Restorative Treatments for Cervical Spinal Cord Injury, a Narrative Review.

STUDY DESIGN: A narrative review. OBJECTIVE: To summarize relevant data from representative studies investigating upper limb restorative therapies for cervical spinal cord injury. SUMMARY OF BACKGROUND DATA: Cervical spinal cord injury (SCI) is a debilitating condition resulting in tetraplegia, lifelong disability, and reduced quality of life. Given the dependence of all activities on hand function, patients with tetraplegia rank regaining hand function as one of their highest priorities. Recovery from cervical SCI is heterogeneous and often incomplete; currently, various novel therapies are under investigation to improve neurological function and eventually better quality of life in patients with tetraplegia. METHODS: In this article, a narrative literature review was performed to identify treatment options targeting the restoration of function in patients with cervical SCI. Studies were included from available literature based on the availability of clinical data and whether they are applicable to restoration of arm and hand function in patients with cervical SCI. RESULTS: We describe relevant studies including indications and outcomes with a focus on arm and hand function. Different treatment modalities described include nerve transfers, tendon transfers, spinal cord stimulation, functional electrical stimulation, non-invasive brain stimulation, brain-machine interfaces and neuroprosthetics, stem cell therapy, and immunotherapy. As the authors' institution leads one of the largest clinical trials on nerve transfers for cervical SCI, we also describe how patients undergoing nerve transfers are managed and followed at our center. CONCLUSIONS: While complete recovery from cervical spinal cord injury may not be possible, novel therapies aimed at the restoration of upper limb motor function have made significant progress toward the realization of complete recovery.

Impact of Upper Limb Motor Recovery on Functional Independence After Traumatic Low Cervical Spinal Cord Injury.

Cervical spinal cord injury (SCI) causes devastating loss of upper limb function and independence. Restoration of upper limb function can have a profound impact on independence and quality of life. In low-cervical SCI (level C5-C8), upper limb function can be restored via reinnervation strategies such as nerve transfer surgery. The translation of recovered upper limb motor function into functional independence in activities of daily living (ADLs), however, remains unknown in low cervical SCI (i.e., tetraplegia). The objective of this study was to evaluate the association of patterns in upper limb motor recovery with functional independence in ADLs. This will then inform prioritization of reinnervation strategies focused to maximize function in patients with tetraplegia. This retrospective study performed a secondary analysis of patients with low cervical (C5-C8) enrolled in the SCI Model Systems (SCIMS) database. Baseline neurological examinations and their association with functional independence in major ADLs-i.e., eating, bladder management, and transfers (bed/wheelchair/chair)-were evaluated. Motor functional recovery was defined as achieving motor strength, in modified research council (MRC) grade, of ≥ 3 /5 at one year from ≤ 2/5 at baseline. The association of motor function recovery with functional independence at one-year follow-up was compared in patients with recovered elbow flexion (C5), wrist extension (C6), elbow extension (C7), and finger flexion (C8). A multi-variable logistic regression analysis, adjusting for known factors influencing recovery after SCI, was performed to evaluate the impact of motor function at one year on a composite outcome of functional independence in major ADLs. Composite outcome was defined as functional independence measure score of 6 or higher (complete independence) in at least two domains among eating, bladder management, and transfers. Between 1992 and 2016, 1090 patients with low cervical SCI and complete neurological/functional measures were included. At baseline, 67% of patients had complete SCI and 33% had incomplete SCI. The majority of patients were dependent in eating, bladder management, and transfers. At one-year follow-up, the largest proportion of patients who recovered motor function in finger flexion (C8) and elbow extension (C7) gained independence in eating, bladder management, and transfers. In multi-variable analysis, patients who had recovered finger flexion (C8) or elbow extension (C7) had higher odds of gaining independence in a composite of major ADLs (odds ratio [OR] = 3.13 and OR = 2.87, respectively, p < 0.001). Age 60 years (OR = 0.44, p = 0.01), and complete SCI (OR = 0.43, p = 0.002) were associated with reduced odds of gaining independence in ADLs. After cervical SCI, finger flexion (C8) and elbow extension (C7) recovery translate into greater independence in eating, bladder management, and transfers. These results can be used to design individualized reinnervation plans to reanimate upper limb function and maximize independence in patients with low cervical SCI.

Cervical spinal cord compression from subdural hematoma caused by traumatic nerve root avulsion: illustrative case.

