Comparing surgeries to restore upper extremity function in tetraplegia: Impact on function during the perioperative period.

CONTEXT/OBJECTIVE: To assess short-term changes in health outcomes in people with cervical-level spinal cord injury (SCI) who underwent upper extremity (UE) reconstruction via either novel nerve transfer (NT) or traditional tendon transfer (TT) surgery with individuals who did not undergo UE surgical reconstruction. DESIGN: Prospective, comparative cohort pilot study. PARTICIPANTS: 34 participants with cervical SCI met the following inclusion criteria: age 18 or older, greater than 6 months post-injury, and mid-cervical level SCI American Spinal Injury Association Impairment Scale (AIS) A, B or C. SETTING: Two tertiary academic hospitals and their affiliated veterans' hospitals. METHODS: Health outcomes were assessed using two previously validated measures, the Spinal Cord Independence Measure (SCIM) and Short-Form Health Survey (SF-36). Demographic, surgical, and survey data were collected at the initial evaluation and one month postoperatively/post-baseline. RESULTS: 34 participants with cervical SCI were recruited across three cohorts: no surgery (n = 16), NT (n = 10), and TT (n = 8). The TT group had a decline in SCIM and SF-36 scores whereas the NT and no surgery groups experienced little change in independence or health status in the immediate perioperative period. CONCLUSIONS: Surgeons and rehabilitation providers must recognize differences in the perioperative needs of people with cervical SCI who chose to have restorative UE surgery. Future work should focus on further investigation of health outcomes, change in function, and improving preoperative counseling and cross-disciplinary management.

Walking Outcome After Traumatic Paraplegic Spinal Cord Injury: The Function of Which Myotomes Makes a Difference?

BACKGROUND: Accurate prediction of walking function after a traumatic spinal cord injury (SCI) is crucial for an appropriate tailoring and application of therapeutical interventions. Long-term outcome of ambulation is strongly related to residual muscle function acutely after injury and its recovery potential. The identification of the underlying determinants of ambulation, however, remains a challenging task in SCI, a neurological disorder presented with heterogeneous clinical manifestations and recovery trajectories. OBJECTIVES: Stratification of walking function and determination of its most relevant underlying muscle functions based on stratified homogeneous patient subgroups. METHODS: Data from individuals with paraplegic SCI were used to develop a prediction-based stratification model, applying unbiased recursive partitioning conditional inference tree (URP-CTREE). The primary outcome was the 6-minute walk test at 6 months after injury. Standardized neurological assessments ≤15 days after injury were chosen as predictors. Resulting subgroups were incorporated into a subsequent node-specific analysis to attribute the role of individual lower extremity myotomes for the prognosis of walking function. RESULTS: Using URP-CTREE, the study group of 361 SCI patients was divided into 8 homogeneous subgroups. The node specific analysis uncovered that proximal myotomes L2 and L3 were driving factors for the differentiation between walkers and non-walkers. Distal myotomes L4-S1 were revealed to be responsible for the prognostic distinction of indoor and outdoor walkers (with and without aids). CONCLUSION: Stratification of a heterogeneous population with paraplegic SCI into more homogeneous subgroups, combined with the identification of underlying muscle functions prospectively determining the walking outcome, enable potential benefit for application in clinical trials and practice.

Spontaneous Motor Recovery after Cervical Spinal Cord Injury: Issues for Nerve Transfer Surgery Decision Making.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To quantify spontaneous upper extremity motor recovery between 6 and 12 months after spinal cord injury (SCI) to help guide timing of nerve transfer surgery to improve upper limb function in cervical SCI. SETTING: Nineteen European SCI rehabilitation centers. METHODS: Data was extracted from the European Multicenter Study of SCI database for individuals with mid-level cervical SCI (N = 268). Muscle function grades at 6 and 12 months post-SCI were categorized for analysis. RESULTS: From 6 to 12 months after SCI, spontaneous surgically-relevant recovery was limited. Of all limbs (N = 263) with grade 0-2 elbow extension at 6 months, 4% regained grade 4-5 and 11% regained grade 3 muscle function at 12 months. Of all limbs (N = 380) with grade 0-2 finger flexion at 6 months, 3% regained grade 4-5 and 5% regained grade 3 muscle function at 12 months. CONCLUSION: This information supports early (6 month) post-injury surgical consultation and evaluation. With this information, individuals with SCI can more fully engage in preference-based decision-making about surgical intervention versus continued rehabilitation and spontaneous recovery to gain elbow extension and/or hand opening and closing.

