PAK1 inhibition with Romidepsin attenuates H-reflex hyperexcitability after spinal cord injury.

Hyperreflexia associated with spasticity is a prevalent neurological condition characterized by excessive and exaggerated reflex responses to stimuli. Hyperreflexia can be caused by several diseases including multiple sclerosis, stroke and spinal cord injury (SCI). Although we have previously identified the contribution of the RAC1-PAK1 pathway underlying spinal hyperreflexia with SCI-induced spasticity, a feasible druggable target has not been validated. To assess the utility of targeting PAK1 to attenuate H-reflex hyperexcitability, we administered Romidepsin, a clinically available PAK1 inhibitor, in Thy1-YFP reporter mice. We performed longitudinal EMG studies with a study design that allowed us to assess pathological H-reflex changes and drug intervention effects over time, before and after contusive SCI. As expected, our results show a significant loss of rate-dependent depression - an indication of hyperreflexia and spasticity - 1 month following SCI as compared with baseline, uninjured controls (or before injury). Romidepsin treatment reduced signs of hyperreflexia in comparison with control cohorts and in pre- and post-drug intervention in SCI animals. Neuroanatomical study further confirmed drug response, as romidepsin treatment also reduced the presence of SCI-induced dendritic spine dysgenesis on α-motor neurons. Taken together, our findings extend previous work demonstrating the utility of targeting PAK1 activity in SCI-induced spasticity and support the novel use of romidepsin as an effective tool for managing spasticity. KEY POINTS: PAK1 plays a role in contributing to the development of spinal cord injury (SCI)-induced spasticity by contributing to dendritic spine dysgenesis. In this study, we explored the preclinical utility of inhibiting PAK1 to reduce spasticity and dendritic spine dysgenesis in an SCI mouse model. Romidepsin is a PAK1 inhibitor approved in the US in 2009 for the treatment of cutaneous T-cell lymphoma. Here we show that romidepsin treatment after SCI reduced SCI-induced H-reflex hyperexcitability and abnormal α-motor neuron spine morphology. This study provides compelling evidence that romidepsin may be a promising therapeutic approach for attenuating SCI-induced spasticity.

Therapeutic use of medical Cannabis in neurological diseases: a clinical update.

The use of medical Cannabis has increased in recent years due to changing legal circumstances in many countries. Approval exists only for a few neurological conditions such as rare forms of epilepsy or spasticity in multiple sclerosis. Beyond that, however, medical Cannabis is used for a wide range of neurological conditions and symptoms. In Germany, in parallel with new legislation that has simplified the prescription of medical Cannabis, an accompanying survey has been implemented for which initial data are now available. In this context, our review provides an overview of the evidence for the therapeutic use of medical Cannabis in neurology, the potential benefits, and side effects.

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.

Neglecting Bone Health: A Critical Gap in Management of Muscle Spasticity with Botulinum Toxin in Spinal Cord Injury.

Neuromuscular inhibitors have been quickly advanced from being used only for aesthetic purposes to being used as a treatment for musculoskeletal pain and muscle spasticity. This phenomenon stems from the diminished force exerted by muscles, which are essential for bone remodeling. In this context, it is hypothesized that botulinum toxin (BTX) might exert a direct influence on bone resorption. Although such treatments have the potential to provide patients with significant relief, bone loss occurring due to elective muscle paralysis has yet to be examined in clinical trials. The disuse model resulting from spinal cord injury, characterized by the absence of ground reaction and muscle forces, provides an ideal context for exploring the skeletal ramifications of intramuscular BTX injection. This approach enables an investigation into the intricate interplay between muscle and bone, encompassing the impact of spasticity on bone preservation, the potential positive and negative outcomes of BTX on bone metabolism, and the involvement of the autonomic nervous system in bone remodeling regulation. This paper presents a narrative review of research findings on the disturbance of the typical balance between muscles and bones caused by acute muscle paralysis from BTX, resulting in osteopenia and bone resorption.

