AAPM&R consensus guidance on spasticity assessment and management.

BACKGROUND: The American Academy of Physical Medicine and Rehabilitation (AAPM&R) conducted a comprehensive review in 2021 to identify opportunities for enhancing the care of adult and pediatric patients with spasticity. A technical expert panel (TEP) was convened to develop consensus-based practice recommendations aimed at addressing gaps in spasticity care. OBJECTIVE: To develop consensus-based practice recommendations to identify and address gaps in spasticity care. METHODS: The Spasticity TEP engaged in a 16-month virtual meeting process, focusing on formulating search terms, refining research questions, and conducting a structured evidence review. Evidence quality was assessed by the AAPM&R Evidence, Quality and Performance Committee (EQPC), and a modified Delphi process was employed to achieve consensus on recommendation statements and evidence grading. The Strength of Recommendation Taxonomy (SORT) guided the rating of individual studies and the strength of recommendations. RESULTS: The TEP approved five recommendations for spasticity management and five best practices for assessment and management, with one recommendation unable to be graded due to evidence limitations. Best practices were defined as widely accepted components of care, while recommendations required structured evidence reviews and grading. The consensus guidance statement represents current best practices and evidence-based treatment options, intended for use by PM&R physicians caring for patients with spasticity. CONCLUSION: This consensus guidance provides clinicians with practical recommendations for spasticity assessment and management based on the best available evidence and expert opinion. Clinical judgment should be exercised, and recommendations tailored to individual patient needs, preferences, and risk profiles. The accompanying table summarizes the best practice recommendations for spasticity assessment and management, reflecting principles with little controversy in care delivery.

Safety of botulinum toxin injections in children less than one year old: A retrospective chart review.

PURPOSE: Infants can have muscle hypertonia due to cerebral palsy, muscle strength imbalances due to brachial plexus palsy, refractory clubfoot, and torticollis. These muscle problems can cause significant development impairments. A child with severe sialorrhea and dysphagia from leukodystrophy can aspirate, causing respiratory problems. Botulinum toxin (BoNT) injections can improve these conditions but may lead to adverse effects from the toxin spreading to non-targeted muscles, potentially impacting breathing, swallowing, and overall strength. This is particularly concerning in infants. This study assessed the safety of BoNT injections in children less than one year of age. METHODS: This was a retrospective cohort study. RESULTS: Forty-seven patients (22 male, 25 female) received BoNT injections before one year of age (three to 12 months). Thirty-seven received one round of injections and 10 were injected on multiple occasions. Forty-five received onabotulinumtoxinA (15-100 units [U], 1.9-15.2 U/kg), one received abobotulinumtoxinA (70 U, 9.0 U/kg), and one received incobotulinumtoxinA (25 U, 3.5 U/kg). Lower extremities were treated in 15 patients, upper extremities in 38, the sternocleidomastoid in two, and the salivary glands in one. Forty-five patients had no reported complications. One experienced transient fever, vomiting, and diarrhea. The parent of another reported subjective weakness in one muscle. CONCLUSION: BoNT injections in children less than one year of age appear to be safe.

Topical Esmolol Hydrochloride as a Novel Treatment Modality for Diabetic Foot Ulcers: A Phase 3 Randomized Clinical Trial.