Inclusive Trial Designs in Acute Spinal Cord Injuries: Prediction-Based Stratification of Clinical Walking Outcome and Projected Enrolment Frequencies.

BACKGROUND: New therapeutic approaches in neurological disorders are progressing into clinical development. Past failures in translational research have underlined the critical importance of selecting appropriate inclusion criteria and primary outcomes. Narrow inclusion criteria provide sensitivity, but increase trial duration and cost to the point of infeasibility, while broader requirements amplify confounding, increasing the risk of trial failure. This dilemma is perhaps most pronounced in spinal cord injury (SCI), but applies to all neurological disorders with low frequency and/or heterogeneous clinical manifestations. OBJECTIVE: Stratification of homogeneous patient cohorts to enable the design of clinical trials with broad inclusion criteria. METHODS: Prospectively-gathered data from patients with acute cervical SCI were analysed using an unbiased recursive partitioning conditional inference tree (URP-CTREE) approach. Performance in the 6-minute walk test at 6 months after injury was classified based on standardized neurological assessments within the first 15 days of injury. Functional and neurological outcomes were tracked throughout rehabilitation up to 6 months after injury. RESULTS: URP-CTREE identified homogeneous outcome cohorts in a study group of 309 SCI patients. These cohorts were validated by an internal, yet independent, validation group of 172 patients. The study group cohorts identified demonstrated distinct recovery profiles throughout rehabilitation. The baseline characteristics of the analysed groups were compared to a reference group of 477 patients. CONCLUSION: URP-CTREE enables inclusive trial design by revealing the distribution of outcome cohorts, discerning distinct recovery profiles and projecting potential patient enrolment by providing estimates of the relative frequencies of cohorts to improve the design of clinical trials in SCI and beyond.

Evaluation of Functional Independence in Cervical Spinal Cord Injury: Implications for Surgery to Restore Upper Limb Function.

PURPOSE: To help individuals make informed choices regarding the optimal type and timing of restorative surgical treatment for cervical spinal cord injury (SCI), more precise information is needed on their ability to perform activities of daily living. The goal of this work was to describe functional independence achieved by individuals with differing levels of cervical SCI. METHODS: Using the comprehensive European Multicenter Study of Spinal Cord Injury dataset, analysis was undertaken of individuals with traumatic SCI, motor-level C5-C8. Data on feeding, bladder management, and transfers (bed to wheelchair) were compared between individuals with different levels of injury. Subgroup analyses of symmetrical and asymmetrical SCI and between complete and incomplete SCI were performed. The impact of age, sex, and time postinjury on functional independence was ascertained. RESULTS: Data were available for individuals with symmetrical (n = 204) and asymmetrical (n = 95) patterns of SCI. Independence with feeding, urinary function, and transfer ability was increased in individuals with strong finger flexion. Unexpectedly, the presence of strong elbow extension did not uniformly result in the ability to transfer independently. There was no change in any of the analyzed activities between 6 and 12 months postinjury. CONCLUSIONS: People with cervical SCI who gain finger flexion have greater independence with feeding, urinary, and transfer activities. Restoration of finger flexion should be a reconstructive priority for individuals with midcervical-level SCI. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

Adaptive trial designs for spinal cord injury clinical trials directed to the central nervous system.