Combining Cyproheptadine Hydrochloride With Targeted Muscle Activation Training to Treat Upper Extremity Stroke: A Randomized, Placebo-Controlled Trial.

OBJECTIVE: To examine a treatment for upper extremity impairment in stroke survivors that combines administration of cyproheptadine hydrochloride with repetitive practice focused on control of muscle activation patterns. DESIGN: Double-blind, randomized controlled trial. SETTINGS: Laboratory within a free-standing rehabilitation hospital. PARTICIPANTS: A total of 94 stroke survivors with severe, chronic hand impairment were randomly assigned to 1 of 4 treatment groups. INTERVENTIONS: Participants received either a placebo or cyproheptadine hydrochloride in identical pill form. The daily dosage of cyproheptadine/placebo was gradually increased from 8 to 24 mg/d over 3 weeks and then maintained over the next 6 weeks while participants completed 18 therapy sessions. Therapy consisted of either (1) active practice of muscle activation patterns to play "serious" computer games or control a custom hand exoskeleton or (2) passive, cyclical finger stretching imposed by the exoskeleton. MAIN OUTCOME MEASURES: Hand control was evaluated with the primary outcome measure of time to complete the Graded Wolf Motor Function Test (GWMFT) and secondary outcome measures including finger strength and spasticity. RESULTS: Across the 88 participants who completed the study, a repeated-measures analysis of variance revealed a significant effect of GroupxEvaluation interaction on GWMFT (F=1.996, P=.026). The 3 groups receiving cyproheptadine and/or actively practicing muscle activation pattern control exhibited significant reduction in mean time to complete the GWMFT tasks; roughly one-third of these participants experienced at least a 10% reduction in completion time. Gains were maintained at the 1-month follow-up evaluation. The group receiving placebo and passive stretching did not show improvement. No significant differences among groups were observed in terms of changes in strength or spasticity. CONCLUSIONS: Despite chronic, severe impairment, stroke survivors were able to complete the therapy focused on muscle activations and achieved statistically significant improvement in hand motor control. Cyproheptadine hydrochloride is a potential complementary treatment modality for stroke survivors with hand impairment.

Immunogenicity of Botulinum Toxin A: Insights.

BACKGROUND: Botulinum toxin A (BoNT-A) is widely used in treating dystonia and spasticity to managing chronic migraine and cosmetic applications. However, its immunogenic potential presents challenges, such as the development of neutralizing antibodies that lead to diminished therapeutic efficacy over time, known as secondary nonresponse. OBJECTIVE: This review aims to bridge the knowledge gap regarding the immunogenic mechanisms of BoNT-A and to explore effective management strategies to mitigate these immune responses. MATERIALS AND METHODS: The authors conducted a systematic search in databases including PubMed, Embase, and Web of Science, using keywords related to BoNT-A's immunogenicity. The selection process refined 157 initial articles down to 23 relevant studies, which underwent analysis to investigate the underlying mechanisms of immunogenicity and the factors influencing it. RESULTS: The analysis revealed that both the neurotoxin component and the neurotoxin-associated proteins could elicit an immune response. However, only antibodies against the core toxin influence therapeutic outcomes. Various patient-specific factors such as genetic predispositions and prior immune experiences, along with treatment-related factors such as dosage and frequency, play crucial roles in shaping these responses. CONCLUSION: Understanding the specific immunogenic triggers and responses to BoNT-A is critical for optimizing treatment protocols and improving patient outcomes.

Cannabis use by individuals with spinal cord injury in the UK: a call for improved patient education and physician awareness for pain and spasticity management.

