible interval, 89 to 90). Between 6 and 24 months after gene transfer, sensory-nerve action potential amplitudes increased, stopped declining, or became recordable after being absent in 6 participants but remained absent in 8. CONCLUSIONS: Intrathecal gene transfer with scAAV9/JeT-GAN for giant axonal neuropathy was associated with adverse events and resulted in a possible benefit in motor function scores and other measures at some vector doses over a year. Further studies are warranted to determine the safety and efficacy of intrathecal AAV-mediated gene therapy in this disorder. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, NCT02362438.).

Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.

BACKGROUND: The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS). METHODS: In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort). RESULTS: A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients. CONCLUSIONS: In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).

Optimal pain management for patients with cancer in the modern era.

Pain is a common symptom among patients with cancer. Adequate pain assessment and management are critical to improve the quality of life and health outcomes in this population. In this review, the authors provide a framework for safely and effectively managing cancer-related pain by summarizing the evidence for the importance of controlling pain, the barriers to adequate pain management, strategies to assess and manage cancer-related pain, how to manage pain in patients at risk of substance use disorder, and considerations when managing pain in a survivorship population. CA Cancer J Clin 2018;68:182-196. © 2018 American Cancer Society.

In vivo selection in non-human primates identifies AAV capsids for on-target CSF delivery to spinal cord.

Systemic administration of adeno-associated virus (AAV) vectors for spinal cord gene therapy has challenges including toxicity at high doses and pre-existing immunity that reduces efficacy. Intrathecal (IT) delivery of AAV vectors into cerebral spinal fluid can avoid many issues, although distribution of the vector throughout the spinal cord is limited, and vector entry to the periphery sometimes initiates hepatotoxicity. Here we performed biopanning in non-human primates (NHPs) with an IT injected AAV9 peptide display library. We identified top candidates by sequencing inserts of AAV DNA isolated from whole tissue, nuclei, or nuclei from transgene-expressing cells. These barcoded candidates were pooled with AAV9 and compared for biodistribution and transgene expression in spinal cord and liver of IT injected NHPs. Most candidates displayed increased retention in spinal cord compared with AAV9. Greater spread from the lumbar to the thoracic and cervical regions was observed for several capsids. Furthermore, several capsids displayed decreased biodistribution to the liver compared with AAV9, providing a high on-target/low off-target biodistribution. Finally, we tested top candidates in human spinal cord organoids and found them to outperform AAV9 in efficiency of transgene expression in neurons and astrocytes. These capsids have potential to serve as leading-edge delivery vehicles for spinal cord-directed gene therapies.

Therapeutic drug monitoring of polymyxin B cerebrospinal fluid concentrations in patients with carbapenem-resistant Gram-negative bacteria-induced central nervous system infection.

OBJECTIVES: Central nervous system (CNS) infections caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) present a major health and economic burden worldwide. This multicentre prospective study aimed to assess the feasibility and usefulness of CSF therapeutic drug monitoring (TDM) after intrathecal/intraventricular administration of polymyxin B in patients with CNS infections. METHODS: Forty-two patients treated with intrathecal/intraventricular administration of polymyxin B against CR-GNB-induced CNS infections were enrolled. CSF trough level (Cmin) was collected beginning on Day 2 post-polymyxin B initiation and thereafter. The primary outcomes were clinical cure and 28-day all-cause mortality. RESULTS: All patients started with intrathecal/intraventricular administration of polymyxin B at a dose of 5 g/day, corresponding to a median CSF Cmin of 2.93 mg/L (range, 0.21-25.74 mg/L). Clinical cure was 71.4%, and the median CSF Cmin of this group was higher than that of clinical failure group [3.31 (IQR, 1.73-5.62) mg/L versus 2.25 (IQR, 1.09-4.12) mg/L; P = 0.011]. In addition, with MICs ≤ 0.5 mg/L, maintaining polymyxin B CSF Cmin above 2.0 mg/L showed a higher clinical cure rate (P = 0.041). The 28-day all-cause mortality rate was 31.0% and had no association with CSF Cmin. CONCLUSIONS: After intrathecal/intraventricular administration of polymyxin B, CSF concentrations fluctuated considerably inter- and intra-individual. Polymyxin B CSF Cmin above 2.0 mg/L was associated with clinical cure when MICs were ≤ 0.5 mg/L, and the feasibility of TDM warrants additional clinical studies.