BACKGROUND: Posttraumatic intradural hematomas of the cervical spine are rare findings that may yield significant neurological deficits if they compress the spinal cord. These compressive hematomas require prompt surgical evacuation. In certain instances, intradural hematomas may form from avulsion of cervical nerve roots. OBSERVATIONS: The authors present the case of a 29-year-old male who presented with right upper-extremity weakness in the setting of polytrauma after a motor vehicle accident. He had no cervical fractures but subsequently developed right lower-extremity weakness. Magnetic resonance imaging (MRI) demonstrated a compressive hematoma of the cervical spine that was initially read as an epidural hematoma. However, intraoperatively, it was found to be a subdural hematoma, eccentric to the right, stemming from an avulsion of the right C6 nerve root. LESSONS: Posttraumatic cervical subdural hematomas require rapid surgical evacuation if neurological deficits are present. The source of the hematoma may be an avulsed nerve root, and the associated deficits may be unilateral if the hematoma is eccentric to one side. Surgeons should be prepared for the possibility of an intradural hematoma even in instances in which MRI appears consistent with an epidural hematoma.

An updated management algorithm for incorporating minimally invasive techniques to treat thoracolumbar trauma.

OBJECTIVE: Minimally invasive surgery (MIS) techniques can effectively stabilize and decompress many thoracolumbar injuries with decreased morbidity and tissue destruction compared with open approaches. Nonetheless, there is limited direction regarding the breadth and limitations of MIS techniques for thoracolumbar injuries. Consequently, the objectives of this study were to 1) identify the range of current practice patterns for thoracolumbar trauma and 2) integrate expert opinion and literature review to develop an updated treatment algorithm. METHODS: A survey describing 10 clinical cases with a range of thoracolumbar injuries was sent to 12 surgeons with expertise in spine trauma. The survey results were summarized using descriptive statistics, along with the Fleiss kappa statistic of interrater agreement. To develop an updated treatment algorithm, the authors used a modified Delphi technique that incorporated a literature review, the survey results, and iterative feedback from a group of 14 spine trauma experts. The final algorithm represented the consensus opinion of that expert group. RESULTS: Eleven of 12 surgeons contacted completed the case survey, including 8 (73%) neurosurgeons and 3 (27%) orthopedic surgeons. For the 4 cases involving patients with neurological deficits, nearly all respondents recommended decompression and fusion, and the proportion recommending open surgery ranged from 55% to 100% by case. Recommendations for the remaining cases were heterogeneous. Among the neurologically intact patients, MIS techniques were typically recommended more often than open techniques. The overall interrater agreement in recommendations was 0.23, indicating fair agreement. Considering both literature review and expert opinion, the updated algorithm indicated that MIS techniques could be used to treat most thoracolumbar injuries. Among neurologically intact patients, percutaneous instrumentation without arthrodesis was recommended for those with AO Spine Thoracolumbar Classification System subtype A3/A4 (Thoracolumbar Injury Classification and Severity Score [TLICS] 4) injuries, but MIS posterior arthrodesis was recommended for most patients with AO Spine subtype B2/B3 (TLICS > 4) injuries. Depending on vertebral body integrity, anterolateral corpectomy or mini-open decompression could be used for patients with neurological deficits. CONCLUSIONS: Spine trauma experts endorsed a range of strategies for treating thoracolumbar injuries but felt that MIS techniques were an option for most patients. The updated treatment algorithm may provide a foundation for surgeons interested in safe approaches for using MIS techniques to treat thoracolumbar trauma.

Incidence and predictors of post-traumatic stress symptoms in a cohort of patients with intracerebral hemorrhage.

OBJECTIVES: Examine the incidence and predictors of PTSD symptoms in a cohort of patients with ICH. PATIENTS AND METHODS: This study uses a prospective cohort of 108 patients with complete follow-up data including a questionnaire regarding stress symptoms (PCL-S: PTSD checklist specific for a stressor) at 3, 6, and 12 months. RESULTS: The incidence of novel stress symptoms following ICH was approximately 6.5%. Age was negatively associated with PTSD symptoms with only trend-level significance (3 months: OR = 0.83, p = 0.087; 6 months: OR = 0.70, p = 0.015; 12 months: OR = 0.88, p = 0.087). Gender did not affect PTSD symptom development, (t = 1.34, p = 0.18). Pre-morbid functioning, initial stroke prognosis, total number of complications, and length of hospital/ICU stay were not associated with PTSD symptoms; however, each was significantly correlated with poorer functional outcomes. Yet, poorer functional outcomes were observed in those with higher reports of PTSD symptoms (r = 0.24, p = 0.01). CONCLUSION: Functional outcomes in ICH are correlated with PTSD symptoms, however the mechanism and relationship are difficult to elucidate. Further research is needed to determine possible mechanisms by which a stroke patient may develop PTSD.