STUDY DESIGN: Prospective observational qualitative study. OBJECTIVE: Cannabis is used by patients for the treatment of chronic pain, spasticity, sleep issues or mood disorders such as anxiety and depression. Since 2018, it has been authorised in the United Kingdom for medical use as an unlicensed medicine. This study aims to determine if patients are using cannabis for the management of symptoms related to spinal cord injury, and if so, whether they are using medical or illicit cannabis. METHODS: Spinal cord injury patients from the Yorkshire Regional Spinal Injuries Centre and SPINE Community in the United Kingdom were surveyed. Participants were sent a 7-point electronic survey. All results were anonymous, and confidentiality was maintained throughout the process. RESULTS: In total, 223 patients completed the survey. Not all patients answered every question. Of those who responded 65.35% (n = 132) were paraplegic and 34.65% (n = 70) were tetraplegic. Patients were suffering from chronic pain (longer than 3 months), spasticity, loss of/difficulty in sleeping or anxiety/depression. Almost 15% (14.93%, n = 33 out of 221) used cannabis to manage their symptoms, out of those the majority used street cannabis (79.41%, n = 27 out of 34) were using street cannabis. CONCLUSION: This study demonstrates that there are spinal cord injury patients in the UK using cannabis to treat their symptoms. A majority appear to be using illicit cannabis. Given that cannabis can interact with other medications, and that the quality and content of illicit cannabis can be highly variable and at times dangerous, it is important for physicians to discuss cannabis use with their patients. This can inform prescribing and allow them to educate patients on the dangers of medical cannabis and potential alternatives.

Outcomes, complications, and dosing of intrathecal baclofen in the treatment of multiple sclerosis: a systematic review.

OBJECTIVE: The purpose of this systematic review was to evaluate empirical outcomes of studies in the literature that investigated effectiveness of intrathecal baclofen (ITB) in the treatment of multiple sclerosis (MS)-related spasticity (MSRS) based on various metrics. Since the first description of this route of baclofen delivery for MS patients by Penn and Kroin in 1984, numerous studies have contributed to the medical community's knowledge of this treatment modality. The authors sought to add to the literature a systematic review of studies over the last 2 decades that elucidates the clinical impact of ITB in treating MSRS with the following endpoints: impact on patient-centered outcomes, such as spasticity reduction (primary), complications (secondary), and dosing (secondary). METHODS: The authors queried three databases (PubMed, Scopus, and Cochrane Library) using the following search terms: (intrathecal baclofen) AND (multiple sclerosis). The set inclusion criteria were as follows: 1) original, full-text article; 2) written in the English language; 3) published between and including the years 2000 and 2023; 4) discussion of pre- and post-ITB pump implantation outcomes (e.g., reduction in spasticity and improved comfort) in MSRS patients with long-term ITB treatment; and 5) contained a minimum of 5 MS patients. Data on study type, patient demographics, follow-up periods, primary outcomes, and secondary outcomes were extracted from the included studies. RESULTS: The authors' search yielded 465 studies, of which 17 met inclusion criteria. Overall, they found evidence for the effectiveness of ITB in treating MSRS patients whose condition was refractory to oral medications, with significant reported changes in spasm frequency from pre- to postimplantation. They also found evidence supporting the positive impact of ITB on MSRS patients' quality of life. Moreover, the authors found that most complications were surgical rather than pharmacological. In addition, the average 1-year dose of ITB (reported in 7 of the included studies) was 191.93 µg/day, which is substantially lower than ITB doses reported in the literature for patients with central (non-MS) or spinal origins of spasticity at 1-year follow-up. CONCLUSIONS: The evidence supports ITB as a clinically effective treatment for MSRS, particularly in patients in whom oral antispasmodics and physiotherapy have failed. This systematic review contributes a comprehensive synthesis of clinical benefits, complications, and dosing of ITB reported over the past 2 decades, which furthers an understanding of ITB's clinical utility in practice.

Uncovering the rate and risk factors of intrathecal baclofen pump-associated complications in the adult population.