Restoration of peripheral neuropathy in Fabry mice via intrathecal administration of an adeno-associated virus vector encoding mGLA cDNA.

Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a pathological variant of the α-galactosidase A (GLA) gene that results in deficient GLA activity. GLA deficiency leads to the accumulation of globotriaosylceramide (Gb3) and lyso-Gb3 in many tissues. A certain number of FD patients have burning pain or acroparesthesia in the feet and hands since childhood. Enzyme replacement therapy (ERT) is available for FD patients. However, ERT does not dramatically improve these FD-related peripheral neuropathic pain. We generated an adeno-associated virus serotype PHP.eB (AAV-PHP.eB) vector encoding mouse GLA cDNA, which was administered to FD mice intrathecally (it) or intravenously (iv). In the it-administered AAV (it-AAV) FD mice, the GLA enzyme activity in the lumbar dorsal root ganglion (DRG) was significantly greater than that in the untreated (NT) FD mice, and the level of activity was similar to that in wild-type (WT) B6 mice. However, in iv-administered AAV (iv-AAV) FD mice, GLA activity in the DRG did not increase compared to that in NT FD mice. Gb3 storage in the DRG of it-AAV FD mice was reduced compared to that in the DRG of NT FD mice. However, compared with NT FD mice, iv-AAV FD mice did not exhibit a significant reduction in the expression of the Gb3 substrate. Compared with WT mice, FD mice were thermally hyposensitive at 52 °C according to the hot plate test. The it-AAV FD mice showed significant recovery from thermal hyposensitivity. However, the iv-AAV FD mice did not exhibit significant improvement in thermal hyposensitivity. These results suggest that the intrathecal delivery of AAV-PHP.eB-mGLA may be a valuable tool for the treatment of FD-related peripheral neuropathic pain.

The effect of intra spinal administration of cerium oxide nanoparticles on central pain mechanism: An experimental study.

This study investigated Cerium oxide nanoparticles (CeONPs) effect on central neuropathic pain (CNP). The compressive method of spinal cord injury (SCI) model was used for pain induction. Three groups were formed by a random allocation of 24 rats. In the treatment group, CeONPs were injected above and below the lesion site immediately after inducing SCI. pain symptoms were evaluated using acetone, Radian Heat, and Von Frey tests weekly for six weeks. Finally, we counted fibroblasts using H&E staining. We evaluated the expression of Cx43, GAD65 and HDAC2 proteins using the western blot method. The analysis of results was done by PRISM software. At the end of the study, we found that CeONPs reduced pain symptoms to levels similar to those observed in normal animals. CeONPs also increased the expression of GAD65 and Cx43 proteins but did not affect HDAC2 inhibition. CeONPs probably have a pain-relieving effect on chronic pain by potentially preserving GAD65 and Cx43 protein expression and hindering fibroblast infiltration.

Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions.

Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

Safety and potential efficacy of expanded mesenchymal stromal cells of bone marrow and umbilical cord origins in patients with chronic spinal cord injuries: a phase I/II study.