Importance: Preclinical and phase 1/2 studies with esmolol hydrochloride suggest its potential role in treatment of diabetic foot ulcers (DFUs). Objective: To study the efficacy of topical esmolol for healing of uninfected DFUs. Design, Setting, and Participants: A randomized, double-blind, multicenter, phase 3 clinical trial was conducted from December 26, 2018, to August 19, 2020, at 27 referral centers across India. Participants included adults with DFUs. Interventions: Participants were randomized after a run-in phase (1 week) to receive esmolol, 14%, gel with standard of care (SoC), SoC only, or vehicle with SoC (3:3:1 proportion) for 12 weeks (treatment phase) and followed up subsequently until week 24. Main Outcomes and Measures: The primary outcome was the proportion of wound closure within the 12-week treatment phase in the esmolol with SoC and SoC only groups. Analysis was conducted using an intention-to-treat safety evaluable population, full analysis set or efficacy-evaluable population, and per-protocol population comparing the esmolol plus SoC and SoC only treatment groups. Results: In the study, 176 participants (122 men [69.3%]; mean [SD] age, 56.4 [9.0] years; mean [SD] hemoglobin A1c level, 8.6% [1.6%]) with DFUs classified as University of Texas Diabetic Wound Classification system grade IA and IC (mean [SD] ulcer area, 4.7 [2.9] cm2) were randomized to the 3 groups. A total of 140 participants were analyzed for efficacy. The proportion of participants in the esmolol with SoC group who achieved target ulcer closure within 12 weeks was 41 of 68 (60.3%) compared with 30 of 72 (41.7%) participants in the SoC only group (odds ratio [OR], 2.13; 95% CI, 1.08-4.17; P = .03). A total of 120 participants completed the end of study visit which were analyzed. Target ulcer closure by the end of the study (week 24) was achieved in 44 of 57 (77.2%) participants in the esmolol with SoC group and 35 of 63 (55.6%) participants in the SoC only group (OR, 2.71; 95% CI, 1.22-5.99; P = .01). The median time for ulcer closure was 85 days for the esmolol with SoC group and was not estimable for SoC only group. Significant benefits of Esmolol with SoC were seen in patients with factors that impede the healing of DFU. Treatment-emergent adverse events were noted in 18.8% of the participants, but most (87.3%) of these events were not attributable to the study drug. Conclusions and Relevance: In this multicenter, randomized, double-blind clinical trial, the addition of esmolol to SoC was shown to significantly improve the healing of DFUs. With these results, topical esmolol may be an appropriate addition to SoC for treating DFUs. Trial Registration: ClinicalTrials.gov Identifier: NCT03998436; Clinical Trial Registry, India CRI Number: CTRI/2018/11/016295.

Novel Topical Esmolol Hydrochloride (Galnobax) for Diabetic Foot Wound: Phase 1/2, Multicenter, Randomized, Double-Blind, Vehicle-Controlled Parallel-Group Study.

We aimed to assess safety and dose-finding efficacy of esmolol hydrochloride (Galnobax) for healing of diabetic foot ulcer (DFU). This is phase 1/2 multicenter, randomized, double-blind vehicle-controlled study. Participants having diabetes and noninfected, full-thickness, neuropathic, grade I or II (Wagner classification) DFU, area 1.5-10 cm2, and unresponsive to standard wound care (at least 4 weeks) were randomized to receive topical Galnobax 14% twice daily (BID), Galnobax 20% BID, Galnobax 20% once daily (OD)+vehicle, or vehicle BID with standard of care. The primary efficacy end point was the reduction in area and volume of target ulcer from baseline to week 12 or wound closure, whichever was earlier. The wound duration was 12.5 weeks (5-49.1 weeks) and wound area 4.10 ± 2.41 cm2 at baseline. The ulcer area reduction was 86.56%, 95.80%, 80.67%, and 82.58% (p = 0.47) in the Galnobax 14%, Galnobax 20%, Galnobax20%+vehicle, and vehicle only groups, respectively. Ulcer volume reduction was 99.40% in the Galnobax14%, 83.36% in Galnobax20%, 55.41% in the Galnobax20%+vehicle, and 84.57% in vehicle group (p = 0.86). The systemic concentration of esmolol was below the quantification limit (10 ng/mL) irrespective of doses of Galnobax (Cmax esmolol acid 340 ng/mL for 14% Galnobax, AUC 2.99 ± 4.31 h*µg/mL after single dose). This is the first clinical study of the short acting beta blocker esmolol hydrochloride used as novel formulation for healing of DFU. We found that esmolol when applied topically over wounds had minimal systemic concentration establishing its safety for wound healing in patients with diabetes. Esmolol hydrochloride is a safe novel treatment for DFU.