STUDY DESIGN: Narrative review. PURPOSE: To provide an overview of adaptive trial designs, and describe how adaptive methods can address persistent challenges encountered by randomized controlled trials of people with spinal cord injury (SCI). RESULTS: With few exceptions, adaptive methodologies have not been incorporated into clinical trial designs of people with SCI. Adaptive methods provide an opportunity to address high study costs, slow recruitment, and excessive amount of time needed to carry out the trial. The availability of existing SCI registries are well poised to support modeling and simulation, both of which are used extensively in adaptive trial designs. Eight initiatives for immediate advancement of adaptive methods in SCI were identified. CONCLUSION: Although successfully applied in other fields, adaptive clinical trial designs in SCI clinical trial programs have been narrow in scope and few in number. Immediate application of several adaptive methods offers opportunity to improve efficiency of SCI trials. Concerted effort is needed by all stakeholders to advance adaptive clinical trial design methodology in SCI.

The challenge of recruitment for neurotherapeutic clinical trials in spinal cord injury.

STUDY DESIGN: Narrative review by individuals experienced in the recruitment of participants to neurotherapeutic clinical trials in spinal cord injury (SCI). OBJECTIVES: To identify key problems of recruitment and explore potential approaches to overcoming them. METHODS: Published quantitative experience with recruitment of large-scale, experimental neurotherapeutic clinical studies targeting central nervous system and using primary outcome assessments validated for SCI over the last 3 decades was summarized. Based on this experience, potential approaches to improving recruitment were elicited from the authors. RESULTS: The rate of recruitment has varied between studies, depending on protocol design and other factors, but particularly inclusion/exclusion criteria. The recruitment rate also ranged over an order of magnitude between individual centers in a given study. In older multicenter studies, average recruitment rate was approximately one person per study center per month. More recent trials experienced lower rates of recruitment and potential reasons for this trend were examined. The current roles and potential of various stakeholder organizations in addressing problems of recruitment were explored. In addition, recent developments in methodology may help reduce the number of subjects required for well-powered studies. CONCLUSIONS: Several approaches are emerging to improve clinical trial design, efficacy outcome measures, and quantifiable surrogate markers, all of which should reduce the number of participants required for adequate statistical power. There is a growing sense of cooperation between various stakeholders but more should be done to bring together consumer and provider groups to improve recruitment and the effectiveness and relevance of neurotherapeutic clinical trials.

Correction: Evidence-based scientific exercise guidelines for adults with spinal cord injury: an update and a new guideline.

Authors Victoria L. Goosey-Tolfrey and Karen M. Smith were listed under the incorrect affiliations at the time of publication.

Considerations and recommendations for selection and utilization of upper extremity clinical outcome assessments in human spinal cord injury trials.

STUDY DESIGN: This is a focused review article. OBJECTIVES: This review presents important features of clinical outcomes assessments (COAs) in human spinal cord injury research. Considerations for COAs by trial phase and International Classification of Functioning, Disability and Health are presented as well as strengths and recommendations for upper extremity COAs for research. Clinical trial tools and designs to address recruitment challenges are identified. METHODS: The methods include a summary of topics discussed during a two-day workshop, conceptual discussion of upper extremity COAs and additional focused literature review. RESULTS: COAs must be appropriate to trial phase and particularly in mid-late-phase trials, should reflect recovery vs. compensation, as well as being clinically meaningful. The impact and extent of upper vs. lower motoneuron disease should be considered, as this may affect how an individual may respond to a given therapeutic. For trials with broad inclusion criteria, the content of COAs should cover all severities and levels of SCI. Specific measures to assess upper extremity function as well as more comprehensive COAs are under development. In addition to appropriate use of COAs, methods to increase recruitment, such as adaptive trial designs and prognostic modeling to prospectively stratify heterogeneous populations into appropriate cohorts should be considered. CONCLUSIONS: With an increasing number of clinical trials focusing on improving upper extremity function, it is essential to consider a range of factors when choosing a COA. SPONSORS: Craig H. Neilsen Foundation, Spinal Cord Outcomes Partnership Endeavor.

Evidence-based scientific exercise guidelines for adults with spinal cord injury: an update and a new guideline.