BACKGROUND AIMS: Spinal cord injury (SCI) affects patients' physical, psychological, and social well-being. Presently, treatment modalities for chronic SCI have restricted clinical effectiveness. Mesenchymal stromal cells (MSCs) demonstrate promise in addressing nervous tissue damage. This single-center, open-label, parallel-group randomized clinical trial aimed to assess the safety and efficacy of intraoperative perilesional administration of expanded autologous bone marrow-derived MSCs (BMMSCs), followed by monthly intrathecal injections, in comparison to monthly intrathecal administration of expanded allogeneic umbilical cord-derived MSCs (UCMSCs) for individuals with chronic SCI. METHODS: Twenty participants, who had a minimum of 1 year of SCI duration, were enrolled. Each participant in Group A received perilesional BMMSCs, followed by monthly intrathecal BMMSCs for three injections, while Group B received monthly intrathecal UCMSCs for three injections. Safety and efficacy were evaluated using the American Spinal Cord Injury Association (ASIA) score for at least 1 year post the final injection. Statistical analysis was conducted using the Wilcoxon signed-rank test. RESULTS: Group A comprised 11 participants, while Group B included 9. The mean follow-up duration was 22.65 months. Mild short-term adverse events encompassed headaches and back pain, with no instances of long-term adverse events. Both groups demonstrated significant improvements in total ASIA scores, with Group A displaying more pronounced motor improvements. CONCLUSIONS: Our findings indicate that perilesional administration of expanded autologous BMMSCs, followed by monthly intrathecal BMMSCs for three injections, or monthly intrathecal UCMSCs for three injections appear to be safe and hold promise for individuals with chronic SCI. Nonetheless, larger-scale clinical trials are imperative to validate these observations.

Ultrasound assisted versus landmark based intrathecal administration of nusinersen in adults with spinal muscular atrophy disease: A randomized trial.

INTRODUCTION/AIMS: Nusinersen intrathecal administration can be challenging in spinal muscular atrophy (SMA) adults. We aimed to determine if the ultrasound (US)-assistance reduces the number of needle attempts and needle redirections needed for intrathecal drug administration and its impact on the procedure time, the incidence of adverse events (AEs), and patient satisfaction in these patients. METHODS: Fifty-eight patients aged 18 years and older scheduled for intrathecal nusinersen injection were enrolled and randomized (1:1 ratio) into Group 1 (nusinersen infusion with US-assisted technique) or Group 2 (nusinersen infusion with landmark-based technique). The number of attempts, number of redirections, periprocedural time, AEs and patient satisfaction were reported. Continuous variables were compared with the Student t-test or Wilcoxon rank sum test. Categorical variables were evaluated with the Chi-square test or Fisher's exact test in case of expected frequencies <5. The p-values <.05 were considered statistically significant. RESULTS: There were no statistical differences in the number of attempts, AEs, or patient satisfaction between the two groups. The number of needle redirections was significantly lower in the ultrasound group versus landmark-based group (p < .05) in both the overall group of patients and in the subgroup with difficult spines. The periprocedural time was about 40 seconds longer in US-group versus landmark-based group (p < .05). DISCUSSION: In SMA adults, US assistance reduces the number of needle redirections needed for intrathecal drug administration. These results suggest that the US assistance may be advantageous for nusinersen therapy to reduce the therapeutic burden of intrathecal infusion.

Transverse interlaminar ultrasound-guided C1-C2 puncture for the intrathecal administration of nusinersen in patients with spinal muscular atrophy.

INTRODUCTION/AIMS: Severe spinal deformities and previous spinal orthopedic instrumentation may result in substantial technical challenges for nusinersen delivery through lumbar puncture in patients with spinal muscular atrophy (SMA). The aim of this paper was to review our experience with ultrasound-guided cervical puncture as an alternative approach for the intrathecal administration of nusinersen. METHODS: This was a retrospective medical record review of transverse interlaminar ultrasound-guided C1-C2 puncture for nusinersen delivery in SMA patients. The details of puncture, complications, and success rate of the procedure were summarized. RESULTS: There were four patients who received a total of 13 cervical punctures for nusinersen delivery. All procedures were technically successful with no major complications. Full doses of nusinersen were delivered intrathecally. DISCUSSION: Transverse interlaminar ultrasound-guided C1-C2 puncture is an alternative approach for administering nusinersen if lumbar puncture fails. The success of the technique requires a thorough preprocedural evaluation of cervical spine imaging, sound knowledge of the cervical sonoanatomy and careful manipulation of the needle.