Acquired amputations in patients with spina bifida.

PURPOSE: The purpose of this study was to assess if the incidence of lower extremity (LE) pressure injuries resulting in amputations was more frequent in ambulatory versus non-ambulatory patients with spina bifida. METHODS: The medical records of all patients at a large pediatric rehabilitation hospital who had spina bifida and a history of a pressure injury between 1997-2018 were retrospectively reviewed. RESULTS: In this study, 112 patients with spina bifida developed LE pressure injuries, 53 patients walked with braces and/or an assistive device, and 59 patients used a wheelchair for mobility. Of the 11 patients who had amputations, 10 walked and 1 did not walk prior to their amputation. Ambulatory patients with LE pressure injuries had a 19% chance (10 out of 53 patients) of requiring an amputation. Non-ambulatory patients with a LE pressure injury had only a 2% chance (1 out of 59 patients) of requiring an amputation. Ambulatory patients with LE pressure injuries were at a much higher risk of requiring an amputation than patients who did not walk (p-value of < 0.005). CONCLUSION: Patients with spina bifida who are ambulatory and develop a pressure injury have a high risk of ultimately needing an amputation and should be monitored and treated aggressively.

Novel topical esmolol hydrochloride improves wound healing in diabetes by inhibiting aldose reductase, generation of advanced glycation end products, and facilitating the migration of fibroblasts.

Aims/Objectives: Wound healing in people with diabetes is delayed secondary to impaired nitric oxide generation, advanced glycation end products (AGE), and poor migration of epithelial cells. We developed a novel topical esmolol hydrochloride (Galnobax) and assessed its efficacy for wound healing in streptozocin-induced diabetic hairless rat. Methods: All experiments were performed at an animal laboratory and tertiary-care research facility. Ex vivo aldose reductase inhibition was assessed from enzymes obtained from a bacterial culture (spectrophotometer), sorbitol content in homogenized red blood cells, and AGE in glucose and bovine serum by fluorometry following the addition of esmolol in varying concentrations. A scratch assay of human fibroblasts, endothelial cells, and keratinocytes was assessed under a high-glucose environment and after esmolol by phase-contrast microscopy. The efficacy evaluation of the topical application of Galnobax (14 and 20%) or vehicle was conducted in streptozotocin-induced diabetic hairless rats, and endogenous nitrite and hydroxyproline from homogenized wound tissue were measured along with pharmacokinetic and dermal toxicity in Hanford miniature swine. Results: Esmolol inhibited the formation of sorbitol by 59% in erythrocytes in comparison to glucose-induced sorbitol levels. AGE generation in bovine serum albumin was reduced at 1 mM esmolol concentrations (2.6 ± 1.7) compared with control (p < 0.05) and similar to that of diclofenac (2.5 ± 1.3). Esmolol at 1 and 10 µM enhanced the migration of fibroblasts, epithelial cells, and keratinocytes compared with control. The nitric oxide levels (day 7) were 44 and 112% higher with Galnobax (14%) than those of the diabetic group (p < 0.05) and the vehicle control group (p < 0.05), respectively. The days 7 and 14 hydroxyproline in the wound was higher by 22 and 44% following Galnobax (14%) compared with the diabetic and vehicle control groups. The wound area exhibited better reduction with Galnobax at 14% up to day 10 follow-up compared with the controls. The pharmacokinetic and dermal toxicity in miniature swine suggested no significant adverse event with Galnobax. Conclusions: Topical esmolol hydrochloride is a novel, safe, and effective treatment modality that acts through pleotropic mechanisms to hasten wound healing in diabetes.

A consensus statement on the use of botulinum toxin in pediatric patients.

