The long-term effects of aggressive spasticity reducing treatment, including selective dorsal rhizotomy, on joint kinematic outcomes of persons with cerebral palsy.

BACKGROUND: Selective dorsal rhizotomy (SDR) creates a large and permanent reduction of spasticity for children with cerebral palsy (CP). Previous SDR outcomes studies have generally lacked appropriate control groups, had limited sample sizes, or reported short-term follow-up, limiting evidence for improvement in long-term gait function. RESEARCH QUESTION: Does aggressive spasticity management for individuals with CP improve long-term gait kinematics (discrete joint kinematics) compared to a control group of individuals with CP with minimal spasticity management? METHODS: This study was a secondary analysis - focused on joint-level kinematics - of a previous study evaluating the long-term outcomes of SDR. Two groups of participants were recruited based on a retrospectively completed baseline clinical gait study. One group received aggressive spasticity treatment including a selective dorsal rhizotomy (Yes-SDR group), while the other group had minimal spasticity management (No-SDR group). Both groups had orthopedic surgery treatment. Groups were matched on baseline spasticity. All participants prospectively returned for a follow-up gait study in young adulthood (greater than 21 years of age and at least 10 years after baseline). Change scores in discrete kinematic variables from baseline to follow-up were assessed using a linear model that included treatment arm (Yes-SDR, No-SDR), baseline age, and baseline kinematic value. For treatment arm, 5° and 5 Gait Deviation Index points were selected as thresholds to be considered a meaningful difference between treatment groups. RESULTS: At follow-up, there were no meaningful differences in pelvis, hip, knee, or ankle kinematic variable changes between treatment arms. Max knee flexion - swing showed a moderate treatment effect for Yes-SDR, although it did not reach the defined threshold. SIGNIFICANCE: Aggressive spasticity treatment does not result in meaningful differences in gait kinematics for persons with cerebral palsy in young adulthood compared to minimal spasticity management with both groups having orthopedic surgery.

Long-term effects of spasticity treatment, including selective dorsal rhizotomy, for individuals with cerebral palsy.

AIM: To understand the long-term effects of comprehensive spasticity treatment, including selective dorsal rhizotomy (SDR), on individuals with spastic cerebral palsy. METHOD: This was a pre-registered, multicenter, retrospectively matched cohort study. Children were matched on age range and spasticity at baseline. Children at one center underwent spasticity treatment including SDR (Yes-SDR, n=35) and antispastic injections. Children at two other centers had no SDR (No-SDR, n=40 total) and limited antispastic injections. All underwent subsequent orthopedic treatment. Participants returned for comprehensive long-term assessment (age ≥21y, follow-up ≥10y). Assessment included spasticity, contracture, bony alignment, strength, gait, walking energy, function, pain, stiffness, participation, and quality of life. RESULTS: Spasticity was effectively reduced at long-term assessment in the Yes-SDR group and was unchanged in the No-SDR group. There were no meaningful differences between the groups in any measure except the Gait Deviation Index (Yes-SDR + 11 vs No-SDR + 5) and walking speed (Yes-SDR unchanged, No-SDR declined 25%). The Yes-SDR group underwent more subsequent orthopedic surgery (11.9 vs 9.7 per individual) and antispastic injections to the lower limbs (14.4 vs <3, by design). INTERPRETATION: Untreated spasticity does not cause meaningful impairments in young adulthood at the level of pathophysiology, function, or quality of life.

Comparing short-term outcomes between conus medullaris and cauda equina surgical techniques of selective dorsal rhizotomy.