Furmonertinib and intrathecal pemetrexed chemotherapy rechallenges osimertinib-refractory leptomeningeal metastasis in a non-small cell lung cancer patient harboring EGFR20 R776S, C797S, and EGFR21 L858R compound EGFR mutations: a case report.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered the first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, due to the rarity of cases, the response of EGFR-TKIs in patients harboring uncommon compound EGFR mutations still needs to be determined. Here, we demonstrated the case of a 47-year-old smoker diagnosed with leptomeningeal metastasis from NSCLC and had EGFR20 R776S, C797S, and EGFR21 L858R compound mutations. He was treated with furmonertinib combined with intrathecal pemetrexed chemotherapy following progression on osimertinib, which led to clinical improvement and successfully prolonged his survival by 3 months. Regrettably, the patient eventually died from heart disease. This report provides the first reported evidence for the use of furmonertinib and intrathecal pemetrexed chemotherapy in NSCLC patients harboring EGFR R776S/C797S/L858R mutations who progressed on previous EGFR-TKIs.

Intrathecal chemotherapy for leptomeningeal disease in high-grade gliomas: a systematic review.

BACKGROUND: Leptomeningeal disease (LMD) secondary to high grade glioma (HGG), such as glioblastoma (GBM), are characterized by the spread of tumor cells to the leptomeninges which further complicates treatment approaches. Intrathecal (IT) chemotherapy has surfaced as a potential strategy to bypass the blood-brain barrier and address the challenges posed by disseminated disease. Here, we present a review of the safety and efficacy of IT chemotherapy in the treatment of LMD secondary to HGG. METHODS: A systematic review following PRISMA guidelines was conducted searching PubMed and Embase from January 1995 to September 2022 using specified terms related to IT chemotherapy for LMD. Included articles involved patients diagnosed with LMD from HGG, treated with intrathecal chemotherapy, and provided survival data. Data, including demographics, tumor characteristics, treatment, and survival information, were collected and independently extracted. RESULTS: A total of 68 patients across 10 clinical studies were diagnosed with LMD from HGG and included in the review. Among these patients, the average age at diagnosis was 44.2 years. GBM was the most common tumor type (n = 58, 85.3%). A majority of the patients presented with recurrent disease (n = 29, 60.4%). The review encompassed various IT chemotherapy regimens, including mafosfamide, thio-TEPA, 5-fluoro-2'-deoxyuridine (FdUrd), methotrexate (MTX), and cytarabine; however, dosages and frequencies were inconsistently reported. The mean progression-free survival (PFS) and overall survival (OS) for this cohort were 7.5 months and 11.7 months, respectively. Common side effects of IT chemotherapy included headaches, nausea, and vomiting, with more severe complications such as myelotoxicity, disseminated intravascular coagulopathy, meningitis, and gastrointestinal toxicity reported in some cases. CONCLUSION: LMD continues to be an uncommon complication associated with HGG with a poor prognosis. This article provides an overview of the presently available literature on IT chemotherapy for LMD secondary to HGG, and their respective treatment protocols with overall survival attributes. Additional research is warranted to ascertain how to maximize the potential efficacy of IT chemotherapy as a treatment option.

The effect of intrathecal recombinant arylsulfatase A therapy on structural brain magnetic resonance imaging in children with metachromatic leukodystrophy.

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.

Intraventricular or intrathecal polymyxin B for treatment of post-neurosurgical intracranial infection caused by carbapenem-resistant gram-negative bacteria: a 8-year retrospective study.