The Intracerebral Hemorrhage Score: Changing Perspectives on Mortality and Disability.

BACKGROUND: Intracerebral hemorrhage (ICH) remains a devastating diagnosis. While the ICH Score continues to be used in the clinical setting to prognosticate outcomes, contemporary improvements in management have reduced mortality rates for each scoring tier. The aims of this study were to examine mortality rates within ICH Score strata and examine if these findings are stable when major disability is included in categorizing poor outcomes. METHODS: From a single-institution cohort built between 2009 and 2016, 582 patients were extracted based on the criteria for complete ICH Score, discharge mortality, and functional status for survivors. Mortality rates were stratified by ICH Score and compared with both historical and similar contemporary cohorts. Poor outcome was defined as severe disability (modified Rankin Scale score 5) in addition to death, stratified by ICH Score, and compared. A secondary analysis of patients with ICH Score of 2 was performed in light of the primary results. RESULTS: Mortality rates stratified by ICH Score were notably lower than expected for low- and moderate-grade ICH compared with the original cohort. However, when defining a poor outcome as including severe disability (modified Rankin Scale score 5) in addition to death, the rates for poor outcomes were higher for patients with ICH Score of 2 (51.16% vs. 26%, P = 0.017) and no different for any other score group compared with the original cohort. CONCLUSIONS: Though the original ICH Score overestimates mortality for low-grade and moderate-grade hemorrhages, it may underpredict severe disability.

Biomarkers of Functional Outcome in Intracerebral Hemorrhage: Interplay between Clinical Metrics, CD163, and Ferritin.

BACKGROUND: Intracerebral hemorrhage (ICH) is associated with neurological decline and poor prognosis. Although many etiologic models have been explored, secondary damage caused by continued inflammation and iron exposure from red blood cell lysis may explain poor outcomes at distant follow-up. Examining serum samples of patients with ICH for biomarkers of iron physiology may yield relationships between iron exposure and functional outcomes. METHODS: The following study retrospectively evaluated 41 patient serum samples obtained 1 day and 7 days post-ictus for CD163, ferritin, and hepcidin concentrations. Functional outcomes, using the modified Rankin Scale, were dichotomized into good (0-3) and poor (4-6). Correlation analysis and logistic regression were used to explore relationships between biomarker values, clinical metrics (such as ICH Score), and functional outcomes at 3 and 12 months. RESULTS: Clinical metrics (Acute Physiology and Chronic Health Evaluation II score, ICH Score, and National Institutes of Health Stroke Scale) were correlated with elevated ferritin levels 7 days post-ictus. Furthermore, it was found that mean CD163 levels on day 1 were significantly associated with functional outcomes at 3 and 12 months; mean serum ferritin concentrations on days 1 and 7 were elevated in those with poor outcomes at 3 months, and day 7 levels were independently correlated with 12-month outcomes. CONCLUSION: Although this study serves to contribute to a growing body of evidence that CD163 and ferritin are biomarkers of functional outcomes, prospective cohort studies may clarify the role of iron-related inflammatory biomarkers as they pertain to neurological decline in patients with ICH.

Prognosticating Functional Outcome After Intracerebral Hemorrhage: The ICHOP Score.

BACKGROUND: The morbidity, mortality, and monetary cost associated with intracerebral hemorrhage (ICH) is devastatingly high. Several scoring systems have been proposed to prognosticate outcomes after ICH, although the original ICH Score is still the most widely used. However, recent research suggests that systemic physiologic factors, such as those included in the Acute Physiology and Chronic Health Evaluation II score, may also influence outcome. In addition, no scoring systems to date have included premorbid functional status. Therefore, we propose a scoring system that incorporates these factors to prognosticate 3-month and 12-month functional outcomes. METHODS: We used the Random Forest machine-learning technique to identify factors from a dataset of more than 200 data points per patient that were most strongly affiliated with functional outcome. We then used linear regression to create an initial model based on these factors and modified weightings to improve accuracy. Our scoring system was compared with the ICH Score for prognosticating functional outcomes. RESULTS: Two separate scoring systems (Intracerebral Hemorrhage Outcomes Project 3 [ICHOP3] and ICHOP12) were developed for 3-month and 12-month functional outcomes using Glasgow Coma Scale, National Institutes of Health Stroke Scale, Acute Physiology and Chronic Health Evaluation II, premorbid modified Rankin Scale (mRS), and hematoma volume (3-month only). Patient outcomes were dichotomized into good (mRS score, 0-3) and poor (mRS score, 4-6) categories based on functional status. Areas under the curve in the derivation cohort for predicting mRS score were 0.89 (3-month) and 0.87 (12-month); both were significantly more discriminatory than the original ICH Score. CONCLUSIONS: The ICHOP scores may provide more comprehensive evaluation of a patient's long-term functional prognosis by taking into account systemic physiologic factors as well as premorbid functional status.