OBJECTIVE: The aim of this study was 1) to describe the rate of intrathecal baclofen (ITB)-associated complications at a large tertiary center, and 2) to evaluate the impact of patient-related factors on the likelihood of developing such complications. METHODS: A retrospective single-center study was carried out. A total of 301 eligible patients were included in the analysis. Univariate regression models were used to evaluate the impact of age, sex, diagnosis, ambulation status, modified Ashworth scale score, body mass index, diabetes status, and pain level on the likelihood of developing a device-related infection, pump malfunction, catheter malfunction, and other clinically significant complications. RESULTS: Overall, 27% of patients experienced an ITB-related complication. The most common complications included infection (6%, 18/301), pump malfunction (7.3%, 22/301), and catheter malfunction (14%, 42/301). The univariate analyses revealed that the patient's ambulatory status had a significant impact on the likelihood of developing a catheter-related malfunction. Furthermore, a trend toward significance was identified between patients' preoperative body mass index and device-related infection. Finally, the risk of suffering any ITB-related complications was statistically correlated with the number of years that had passed since the initial pump implantation. CONCLUSIONS: The authors' analysis reveals a previously underrecognized association between ambulatory status at the time of ITB pump implantation and the incidence of catheter-related complications, and confirms the impact of time since surgery on the risk of developing any ITB-related complication. The patient's age, sex, diagnosis, diabetes status, or pain level at baseline were not associated with the risk of complications. Collectively, these insights contribute novel information to the existing literature, providing practical value for physicians in guiding patient selection for ITB therapy.

Spinal catheter revision in pediatric intrathecal baclofen pumps: risk factors and postoperative outcomes.

OBJECTIVE: Intrathecal baclofen (ITB) pumps are commonly used in pediatric patients with cerebral palsy (CP) and medically refractory spasticity. However, catheter malfunction and associated risk factors are not well understood. The aim of this study was to examine potential risk factors for spinal catheter malfunction and characterize postoperative follow-up to understand the clinical consequences. METHODS: Patients who received ITB pump replacement or revision at Boston Children's Hospital between 2010 and 2023 were retrospectively reviewed. The spinal catheter revision cohort (SCRC) included patients whose spinal catheter was occluded requiring lumbar catheter revision. The second cohort included abdominal pump replacements only (APRC). Between-group comparisons and multivariable regression identified factors associated with catheter revision and postoperative outcomes. RESULTS: Forty-one (33.6%) patients underwent spinal catheter revision and were compared with 81 patients (66.4%) who underwent abdominal pump replacement only. Younger age at surgery and an elevated preoperative lower-extremity modified Ashworth scale grade were associated with spinal catheter revision (p < 0.05). Catheter model type, tip location, and history of spinal fusion were not associated with obstruction. Postoperatively, SCRC patients experienced a higher rate of infection (17.1%) relative to APRC patients (0%) within 30 days from their ITB pump replacement procedure (p < 0.05) and greater likelihood of subsequent ITB system removal compared with the APRC (24.4% vs 7.4%, p < 0.05). Although not differing preoperatively, SCRC patients had lower postoperative ITB doses when compared with the APRC group (median dose 143 vs 350 µg/day, p < 0.05) at hospital discharge and remained statistically different at the 6-month and 1-year follow-ups (p < 0.05). There were no postoperative differences in baclofen overdose, withdrawal, or median number of hospital readmissions within 30 days. Overall, 31.7% of spinal catheter revisions were unanticipated by the clinical team at time of surgery. CONCLUSIONS: Younger age at surgery and increased preoperative lower-extremity tone may be risk factors for catheter obstruction, resulting in a higher rate of postoperative infection and subsequent ITB pump removal compared with pump replacement alone. Spinal catheter occlusion can complicate revision or replacement procedures, especially when unanticipated. Routine clinical assessment may be inadequate for diagnosing insidious catheter malfunction. Catheter occlusion deserves further study, and routine assessment of catheter patency may be warranted to prevent suboptimal tone therapy.

Intraventricular baclofen for intractable spasticity and secondary dystonia: a frame-based stereotactic approach and case series.