AIM: To compare short-term outcomes between conus medullaris (conus) and cauda equina (cauda) selective dorsal rhizotomy (SDR) techniques in children with spastic cerebral palsy. METHOD: This was a retrospective review of SDR at a single center from 2013 to 2017. Gait and functional outcome measures were assessed at no more than 18 months pre-SDR (baseline) and 8 to 36 months post-SDR (follow-up). Transient complications during inpatient stay were quantified. RESULTS: In total, 21 and 59 children underwent conus and cauda SDR respectively. Ashworth Scale scores were nearly normalized at follow-up. Most physical examination and functional measures exhibited similar baseline to follow-up responses for both groups. From baseline to follow-up, sagittal plane knee kinematics for both groups significantly improved (p<0.01) by 11° at initial contact, 9° to 10° in stance phase, and 4° in swing phase. Sagittal plane ankle kinematics improved more for the cauda group than the conus group in both stance phase (10° vs 2°, p<0.01) and swing phase (13° vs 3°, p<0.01). Post-surgical complications were similar between groups. INTERPRETATION: Conus and cauda SDR techniques resulted in similar short-term outcomes except in ankle kinematics at follow-up. The cauda group exhibited a large improvement towards dorsiflexion, while there was residual equinus in the conus group despite Ashworth Scale scores normalizing equally in both groups. WHAT THIS PAPER ADDS: Conus and cauda selective dorsal rhizotomy (SDR) resulted in mostly similar short-term gait and functional outcomes. Conus SDR resulted in residual equinus dynamically, despite normalized spasticity measures. Post-surgical complications were mostly similar between SDR techniques.

Comparing the effects of two spasticity management strategies on the long-term outcomes of individuals with bilateral spastic cerebral palsy: a multicentre cohort study protocol.

INTRODUCTION: Spasticity is one of the primary pathologies associated with cerebral palsy (CP), yet no definitive evidence exists to guide the appropriate level of spasticity management for an individual. Spasticity management strategies often differ by center. On one end of this strategy spectrum is a highly-interventional approach, characterized by treatments such as a selective dorsal rhizotomy (SDR), intrathecal baclofen pump (ITB), and anti-spasticity injections and medications. On the other end of the spectrum is a less interventional approach, involving minimal use of these treatments, and no SDR. METHODS AND ANALYSIS: A retrospectively-matched, multi-center study protocol is described that comprehensively compares the long-term outcomes of a highly-interventional versus a minimally-interventional spasticity management strategy. We will analyze two groups of adults with spastic bilateral CP (≥21 years). In one group are individuals who underwent an SDR between the ages of 4 and 10 years, along with ongoing spasticity management during childhood and adolescence. In the other group are individuals who received minimal spasticity management and did not undergo an SDR. Individuals with prolonged use of an intrathecal baclofen (ITB) pump will be excluded. The two groups will be matched for spasticity and other important clinical characteristics at baseline. This study design improves on many of the limitations found in the existing outcome literature. ETHICS AND DISSEMINATION: This study received necessary approval from the University of Minnesota and Western Institutional Review Boards. Results will be disseminated via peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT03789786.

Repeatability of electromyography recordings and muscle synergies during gait among children with cerebral palsy.

BACKGROUND: Clinical gait analysis is commonly used in the evaluation and treatment of children with cerebral palsy (CP). While the repeatability of kinematic and kinetic measures of gait has previously been evaluated, the repeatability of electromyography (EMG) recordings or measures calculated from EMG data, such as muscle synergies, remains unclear for this population. RESEARCH QUESTION: Are EMG recordings and muscle synergies from clinical gait analysis repeatable between visits for children with CP? METHODS: We recruited 20 children with bilateral CP who had been referred for clinical gait analysis. The children completed two visits less than six weeks apart with EMG data collected bilaterally from five muscles (rectus femoris, medial hamstrings, vastus lateralis, anterior tibialis, and medial gastrocnemius). Variance ratio and cosine similarity were used to evaluate repeatability of EMG waveforms between visits. Nonnegative matrix factorization was used to calculate synergies from EMG data at each visit to compare synergy weights and activations. RESULTS & SIGNIFICANCE: The inter-visit variance ratios of EMG data for children with CP were similar to previously reported results for typically-developing children and unimpaired adults (range: 0.39 for vastus lateralis to 0.66 for rectus femoris). The average cosine similarity of the EMG waveforms between visits was greater than 0.9 for all muscles, while synergy weights and activations also had high similarity - greater than 0.8 and 0.9 between visits, respectively. These results demonstrate that EMG repeatability between visits during clinical gait analysis for children with CP is similar to unimpaired individuals. These results provide a baseline for evaluating whether observed changes in EMG recordings between visits reflect real changes in muscle activity or are within the range of inter-visit variability.