OBJECTIVES: To describe the process and outcomes of using a new evidence base to develop scientific guidelines that specify the type and minimum dose of exercise necessary to improve fitness and cardiometabolic health in adults with spinal cord injury (SCI). SETTING: International. METHODS: Using Appraisal of Guidelines, Research and Evaluation (AGREE) II reporting criteria, steps included (a) determining the guidelines' scope; (b) conducting a systematic review of relevant literature; (c) holding three consensus panel meetings (European, Canadian and International) to formulate the guidelines; (d) obtaining stakeholder feedback; and (e) process evaluation by an AGREE II consultant. Stakeholders were actively involved in steps (c) and (d). RESULTS: For cardiorespiratory fitness and muscle strength benefits, adults with a SCI should engage in at least 20 min of moderate to vigorous intensity aerobic exercise 2 times per week AND 3 sets of strength exercises for each major functioning muscle group, at a moderate to vigorous intensity, 2 times per week (strong recommendation). For cardiometabolic health benefits, adults with a SCI are suggested to engage in at least 30 min of moderate to vigorous intensity aerobic exercise 3 times per week (conditional recommendation). CONCLUSIONS: Through a systematic, rigorous, and participatory process involving international scientists and stakeholders, a new exercise guideline was formulated for cardiometabolic health benefits. A previously published SCI guideline was endorsed for achieving fitness benefits. These guidelines represent an important step toward international harmonization of exercise guidelines for adults with SCI, and a foundation for developing exercise policies and programs for people with SCI around the world.

Autoregressive transitional ordinal model to test for treatment effect in neurological trials with complex endpoints.

BACKGROUND: A number of potential therapeutic approaches for neurological disorders have failed to provide convincing evidence of efficacy, prompting pharmaceutical and health companies to discontinue their involvement in drug development. Limitations in the statistical analysis of complex endpoints have very likely had a negative impact on the translational process. METHODS: We propose a transitional ordinal model with an autoregressive component to overcome previous limitations in the analysis of Upper Extremity Motor Scores, a relevant endpoint in the field of Spinal Cord Injury. Statistical power and clinical interpretation of estimated treatment effects of the proposed model were compared to routinely employed approaches in a large simulation study of two-arm randomized clinical trials. A revisitation of a key historical trial provides further comparison between the different analysis approaches. RESULTS: The proposed model outperformed all other approaches in virtually all simulation settings, achieving on average 14 % higher statistical power than the respective second-best performing approach (range: -1 %, +34 %). Only the transitional model allows treatment effect estimates to be interpreted as conditional odds ratios, providing clear interpretation and visualization. CONCLUSION: The proposed model takes into account the complex ordinal nature of the endpoint under investigation and explicitly accounts for relevant prognostic factors such as lesion level and baseline information. Superior statistical power, combined with clear clinical interpretation of estimated treatment effects and widespread availability in commercial software, are strong arguments for clinicians and trial scientists to adopt, and further extend, the proposed approach.

Bench to bedside: challenges of clinical translation.

Translating a scientific discovery from the laboratory to human application involves a series of challenges. Each requirement must be satisfactorily answered before moving to the next phase. Initially, there are several issues associated with the reproducibility of the original discovery. Subsequently, additional preclinical aspects of safety, formulation, dose, administration route, timing of delivery, and pharmacokinetics must be completed before entering human trials. Central nervous system disorders, such as spinal cord injury (SCI), are heterogeneous. The level and severity of SCI impacts the functional capacity of an individual and their prognosis for recovery. Thus, the selection and stratification of appropriate participants, as well as the choice of an appropriate outcome measure, should be based on prior analysis and modeling of the natural history for both neurological impairment and activities of daily living. A great deal of wisdom can be gathered from historical datasets to assure that a clinical trial program has the best study protocol to clearly detect any potential therapeutic benefit.

Toward Inclusive Trial Protocols in Heterogeneous Neurological Disorders: Prediction-Based Stratification of Participants With Incomplete Cervical Spinal Cord Injury.