OBJECTIVE: Intraventricular baclofen has been reported as an alternative to intrathecal baclofen for managing refractory spasticity and dystonia in some circumstances. In this report, we described a frame-based stereotactic approach for precisely positioning of the infusion catheter into the third ventricle. MATERIAL AND METHODS: High resolution contrast-enhanced anatomical MR sequences was acquired prior to surgery for pre-planning. Catheter trajectory was planned to pass from the lateral ventricle to the third ventricle through the Foramen of Monro. The surgical procedure was adapted from the frame-based deep brain stimulation surgery. The Touch-Loc kit (SceneRay, China) was used to temporarily secure the catheter in place during the surgery. From July 2022 to December 2022, three patients suffering from intractable spasticity and/or secondary dystonia received IVB successfully using the described technique. RESULTS: No severe adverse events, including death, intracranial hemorrhage, infection, catheter migration or fracture, were documented at the last follow-up (range: 12‒24 months). Transient side effects included mild nausea following the initiation of infusion or the increase in infusion rate. All three patients responded to the IVB. CONCLUSIONS: The described frame-based stereotactic technique for IVB catheter implant is feasible and could be quickly mastered by neurosurgeons in related fields. Larger prospective cohorts with longer follow-up periods are necessary to further evaluate the long-term safety and efficacy of this procedure.

Postoperative outcomes and stimulation responses for sectioned nerve roots during selective dorsal rhizotomy in cerebral palsy.

BACKGROUND: Cerebral palsy (CP) is the most cause of motor dysfunction in children. Selective dorsal rhizotomy (SDR) plays a major role in long term spasticity control. However, limited data exists on the effect of SDR on postoperative spasticity treatment requirements and supraspinal effects, and the stimulation responses of dorsal nerve roots in those with CP. METHODS: The current study included the outcome for 35 individuals undergoing SDR for motor functional outcome, spasticity, baclofen dose changes, botulinum toxin injection frequency, and spasticity related orthopedic procedures. We also report on the stimulation responses in 112 individuals who underwent SDR at our institution. RESULTS: There was a significant difference in gross motor function measures (GMFM)-66 scores at last follow up that remained present when considering only ambulatory children but not with non-ambulatory children. Ashworth scores were significantly decreased for both upper and lower extremities after SDR at all follow up points. There was a significant decrease in Baclofen dose and botulinum toxin injections requirements after SDR, but no significant difference in the need for orthopedic intervention. A total of 5502 dorsal nerve roots were tested showing a decrease in stimulation intensity and increase in grade on the right side and for descending lumbosacral levels. CONCLUSIONS: SDR improves gross motor scores during short term follow up but has additional benefits in decreasing baclofen dosing and botulinum toxin injections requirements after surgery. They stimulation responses of sectioned dorsal nerve roots adds to the limited available data and our understanding of the pathological changes that occur in CP.

Phase-Based Gait Prediction after Botulinum Toxin Treatment Using Deep Learning.

Gait disorders in neurological diseases are frequently associated with spasticity. Intramuscular injection of Botulinum Toxin Type A (BTX-A) can be used to treat spasticity. Providing optimal treatment with the highest possible benefit-risk ratio is a crucial consideration. This paper presents a novel approach for predicting knee and ankle kinematics after BTX-A treatment based on pre-treatment kinematics and treatment information. The proposed method is based on a Bidirectional Long Short-Term Memory (Bi-LSTM) deep learning architecture. Our study's objective is to investigate this approach's effectiveness in accurately predicting the kinematics of each phase of the gait cycle separately after BTX-A treatment. Two deep learning models are designed to incorporate categorical medical treatment data corresponding to the injected muscles: (1) within the hidden layers of the Bi-LSTM network, (2) through a gating mechanism. Since several muscles can be injected during the same session, the proposed architectures aim to model the interactions between the different treatment combinations. In this study, we conduct a comparative analysis of our prediction results with the current state of the art. The best results are obtained with the incorporation of the gating mechanism. The average prediction root mean squared error is 2.99° (R2 = 0.85) and 2.21° (R2 = 0.84) for the knee and the ankle kinematics, respectively. Our findings indicate that our approach outperforms the existing methods, yielding a significantly improved prediction accuracy.