ESMAC BEST PAPER 2017: Using machine learning to overcome challenges in GMFCS level assignment.

We used the random forest classifier to predict Gross Motor Function Classification System (GMFCS) levels I-IV from patient reported abilities recorded on the Gillette Functional Assessment Questionnaire (FAQ). The classifier exhibited outstanding accuracy across GMFCS levels I-IV, with 83%-91% true positive rate (TPR), area under the receiver operation characteristic (ROC) curve greater than 0.96 for all levels, and misclassification by more than one level only occurring 1.2% of the time. This new approach to GMFCS level assignment overcomes several difficulties with the current method: (i) it is based on a broad spectrum of functional abilities, (ii) it resolves functional ability profiles that conflict with existing GMFCS level definitions, (iii) it is based entirely on self-reported abilities, and (iv) it removes complex age dependence. Further work is needed to examine inter-center differences in classifier performance-which would most likely reflect interpretive differences in GMFCS level definitions between centers.

Long-Term Outcomes of Distal Femoral Extension Osteotomy and Patellar Tendon Advancement in Individuals with Cerebral Palsy.

BACKGROUND: We examined long-term outcomes across the domains of the International Classification of Functioning, Disability and Health for 2 groups of participants with cerebral palsy who demonstrated crouch gait at clinical gait analysis. One group underwent a distal femoral extension osteotomy with patellar tendon advancement (DFEO + PTA). The other group received other treatments (non-DFEO + PTA). METHODS: Fifty-one participants returned for a long-term gait analysis, physical examination, energy consumption test, knee radiographs, and questionnaires (median, 13 years post-DFEO + PTA or post-baseline [range, 8 to 21 years]). A subset of participants in the DFEO + PTA group also had a short-term analysis (9 to 24 months postoperatively). RESULTS: Participants were reasonably well-matched at baseline, although the DFEO + PTA group demonstrated greater crouch: minimum knee flexion, a median of 37° (width of the interquartile range, 12°) compared with 27° (9°); and knee flexion contracture, a median of 15° (10°) compared with 10° (5°). The gait deviation index (GDI) and sagittal plane knee kinematics were most improved at short term for the DFEO + PTA participants, with a subsequent slight decline at long-term analysis. Fewer DFEO + PTA participants were in crouch at long term (37% compared with 65%). At the long-term assessment, group scores for function, mobility, participation, quality of life, and most pain questionnaires were similar. Knee pain and osteoarthritis ratings did not differ between the groups. CONCLUSIONS: At long-term analysis, DFEO + PTA improves stance phase knee extension and knee flexion contracture compared with conventional treatment, but these benefits do not translate to improved activity, participation, or knee pain in early adulthood. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Evidence of knee extensor dysfunction during sit-to-stand following distal femoral extension osteotomy and patellar tendon advancement in young adults with cerebral palsy: A pilot study.

A distal femoral extension osteotomy with patellar tendon advancement (DFEO+PTA) is a common treatment for individuals with cerebral palsy (CP) who walk in crouch. Musculoskeletal modeling suggests that the typical patella baja position post-DFEO+PTA may limit one's abilities to perform sit-to-stand (STS) tasks; however, STS function has not been assessed. Our purpose was to compare how well individuals who received a DFEO+PTA can perform a 5-times STS test (FTSST) eight or more years after surgery compared to their peers who did not receive a DFEO+PTA (non-DFEO+PTA group). Twenty-one participants completed the task (12 DFEO+PTA, 9 non-DFEO+PTA). Three-dimensional kinematics and kinetics were captured. Kinetics were non-dimensionalized to facilitate group comparisons. Non-DFEO+PTA participants performed the FTSST moderately faster than the DFEO+PTA group (median(IQR), 14.6(9.3) seconds vs. 20.3(10.1) seconds, non-parametric effect size É£=0.97, p=0.241). Peak negative knee power was larger for the non-DFEO+PTA group (Mean±SD, -0.063±0.025 vs. -0.048± 0.020, Cohen's d=0.66, p=0.165). A similar but weaker trend was observed for negative hip power (median(IQR) -0.120(0.066) vs. -0.105(0.044), É£=0.43, p=0.671). Both groups used their hips approximately twice as much as their knees to perform the task. The functional deficit among DFEO+PTA participants may be due to patella baja decreasing the knee extensor moment arm, which concurs with the modeling prediction. The group differences may also be due to the non-DFEO+PTA group being slightly higher functioning. Future research is warranted to determine if optimizing patella position during a DFEO+PTA may improve unaided STS function without compromising gait improvements.