PURPOSE: Post-neurosurgical intracranial infection caused by carbapenem-resistant gram-negative bacteria (CRGNB) is a life-threatening complication. This study aimed to assess the current practices and clinical outcomes of intravenous (IV) combined with intraventricular (IVT)/intrathecal (ITH) polymyxin B in treating CRGNB intracranial infection. METHODS: A retrospective study was conducted on patients with post-neurosurgical intracranial infection due to CRGNB from January 2013 to December 2020. Clinical characteristics and treatment outcomes were collected and described. Kaplan-Meier survival and multivariate logistic regression analyses were performed. RESULTS: The study included 114 patients, of which 72 received systemic antimicrobial therapy combined with IVT/ITH polymyxin B, and 42 received IV administration alone. Most infections were caused by carbapenem-resistant Acinetobacter baumannii (CRAB, 63.2%), followed by carbapenem-resistant Klebsiella pneumoniae (CRKP, 31.6%). Compared with the IV group, the IVT/ITH group had a higher cerebrospinal fluid (CSF) sterilization rate in 7 days (p < 0.001) and lower 30-day mortality (p = 0.032). In the IVT/ITH group, patients with CRKP infection had a higher initial fever (p = 0.014), higher incidence of bloodstream infection (p = 0.040), lower CSF sterilization in 7 days (p < 0.001), and higher 30-day mortality (p = 0.005) than those with CRAB infection. Multivariate logistic regression analysis revealed that the duration of IVT/ITH polymyxin B (p = 0.021) was independently associated with 30-day mortality. CONCLUSIONS: Intravenous combined with IVT/ITH polymyxin B increased CSF microbiological eradication and improved clinical outcomes. CRKP intracranial infections may lead to more difficult treatment and thus warrant attention and further optimized treatment.

Efficacy and safety of intrathecal dexamethasone combined with isoniazid in the treatment of tuberculous meningitis: a meta-analysis.

BACKGROUND: The treatment regimen for tuberculous meningitis (TBM) remains unclear and requires optimization. There are some reports on successful adjunct intrathecal dexamethasone and isoniazid (IDI) treatment strategies for TBM, however, there is equivocal evidence on their efficacy and safety. METHODS: A comprehensive search of English and Chinese databases was conducted from inception to February 2024. A meta-analysis was performed on randomized controlled trials (RCTs) estimating the effects of adjunct IDI on conventional anti-TB (C anti-TB) treatments or C anti-TB alone. Efficacy, adverse reaction rate, cerebrospinal fluid (CSF) leukocytes, and CSF protein were used as primary outcome indicators. CSF glucose, CSF chlorides, CSF pressure, recovery time for laboratory indicators and recovery time for clinical symptoms were used as secondary outcome indicators. RESULTS: A total of 17 studies involving 1360 (IDI group vs. C anti-TB group: 392 vs. 372; higher-dose IDI group vs. lower-dose IDI group: 319 vs. 277) patients were included in our analysis. Efficacy was significantly higher (RR 1.3, 95% CI 1.2-1.4, P < 0.001) and adverse reaction rate was significantly lower in the IDI groups (RR 0.59, 95% CI 0.37-0.92, P = 0.021). Furthermore, CSF leukocytes (WMD - 29.33, 95% CI [- 40.64 to-18.02], P < 0.001) and CSF protein (WMD - 0.79, 95%CI [-0.96 to-0.61], P < 0.001) were significantly lower in the IDI groups. Recovery time indicators were all shorter in the IDI groups, fever (SMD - 2.45, 95% CI [-3.55 to-1.35], P < 0.001), coma (SMD-3.75, 95% CI [-4.33 to-3.17], P < 0.001), and headache (SMD  - 3.06, 95% CI [- 4.05 to-2.07], P < 0.001), respectively. Higher-dose IDI was more effective than lower-dose IDI (RR 1.23, 95% CI 1.14-1.33, P < 0.001), with no significant difference in adverse reaction rate between the two (RR 0.82, 95%CI 0.43-1.56, P = 0.544). CONCLUSION: Adjunct IDI with C anti-TB can enhance therapeutic outcomes and reduce adverse reaction rate in adult TBM patients, with higher-dose IDI showing superior efficacy. These findings highlight the potential of IDI as an adjunctive therapy in TBM management. However, more high-quality RCTs from more regions should be conducted to support our results. TRIAL REGISTRATION: Retrospectively registered in PROSPERO  https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023388860 .