BACKGROUND: Several novel drug- and cell-based potential therapies for spinal cord injury (SCI) have either been applied or will be considered for future clinical trials. Limitations on the number of eligible patients require trials be undertaken in a highly efficient and effective manner. However, this is particularly challenging when people living with incomplete SCI (iSCI) represent a very heterogeneous population in terms of recovery patterns and can improve spontaneously over the first year after injury. OBJECTIVE: The current study addresses 2 requirements for designing SCI trials: first, enrollment of as many eligible participants as possible; second, refined stratification of participants into homogeneous cohorts from a heterogeneous iSCI population. METHODS: This is a retrospective, longitudinal analysis of prospectively collected SCI data from the European Multicenter study about Spinal Cord Injury (EMSCI). We applied conditional inference trees to provide a prediction-based stratification algorithm that could be used to generate decision rules for the appropriate inclusion of iSCI participants to a trial. RESULTS: Based on baseline clinical assessments and a defined subsequent clinical endpoint, conditional inference trees partitioned iSCI participants into more homogeneous groups with regard to the illustrative endpoint, upper extremity motor score. Assuming a continuous endpoint, the conditional inference tree was validated both internally as well as externally, providing stable and generalizable results. CONCLUSION: The application of conditional inference trees is feasible for iSCI participants and provides easily implementable, prediction-based decision rules for inclusion and stratification. This algorithm could be utilized to model various trial endpoints and outcome thresholds.

Identifying Homogeneous Subgroups in Neurological Disorders: Unbiased Recursive Partitioning in Cervical Complete Spinal Cord Injury.

Background The reliable stratification of homogeneous subgroups and the prediction of future clinical outcomes within heterogeneous neurological disorders is a particularly challenging task. Nonetheless, it is essential for the implementation of targeted care and effective therapeutic interventions. Objective This study was designed to assess the value of a recently developed regression tool from the family of unbiased recursive partitioning methods in comparison to established statistical approaches (eg, linear and logistic regression) for predicting clinical endpoints and for prospective patients' stratification for clinical trials. Methods A retrospective, longitudinal analysis of prospectively collected neurological data from the European Multicenter study about Spinal Cord Injury (EMSCI) network was undertaken on C4-C6 cervical sensorimotor complete subjects. Predictors were based on a broad set of early (<2 weeks) clinical assessments. Endpoints were based on later clinical examinations of upper extremity motor scores and recovery of motor levels, at 6 and 12 months, respectively. Prediction accuracy for each statistical analysis was quantified by resampling techniques. Results For all settings, overlapping confidence intervals indicated similar prediction accuracy of unbiased recursive partitioning to established statistical approaches. In addition, unbiased recursive partitioning provided a direct way of identification of more homogeneous subgroups. The partitioning is carried out in a data-driven manner, independently from a priori decisions or predefined thresholds. Conclusion Unbiased recursive partitioning techniques may improve prediction of future clinical endpoints and the planning of future SCI clinical trials by providing easily implementable, data-driven rationales for early patient stratification based on simple decision rules and clinical read-outs.

Differences in spinothalamic function of cervical and thoracic dermatomes: insights using contact heat evoked potentials.

INTRODUCTION: After spinal cord injury, contact heat evoked potentials (CHEPs) may represent a means to refine the clinical assessment of sensory function from each spinal cord segment by quantifying nociception, including conduction along the spinothalamic tract. METHODS: The influence of stimulation site (i.e., dermatomes) on CHEPs and thermal thresholds in 19 healthy subjects (mean age, 45.2 ± 18.3 years) divided into 2 age classes (younger subjects, n = 10; mean age, 28.8 ± 5.2 years; older subjects, n = 9; mean age, 63.4 ± 3.4 years) at 5 different dermatomes (C4, C5, C6, C8, and T4) was assessed. RESULTS: In terms of distance from the body midline (i.e., spinal cord entry), there was a reduction in CHEP amplitudes from proximal (C4 and T4) to distal (C6 and C8) dermatomes with a corresponding reduction in nociceptive perception (i.e., pain threshold and rating). Within primary and secondary cortical sensory areas, including areas associated with affective noxious processing, the cortical source density analysis showed a similar current density distribution between C4 and C8 dermatomes but consistent higher current densities for C4. CONCLUSIONS: The study supports CHEPs as a feasible tool for assessing discrete dermatomes corresponding to spinal cord segments. The results suggest that the proximodistal pattern in the intensity of perceived pain and CHEP amplitudes is likely attributable to the distribution of heat nociceptors and the increase in conduction distance from proximal to distal dermatomes. The present findings emphasize on the importance that if patients are assessed segment by segment, the underlying topographical differences need to be accounted for.