[Intrathecal baclofen therapy: a 30-year experience]. / Intratekal'naya baklofenovaya terapiya: 30 let primeneniya.

BACKGROUND: The first pump for intrathecal administration of baclofen was implanted in 1984. Over thirty years, intrathecal prolonged infusion of muscle relaxants has occupied a worthy niche among all methods for correction of non-focal drug-resistant disabling muscle spasticity. However, this method has not become routine despite high awareness of specialists in Russia and abroad, as well as undeniable advantages for restoring the daily activity, improving the walking pattern and providing care and quality of life in people with limited mobility. This is due to scrupulous analysis of adverse events and accurate attitude towards its use.The purpose of this review was to systematize data on indications, selection criteria, pump implantation technique, subsequent patient management and treatment outcomes over a 30-year history. METHOD: A review of national and foreign literature was performed. RESULTS AND CONCLUSION: Prolonged intrathecal baclofen therapy is perspective for long-term treatment of severe spasticity interfering with quality of life and self-care if oral muscle relaxants are contraindicated or ineffective. This procedure is effective for impaired articulation, chewing and spastic pain syndrome. One can reduce the incidence of side effects via correct dosage of the drug, and tolerance to therapy can be reduced by timely elimination of problems with catheter.

Spasticity treatment patterns among people with multiple sclerosis: a Swedish cohort study.

BACKGROUND: Spasticity is common among people with multiple sclerosis (MS), but there are few studies of spasticity treatment patterns. We aim to describe associations with spasticity treatment measured primarily by oral baclofen use. METHODS: This cohort study using Swedish registers included 1826 and 3519 people with incident and prevalent MS (pwIMS, pwPMS) respectively, followed from 2005 to 2014. Cox regression assessed factors associated with new baclofen prescriptions and its discontinuation. RESULTS: A total of 10% of pwIMS and 19% of pwPMS received baclofen, a drug prescribed specifically for spasticity in Sweden, of which many patients had relapsing-remitting course. Prescriptions occurred soon after MS diagnosis: pwIMS received baclofen typically within 6 months of diagnosis, and pwPMS within 3 years. Younger patients compared with older patients were three times more likely to receive baclofen with similar disability level measured using Expanded Disability Severity Scores (EDSS). Patients aged 18-44 years with EDSS 3.0-5.0 have an HR for baclofen use of 5.62 (95% CI 2.91 to 10.85) and EDSS 6+ have an HR of 15.41 (95% CI 7.07 to 33.58) compared with individuals with EDSS 0-2.5. In comparison, patients aged 45+ years with EDSS 3.0-5.0 have an HR of 2.05 (95% CI 1.10 to 3.82) and EDSS 6+ an HR of 4.26 (95% CI 1.96 to 9.17). Baclofen discontinuation was high: 49% (95% CI 0.42 to 0.57) of pwIMS discontinued within 150 days of dispensation, 90% discontinued within 2 years including patients with progressive course or higher EDSS. Associations among pwPMS and sensitivity analyses including additional treatments were similar. CONCLUSIONS: Younger patients with MS are more likely to receive baclofen compared with older patients with MS. High rates of baclofen discontinuation highlight the need for more tolerable and efficacious spasticity treatments and monitoring of spasticity among people with MS.

Resting-state functional connectivity in multiple sclerosis patients receiving nabiximols for spasticity.