Intrathecal baclofen efficacy for managing motor function and spasticity severity in patients with cerebral palsy: a systematic review and meta-analysis.

BACKGROUND: Spasticity can significantly affect a patient's quality of life, caregiver satisfaction, and the financial burden on the healthcare system. Baclofen is one of only a few options for treating spasticity. The purpose of this study is to investigate the impact of intrathecal baclofen (ITB) therapy on severe40.23 spasticity and motor function in patients with cerebral palsy. METHODS: We conducted a systematic review in PubMed, Scopus, Ovid, and the Cochrane Library in accordance with the PRISMA guidelines. We included studies based on eligibility criteria that included desired participants (cerebral palsy patients with spasticity), interventions (intrathecal baclofen), and outcomes (the Ashworth scales and the Gross Motor Function Measure [GMFM]). The within-group Cohen's d standardized mean differences (SMD) were analyzed using the random effect model. RESULTS: We screened 768 papers and included 19 in the severity of spasticity section and 6 in the motor function section. The pre-intervention average spasticity score (SD) was 3.2 (0.78), and the post-intervention average score (SD) was 1.9 (0.72), showing a 40.25% reduction. The SMD for spasticity reduction was - 1.7000 (95% CI [-2.1546; -1.2454], p-value < 0.0001), involving 343 patients with a weighted average age of 15.78 years and a weighted average baclofen dose of 289 µg/day. The SMD for the MAS and Ashworth Scale subgroups were - 1.7845 (95% CI [-2.8704; -0.6986]) and - 1.4837 (95% CI [-1.8585; -1.1088]), respectively. We found no relationship between the participants' mean age, baclofen dose, measurement time, and the results. The pre-intervention average GMFM (SD) was 40.03 (26.01), and the post-intervention average score (SD) was 43.88 (26.18), showing a 9.62% increase. The SMD for motor function using GMFM was 0.1503 (95% CI [0.0784; 0.2223], p-value = 0.0030), involving 117 patients with a weighted average age of 13.63 and a weighted average baclofen dose of 203 µg/day. In 501 ITB implantations, 203 medical complications were reported, including six new-onset seizures (2.96% of medical complications), seven increased seizure frequency (3.45%), 33 infections (16.26%), eight meningitis (3.94%), and 16 cerebrospinal fluid leaks (7.88%). Delivery system complications, including 75 catheter and pump complications, were also reported. CONCLUSION: Despite the risk of complications, ITB has a significant impact on the reduction of spasticity. A small but statistically significant improvement in motor function was also noted in a group of patients.

Actions of remimazolam on inhibitory transmission of rat spinal dorsal horn neurons.

Remimazolam is an ultra-short benzodiazepine that acts on the benzodiazepine site of γ-aminobutyric acid (GABA) receptors in the brain and induces sedation. Although GABA receptors are found localized in the spinal dorsal horn, no previous studies have reported the analgesic effects or investigated the cellular mechanisms of remimazolam on the spinal dorsal horn. Behavioral measures, immunohistochemistry, and in vitro whole-cell patch-clamp recordings of dorsal horn neurons were used to assess synaptic transmission. Intrathecal injection of remimazolam induced behavioral analgesia in inflammatory pain-induced mechanical allodynia (six rats/dose; p < 0.05). Immunohistochemical staining revealed that remimazolam suppressed spinal phosphorylated extracellular signal-regulated kinase activation (five rats/group, p < 0.05). In vitro whole-cell patch-clamp analysis demonstrated that remimazolam increased the frequency of GABAergic miniature inhibitory post-synaptic currents, prolonged the decay time (six rats; p < 0.05), and enhanced GABA currents induced by exogenous GABA (seven rats; p < 0.01). However, remimazolam did not affect miniature excitatory post-synaptic currents or amplitude of monosynaptic excitatory post-synaptic currents evoked by Aδ- and C-fiber stimulation (seven rats; p > 0.05). This study suggests that remimazolam induces analgesia by enhancing GABAergic inhibitory transmission in the spinal dorsal horn, suggesting its potential utility as a spinal analgesic for inflammatory pain.