Long-term outcomes after selective dorsal rhizotomy: a retrospective matched cohort study.

AIM: To examine long-term outcomes of selective dorsal rhizotomy (SDR) 10 to 17 years after surgery. METHOD: Participants who underwent SDR had spastic diplegic cerebral palsy (CP), completed baseline gait analysis, and were 16 to 25 years old at follow-up. Non-SDR participants (i.e. controls) were matched on important clinical parameters at baseline but did not undergo SDR. All study participants completed six surveys assessing pain, quality of life, participation, function, and mobility. Treatment history for lower extremity surgery and antispasticity injections was tabulated. A subset of each study group returned for three-dimensional gait analysis, including kinematics, metabolic energy cost, and physical examination. Gait Deviation Index (GDI) was calculated to measure gait quality. RESULTS: The study cohort had 24 participants with SDR and 11 without SDR. Of these, 13 patients with SDR (five males, eight females; median [IQR] age 17y 2mo [16y 8mo-17y 9mo]) and eight without SDR (three males, five females; median [IQR] age 19y 2mo [17y 3mo-21y 11mo]) completed baseline and follow-up gait analysis. Spasticity significantly decreased in those with SDR (p<0.05). Gait Deviation Index improved more in participants without SDR than those with SDR (Δnon-SDR =12.8 vs ΔSDR =9.1; p=0.01). Compared with the SDR group, participants without SDR underwent significantly more subsequent interventions (p<0.05). INTERPRETATION: Patients in both the SDR and non-SDR groups showed improved gait quality more than 10 years after surgery. Participants without SDR had a larger improvement in gait pathology but underwent significantly more intervention. There were no differences between groups in survey measures. These results suggest differing treatment courses provide similar outcomes into early adulthood. WHAT THIS PAPER ADDS: Selective dorsal rhizotomy (SDR) and non-SDR groups had significant improvement in gait pathology over time. The non-SDR group had significantly better gait compared with the SDR group at follow-up. The groups had similar levels of energy cost, pain, and quality of life. Non-SDR participants underwent significantly more orthopaedic surgery and antispasticity injections than SDR participants. Use of a clinically similar control group highlights that different treatment courses may result in similar outcomes into young adulthood.

Ambulatory children with cerebral palsy do not exhibit unhealthy weight gain following selective dorsal rhizotomy.

AIM: The aim of this study was to retrospectively analyze changes in age- and sex-adjusted body mass index (BMI) in ambulatory children with cerebral palsy (CP) who underwent selective dorsal rhizotomy (SDR). METHOD: Raw BMI, age- and sex-adjusted BMI z-scores, weight classification status, energy expenditure, and ambulation function were calculated before and after SDR at multiple post-SDR time points: 6 to <24 months, 24 to <48 months, 48 to <72, and 72 to <96 months. Linear mixed models were used to analyze changes in raw BMI, BMI z-scores, energy expenditure, and ambulation function. RESULTS: Pre- and post-surgical data were available for 363 children diagnosed with CP who underwent SDR (219 males, 144 females; mean age 6y [SD 2y 1mo]; mean BMI z-score 0.09 [SD 1.21]). Data from additional post-surgical time points were collected on subsamples. Although raw BMI significantly increased (p<0.01), these increases were consistent with anticipated growth. BMI z-scores did not significantly change over the 10-year study period. INTERPRETATION: Concerns of unhealthy weight gain following SDR are not supported by this study. Further work examining possible risk factors for BMI increase following SDR, as well as examining disparities in existing criteria for patient selection, is merited.

Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia.

Tumor-associated immune suppression can lead to defective T cell-mediated antitumor immunity. Here, we identified a unique phenotype of exhausted T cells in mice with advanced acute myelogenous leukemia (AML). This phenotype is characterized by the coexpression of Tim-3 and PD-1 on CD8(+) T cells in the liver, the major first site of AML metastases. PD-1 and Tim-3 coexpression increased during AML progression. PD-1(+)Tim-3(+) CD8(+) T cells were deficient in their ability to produce IFN-γ, TNF-α, and IL-2 in response to PD-1 ligand (PDL1) and Tim-3 ligand (galectin-9) expressing AML cells. PD-1 knockout (KO), which were partially resistant to AML challenge, up-regulated Tim-3 during AML progression and such Tim-3(+)PD-1- KO CD8(+) T cells had reduced cytokine production. Galectin-9 KO mice were more resistant to AML, which was associated with reduced T-regulatory cell accumulation and a modest induction of PD-1 and Tim-3 expression on CD8(+) T cells. Whereas blocking the PD-1/PDL1 or Tim-3/galectin-9 pathway alone was insufficient to rescue mice from AML lethality, an additive effect was seen in reducing-albeit not eliminating-both tumor burden and lethality when both pathways were blocked. Therefore, combined PD-1/PDL1 and Tim-3/galectin-9 blockade may be beneficial in preventing CD8(+) T-cell exhaustion in patients with hematologic malignancies such as advanced AML.

Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia.

Tumor-induced immune defects can weaken host immune response and permit tumor cell growth. In a systemic model of murine acute myeloid leukemia (AML), tumor progression resulted in increased regulatory T cells (Treg) and elevation of program death-1 (PD-1) expression on CD8(+) cytotoxic T cells (CTLs) at the tumor site. PD-1 knockout mice were more resistant to AML despite the presence of similar percentage of Tregs compared with wild type. In vitro, intact Treg suppression of CD8(+) T-cell responses was dependent on PD-1 expression by T cells and Tregs and PD-L1 expression by antigen-presenting cells. In vivo, the function of adoptively transferred AML-reactive CTLs was reduced by AML-associated Tregs. Anti-PD-L1 monoclonal antibody treatment increased the proliferation and function of CTLs at tumor sites, reduced AML tumor burden, and resulted in long-term survivors. Treg depletion followed by PD-1/PD-L1 blockade showed superior efficacy for eradication of established AML. These data demonstrated that interaction between PD-1 and PD-L1 can facilitate Treg-induced suppression of T-effector cells and dampen the antitumor immune response. PD-1/PD-L1 blockade coupled with Treg depletion represents an important new approach that can be readily translated into the clinic to improve the therapeutic efficacy of adoptive AML-reactive CTLs in advanced AML disease.

Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia.

Tumor-induced immune suppression can permit tumor cells to escape host immune resistance. To elucidate host factors contributing to the poor response of adoptively transferred tumor-reactive cytotoxic T lymphocytes (CTLs), we used a systemic model of murine acute myeloid leukemia (AML). AML progression resulted in a progressive regulatory T-cell (Treg) accumulation in disease sites. The adoptive transfer of in vitro-generated, potently lytic anti-AML-reactive CTLs failed to reduce disease burden or extend survival. Compared with non-AML-bearing hosts, transferred CTLs had reduced proliferation in AML sites of metastases. Treg depletion by a brief course of interleukin-2 diphtheria toxin (IL-2DT) transiently reduced AML disease burden but did not permit long-term survival. In contrast, IL-2DT prevented anti-AML CTL hypoproliferation, increased the number of transferred CTLs at AML disease sites, reduced AML tumor burden, and resulted in long-term survivors that sustained an anti-AML memory response. These data demonstrated that Tregs present at AML disease sites suppress adoptively transferred CTL proliferation, limiting their in vivo expansion, and Treg depletion before CTL transfer can result in therapeutic efficacy in settings of substantial pre-existing tumor burden in which antitumor reactive CTL infusion alone has proven ineffective.