BACKGROUND: Nabiximols (Sativex®) is a cannabinoid approved for multiple sclerosis (MS)-related spasticity. Its mechanism of action is partially understood, and efficacy is variable. OBJECTIVE: To conduct an exploratory analysis of brain networks connectivity changes on resting state (RS) functional MRI (fMRI) of MS patients treated with nabiximols. METHODS: We identified a group of MS patients treated with Sativex® at Verona University Hospital, who underwent RS brain fMRI in the 4 weeks before (T0) and 4-8 weeks after (T1) treatment start. Sativex® response was defined as ≥ 20% spasticity Numerical Rating Scale score reduction at T1 vs. T0. Connectivity changes on fMRI were compared between T0 and T1 in the whole group and according to response status. ROI-to-ROI and seed-to-voxel connectivity were evaluated. RESULTS: Twelve MS patients (7 males) were eligible for the study. Seven patients (58.3%) resulted Sativex® responders at T1. On fMRI analysis, Sativex® exposure was associated with global brain connectivity increase (particularly in responders), decreased connectivity of motor areas, and bidirectional connectivity changes of the left cerebellum with a number of cortical areas. CONCLUSIONS: Nabiximols administration is associated with brain connectivity increase of MS patients with spasticity. Modulation of sensorimotor cortical areas and cerebellum connectivity could play a role in nabiximols effect.

Clinical efficacy of ultrasound-guided stellate ganglion block combined with extracorporeal shock wave therapy on limb spasticity in patients with ischemic stroke.

INTRODUCTION: To observe the clinical efficacy of ultrasound-guided stellate ganglion block (SGB) + extracorporeal shock wave therapy (ESWT) for limb spasticity in patients with ischemic stroke. METHODS: A total of 60 patients with post-stroke limb spasticity in our hospital were selected and randomly divided into four groups (n = 15). In the control group, patients received routine rehabilitation training. Based on routine rehabilitation training, SGB group patients underwent ultrasound-guided SGB, ESWT group patients received ESWT, and SGB + ESWT group patients received ultrasound-guided SGB combined with ESWT. The total treatment course was one month. The Modified Barthel Index (MBI) score, Fugl-Meyer Assessment and upper limb rehabilitation training system were applied to evaluate the activities of daily living, upper limb motor function and upper limb performance before and after treatment. Finally, the improvement after treatment was compared among different groups. RESULTS: After treatment, compared with the control group, the MBI score and the upper limb score based on Fugl-Meyer Assessment in the SGB, ESWT, and SGB + ESWT groups were significantly increased (P < 0.05). Furthermore, compared with the SGB and ESWT groups, SGB + ESWT exhibited a higher upper limb function score (P < 0.05), while the MBI score was not significantly different (P > 0.05). In terms of upper limb performance ability, patients in the SGB, ESWT and SGB + ESWT groups had better fitting degree, participation and exertion of exercise than those in the control group, and the SGB + ESWT group patients had the same movement trajectory as robots. CONCLUSION: Ultrasound-guided SGB and ESWT can reduce the muscle tension of patients, alleviate spasticity, promote the motor function of the upper limb, and improve the working performance of patients. However, the effect of SGB combined with ESWT is better.

Cannabis and Cannabinoids in Multiple Sclerosis: From Experimental Models to Clinical Practice-A Review.