Improving the acquisition of nociceptive evoked potentials without causing more pain.

Following nociceptive heat or laser stimulation, an early contralateral and later vertex potential can be recorded. Although more indicative of the nociceptive input, the acquisition of the contralateral N1 after contact heat stimulation (contact heat-evoked potentials [CHEPs]) remains difficult. An advantage of contact heat is that the baseline skin temperature preceding peak stimulation can be controlled. Increasing the baseline temperature may represent a novel strategy to improve the acquisition of CHEPs without resulting in more subjective pain to stimulation. A study was undertaken in 23 healthy subjects to examine the effects of increasing the baseline temperature but not the perceived intensity of contact heat stimulation. A combined standard averaging and single-trial analysis was performed to disclose how changes in averaged waveforms related to latency jitter and individual trial amplitudes. By increasing the baseline temperature, the acquisition of N1 was improved among subjects with a low-amplitude response (greater than -4µV) following 35°C baseline temperature stimulation (P<.05). Based on standard averaging, N2/P2 amplitudes were also significantly increased with and without an accompanying change in the rating of perceived pain when the baseline temperature was increased (P<.05). In contrast, automated single-trial averaging revealed no significant difference in N2 amplitude when the baseline temperature was increased to 42°C and the peak temperature reduced. These findings suggest that 2 mechanisms underlie the improved acquisition of CHEPs: increased synchronization of afferent volley, yielding larger-amplitude evoked potentials in response to the same rating of intensity; and reduced inter-trial variability.

Outcome Measures for Acute/Subacute Cervical Sensorimotor Complete (AIS-A) Spinal Cord Injury During a Phase 2 Clinical Trial.

Effective treatment after cervical spinal cord injury (SCI) is imperative as so many activities of daily living (ADLs) are dependent on functional recovery of arm and hand actions. We focus on defining and comparing neurological and functional endpoints that might be used during acute or subacute Phase 2 clinical trials involving subjects with cervical sensorimotor complete SCI (ASIA Impairment Scale [AIS-A]). For the purposes of this review, the trial would examine the effects of a pharmaceutical small molecule, drug, biologic, or cell transplant on spinal tissue. Thus, neurological improvement is the intended consequence and is most directly measured by assessing neurological impairment (eg, motor aspects of the International Standards Neurological Classification of Spinal Cord Injury [ISNCSCI]). However, changes in neurological function, even if statistically significant, may not be associated with a clear functional impact (ie, a meaningful improvement in individual activity, such as independent self-care ADLs). The challenge is to measure improvement as precisely as possible (change in impairment), but to define a clinically meaningful response in the context of functional improvement (impact on activity limitations). The principal comparisons focused on elements of the ISNCSCI assessment, including upper extremity motor score and motor level. Personal activity capabilities were also examined at various time points. The data suggest that an improvement of 2 or more motor levels after cervical sensorimotor complete SCI may be a clinically meaningful endpoint threshold that could be used for acute and subacute Phase 2 trials with subjects having sensorimotor complete cervical SCI.

Relationship between motor recovery and independence after sensorimotor-complete cervical spinal cord injury.