Intrathecal injection of human placental mesenchymal stem cells derived exosomes significantly improves functional recovery in spinal cord injured rats.

BACKGROUND: Spinal cord injury (SCI) due to lack of restoration of damaged neuronal cells is associated with sensorimotor impairment. This study was focused on using the human placental mesenchymal stem cells- exosome (HPMSCs- Exosomes) in an animal model of severe SCI under myelogram procedure. METHODS AND RESULTS: Intrathecal injection of exosomes was performed in the acute phase of SCI in female rats. The improved functional recovery of the animals was followed for 6 weeks in control (saline, n = 6) and HPMSCs- EXO (HPMSCs-Exosomes, n = 6) groups. Pathological changes and glial scar size were evaluated. The Immunohistochemistry (IHC) of GFAP and NF200 factors as well as the apoptosis assay was investigated in the tissue samples from the injury site. The results demonstrated that HPMSCs-exosomes can improve motor function by attenuating apoptosis of neurons at the injury site, decreasing GFAP expression and increasing NF200 in the HPMSCs-EXO group. Also, HPMSCs-exosomes by preventing the formation of cavities causes preservation of tissue in SCI rats. CONCLUSIONS: These findings demonstrate the effectiveness of HPMSC-Exosomes as a therapeutic method to improve functional recovery, reduce pathological changes associated with injury, and prevent chronicity after SCI. The neuroprotective and anti-apoptotic potential of HPMSCs- Exosomes may be a promising therapeutic approach for SCI. Another result was the importance of intrathecal injection of exosomes in the acute phase, which accelerated the healing process. Furthermore, the myelogram can be a feasible and suitable method to confirm the accuracy of intrathecal injection and examine the subarachnoid space in the laboratory animals.

Effect of nusinersen on motor, respiratory and bulbar function in early-onset spinal muscular atrophy.

5q-associated spinal muscular atrophy is a rare neuromuscular disorder with the leading symptom of a proximal muscle weakness. Three different drugs have been approved by the European Medicines Agency and Food and Drug Administration for the treatment of spinal muscular atrophy patients, however, long-term experience is still scarce. In contrast to clinical trial data with restricted patient populations and short observation periods, we report here real-world evidence on a broad spectrum of patients with early-onset spinal muscular atrophy treated with nusinersen focusing on effects regarding motor milestones, and respiratory and bulbar insufficiency during the first years of treatment. Within the SMArtCARE registry, all patients under treatment with nusinersen who never had the ability to sit independently before the start of treatment were identified for data analysis. The primary outcome of this analysis was the change in motor function evaluated with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and motor milestones considering World Health Organization criteria. Further, we evaluated data on the need for ventilator support and tube feeding, and mortality. In total, 143 patients with early-onset spinal muscular atrophy were included in the data analysis with a follow-up period of up to 38 months. We observed major improvements in motor function evaluated with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders. Improvements were greater in children >2 years of age at start of treatment than in older children. 24.5% of children gained the ability to sit independently. Major improvements were observed during the first 14 months of treatment. The need for intermittent ventilator support and tube feeding increased despite treatment with nusinersen. Our findings confirm the increasing real-world evidence that treatment with nusinersen has a dramatic influence on disease progression and survival in patients with early-onset spinal muscular atrophy. Major improvements in motor function are seen in children younger than 2 years at the start of treatment. Bulbar and respiratory function needs to be closely monitored, as these functions do not improve equivalent to motor function.