BACKGROUND: As far as 80% of people diagnosed with multiple sclerosis (MS) experience disabling symptoms in the course of the disease, such as spasticity and neuropathic pain. As first-line symptomatic therapy is associated with important adverse reactions, cannabinoids have become increasingly popular among patients with MS. This review intends to provide an overview of the evidence of the role of cannabinoids in treating symptoms related to MS and to encourage further research on this matter. AREAS OF UNCERTAINTY: To date, the evidence supporting the role of cannabis and its derivatives in alleviating the MS-related symptoms comes only from studies on experimental models of demyelination. To the best of our knowledge, relatively few clinical trials inquired about the therapeutic effects of cannabinoids on patients with MS, with variable results. DATA SOURCES: We conducted a literature search through PubMed and Google Scholar from the beginning until 2022. We included articles in English describing the latest findings regarding the endocannabinoid system, the pharmacology of cannabinoids, and their therapeutic purpose in MS. RESULTS: Evidence from preclinical studies showed that cannabinoids can limit the demyelination process, promote remyelination, and have anti-inflammatory properties by reducing immune cell infiltration of the central nervous system in mice with experimental autoimmune encephalomyelitis. Moreover, it has been established that experimental autoimmune encephalomyelitis mice treated with cannabinoids experienced a significant reduction of symptoms and slowing of the disease progression. Given the complexity of human immune and nervous systems, cannabinoids did not have the anticipated effects on human subjects. However, data obtained from clinical trials showed some beneficial results of cannabinoids as a single or as add-on therapy in reducing the spasticity and pain related to MS. CONCLUSION: Considering their various mechanisms of action and good tolerability, cannabinoids remain an interesting therapy for spasticity and chronic pain related to MS.

Does intrathecal baclofen therapy decrease the progression of hip displacement in young patients with cerebral palsy?

AIM: To evaluate the effects of intrathecal baclofen pump (ITBP) therapy on hip dysplasia in young patients with cerebral palsy (CP). METHOD: This was a retrospective cohort series of prospectively collected data. Inclusion criteria were all patients with CP in Gross Motor Function Classification System (GMFCS) levels IV or V who underwent ITBP placement under 8 years old with at least 5 years of follow-up. Thirty-four patients were matched to a control group of 71 patients based on GMFCS level, motor type, medical comorbidities, worst hip migration percentage at ITBP placement, age, and Modified Ashworth scale scores. Patients were followed for at least 5 years or until they had hip reconstructive surgery. The primary outcome was the development of hip displacement as measured by the migration percentage at the latest follow-up or the preoperative migration percentage before hip reconstruction. RESULTS: The migration percentage at last follow-up was not statistically different between groups (ITBP: 36.2%, non-ITBP: 44.4%, p = 0.14). The rates of future preventative, reconstructive, and recurrent hip surgery were not different between groups. INTERPRETATION: The use of ITBP as an early treatment of spasticity did not alter the natural history of progressive hip displacement in non-ambulatory patients with CP and hip displacement is likely multifactorial, not solely due to spasticity.

Change in upper limb function in people with multiple sclerosis treated with nabiximols: a quantitative kinematic pilot study.

OBJECTIVES: Nabiximols represents an increasingly employed add-on treatment option for spasticity in people with multiple sclerosis (PwMS) who either were unresponsive or reported excessive adverse reactions to other therapies. While several studies performed in the last decade demonstrated its effectiveness, safety, and tolerability, few quantitative data are available on the impact on motor dysfunctions. In this open-label, not concurrently controlled study, we aimed to assess the impact of a 4-week treatment with nabiximols on upper limb functionality. METHODS: Thirteen PwMS (9 female, 4 male) with moderate-severe spasticity underwent a combination of clinical tests (i.e., Box and Block, BBT and Nine-Hole Peg test, 9HPT) and instrumental kinematic analysis of the "hand to mouth" (HTM) movement by means of optical motion capture system. RESULTS: After the treatment, improvements in gross and fine dexterity were found (BBT + 3 blocks/min, 9HPT - 2.9 s, p < 0.05 for both cases). The kinematic analysis indicated that HTM movement was faster (1.69 vs. 1.83 s, p = 0.05), smoother, and more stable. A significant reduction of the severity of spasticity, as indicated by the 0-10 numerical rating scale (4.2 vs. 6.3, p < 0.001), was also observed. CONCLUSION: The findings from the present pilot study suggest that a 4-week treatment with nabiximols ameliorates the spasticity symptoms and the overall motor function of upper limb in PwMS with moderate-severe spasticity. The use of quantitative techniques for human movement analysis may provide valuable information about changes originated by the treatment in realistic upper limb motor tasks involved in activities of daily living.