BACKGROUND: For therapeutics directed to the injured spinal cord, a change in neurological impairment has been proposed as a relevant acute clinical study end point. However, changes in neurological function, even if statistically significant, may not be associated with a functional impact, such as a meaningful improvement in items within the self-care subscore of the Spinal Cord Independence Measure (SCIM). OBJECTIVE: The authors examined the functional significance associated with spontaneously recovering upper-extremity motor function after sensorimotor-complete cervical spinal cord injury (SCI). METHODS: Using the European Multi-center Study about Spinal Cord Injury (EMSCI) data set, a retrospective analysis was undertaken of individuals with cervical sensorimotor-complete SCI (initial motor level, C4-C7). Specifically, changes in upper-extremity motor score (UEMS), motor level, and SCIM (total and self-care subscore) were assessed between approximately 1 and 48 weeks after injury (n = 74). RESULTS: The initial motor level did not significantly influence the total UEMS recovered or number of motor levels recovered. SCIM self-care subscore recovery was significantly greater for those individuals regaining 2 motor levels compared with those recovering only 1 or no motor levels. However, the recovery in the SCIM self-care subscore was not significantly different between individuals recovering only 1 motor level and those individuals who showed no motor-level improvement. CONCLUSIONS: A 2 motor-level improvement indicates a clinically meaningful change and might be considered a primary outcome in acute and subacute interventional trials enrolling individuals with cervical sensorimotor-complete SCI.

Sacral sparing in SCI: beyond the S4-S5 and anorectal examination.

BACKGROUND CONTEXT: Sensory and/or motor function sparing, including the S4-S5 spinal cord segment, is central to classifying neurologic impairment after spinal cord injury (SCI) using the American Spinal Injury Association Impairment Scale (AIS) grades within the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). Within the ISNCSCI protocol, which is essential for both clinical and research purposes, assessing sacral sparing requires an anorectal and S4-S5 examination. However, in situations where these data are incomplete, the relationships between anorectal/S4-S5 examinations and functional preservation at more rostral sacral segments may be useful. PURPOSE: To evaluate whether slightly more rostral sensory and motor outcomes of the ISNCSCI can accurately predict caudal sacral sparing (S4-S5 dermatome sensation, "deep pressure" anal sensation [AS], and voluntary anal contraction [AC]). STUDY DESIGN: Retrospective analysis of the European Multicenter Study about Spinal Cord Injury database. PATIENT SAMPLE: One thousand four hundred sixty-seven AIS-A, AIS-B, and AIS-C subjects. OUTCOME MEASURES: International Standards for Neurological Classification of Spinal Cord Injury examinations. METHODS: The value of six factors (sensory preservation at S1, S2, and S3; motor preservation at S1; motor function at more than three segments below the motor level; and sensory function at more than three segments below the neurologic level) for predicting ISNCSCI sacral sparing measures (AS, S4-S5 dermatome sensation, AC) was evaluated. Combinations of the most promising factors were then evaluated for their ability to accurately predict the AIS grade. RESULTS: Preserved sensation at the first sacral segment (S1S) provided good prediction (90.5%) of caudal sacral sensory sparing (ie, AS or S4-S5 sensation). Voluntary anal contraction was accurately predicted by preserved motor function within the first sacral segment (S1M) in 85.4% of cases. The alternate classification schemes evaluated for accurately predicting the AIS classification grade were S1S+S1M and S1S+motor preservation more than three segments below the motor level. The ability of these schemes to accurately predict AIS grades was stable over time but varied with the rostrocaudal level of spinal injury. For the initial baseline examination, the alternate classification schemes were accurate in ~95% of cases for T2-T9 SCI, with slightly lower accuracy for cervical SCI (~80%). CONCLUSIONS: There are close relationships between functional sparing at different sacral segments. These relationships can be used to estimate AIS grades when complete information about the anorectal and S4-S5 examination is not available. The accuracy of the classification remains stable over time, while the increased variability in lower levels of SCI, that is, lumbar injuries, emphasizes the importance of careful sacral examinations. The highly reliable predictive values of S1-S3 segments can complement conclusions from anorectal examinations if the latter are considered to be confounded or incomplete.