Botulinum toxin has been used in medicine for the past 30 years. However, there continues to be controversy about the appropriate uses and dosing, especially in the pediatric population. A panel of nine pediatric physiatrists from different regions and previous training programs in the United States were nominated based on institutional reputation and botulinum toxin (BoNT) experience. Based on a review of the current literature, the goal was to provide the rationale for recommendations on the administration of BoNT in the pediatric population. The goal was not only to review safety, dosing, and injection techniques but also to develop a consensus on the appropriate uses in the pediatric population. In addition to upper and lower limb spasticity, the consensus also provides recommendations for congenital muscular torticollis, cervical dystonia, sialorrhea, and brachial plexus palsies.

Psychometric properties of the brief pain inventory modified for proxy report of pain interference in children with cerebral palsy with and without cognitive impairment.

INTRODUCTION: Cerebral palsy (CP) is the most common cause of physical disability in children and is often associated with secondary musculoskeletal pain. Cerebral palsy is a heterogeneous condition with wide variability in motor and cognitive capacities. Although pain scales exist, there remains a need for a validated chronic pain assessment tool with high clinical utility for use across such a heterogeneous patient population with and without cognitive impairment. OBJECTIVES: The purpose of this study was an initial assessment of several psychometric properties of the 12-item modified brief pain inventory (BPI) pain interference subscale as a proxy-report tool in a heterogeneous sample of children with CP with and without cognitive impairment. METHODS: Participants (n = 167; 47% male; mean age = 9.1 years) had pain assessments completed through caregiver report in clinic before spasticity treatment (for a subgroup, the modified BPI was repeated after procedure). To measure concurrent validity, we obtained pain intensity ratings (Numeric Rating Scale of pain) and pain intensity, duration, and frequency scores (Dalhousie Pain Interview). RESULTS: Modified BPI scores were internally consistent (Cronbach α = 0.96) and correlated significantly with Numeric Rating Scale intensity scores (rs = 0.67, P < 0.001), Dalhousie Pain Interview pain intensity (rs = 0.65, P < 0.001), pain frequency (rs = 0.56, P = 0.02), and pain duration scores (rs = 0.42, P = 0.006). Modified BPI scores also significantly decreased after spasticity treatment (pretest [scored 0-10; 3.27 ± 2.84], posttest [2.27 ± 2.68]; t (26) = 2.14, 95% confidence interval [0.04-1.95], P = 0.04). CONCLUSION: Overall, the modified BPI produced scores with strong internal consistency and that had concurrent validity as a proxy-report tool for children with CP.

Severity of disability in patients with cerebral palsy secondary to symptomatic congenital cytomegalovirus encephalopathy.

PURPOSE: Cytomegalovirus (CMV) is a leading cause of congenital encephalopathy and cerebral palsy (CP). In this study we report the severity of disability in individuals who developed CP secondary to symptomatic congenital CMV encephalopathy. METHODS: The medical records of patients with CP secondary to symptomatic congenital CMV encephalopathy diagnosed from 1995 to 2011 were retrospectively reviewed. Gross Motor Functional Classification Scale (GMFCS) level, language function, and swallowing function were collected. RESULTS: Twenty-three patients were found. Of those 23 patients, 83% (19/23) were at a GMFCS level IV or V, 9% (2/23) each GMFCS level II or III and none (0%) at GMFCS I. Eighteen patients were non-verbal, 3 had minimal to moderate verbal skills and 2 had no verbal impairment. Eighteen patients also had severe dysphagia requiring gastrostomy tube (GT) feedings, and 5 ate orally. There was a strong correlation between the severity of GMFCS and having a gastrostomy tube (p< 0.0006) and GMFCS and verbal skills (p< 0.0023). CONCLUSION: This study shows that patients with CP secondary to symptomatic congenital cytomegalovirus encephalopathy have a very high risk of having severe physical and cognitive disabilities. This information can help healthcare providers and caregivers plan for the potential long-term medical, rehabilitation, and financial needs of this group of patients.