Computerized spiral analysis using the iPad.

BACKGROUND: Digital analysis of writing and drawing has become a valuable research and clinical tool for the study of upper limb motor dysfunction in patients with essential tremor, Parkinson's disease, dystonia, and related disorders. We developed a validated method of computerized spiral analysis of hand-drawn Archimedean spirals that provides insight into movement dynamics beyond subjective visual assessment using a Wacom graphics tablet. While the Wacom tablet method provides robust data, more widely available mobile technology platforms exist. NEW METHOD: We introduce a novel adaptation of the Wacom-based method for the collection of hand-drawn kinematic data using an Apple iPad. This iPad-based system is stand-alone, easy-to-use, can capture drawing data with either a finger or capacitive stylus, is precise, and potentially ubiquitous. RESULTS: The iPad-based system acquires position and time data that is fully compatible with our original spiral analysis program. All of the important indices including degree of severity, speed, presence of tremor, tremor amplitude, tremor frequency, variability of pressure, and tightness are calculated from the digital spiral data, which the application is able to transmit. COMPARISON WITH EXISTING METHOD: While the iPad method is limited by current touch screen technology, it does collect data with acceptable congruence compared to the current Wacom-based method while providing the advantages of accessibility and ease of use. CONCLUSIONS: The iPad is capable of capturing precise digital spiral data for analysis of motor dysfunction while also providing a convenient, easy-to-use modality in clinics and potentially at home.

Persistent Interneuronopathy in the Prefrontal Cortex of Young Adult Offspring Exposed to Ethanol In Utero.

Gestational exposure to ethanol has been reported to alter the disposition of tangentially migrating GABAergic cortical interneurons, but much remains to be elucidated. Here we first established the migration of interneurons as a proximal target of ethanol by limiting ethanol exposure in utero to the gestational window when tangential migration is at its height. We then asked whether the aberrant tangential migration of GABAergic interneurons persisted as an enduring interneuronopathy in the medial prefrontal cortex (mPFC) later in the life of offspring prenatally exposed to ethanol. Time pregnant mice with Nkx2.1Cre/Ai14 embryos harboring tdTomato-fluorescent medial ganglionic eminence (MGE)-derived cortical GABAergic interneurons were subjected to a 3 day binge-type 5% w/w ethanol consumption regimen from embryonic day (E) 13.5-16.5, spanning the peak of corticopetal interneuron migration in the fetal brain. Our binge-type regimen increased the density of MGE-derived interneurons in the E16.5 mPFC. In young adult offspring exposed to ethanol in utero, this effect persisted as an increase in the number of mPFC layer V parvalbumin-immunopositive interneurons. Commensurately, patch-clamp recording in mPFC layer V pyramidal neurons uncovered enhanced GABA-mediated spontaneous and evoked synaptic transmission, shifting the inhibitory/excitatory balance toward favoring inhibition. Furthermore, young adult offspring exposed to the 3 day binge-type ethanol regimen exhibited impaired reversal learning in a modified Barnes maze, indicative of decreased PFC-dependent behavioral flexibility, and heightened locomotor activity in an open field arena. Our findings underscore that aberrant neuronal migration, inhibitory/excitatory imbalance, and thus interneuronopathy contribute to indelible abnormal cortical circuit form and function in fetal alcohol spectrum disorders. SIGNIFICANCE STATEMENT: The significance of this study is twofold. First, we demonstrate that a time-delimited binge-type ethanol exposure in utero during early gestation alters corticopetal tangential migration of GABAergic interneurons in the fetal brain. Second, our study is the first to integrate neuroanatomical, electrophysiological, and behavioral evidence that this "interneuronopathy" persists in the young adult offspring and contributes to enduring changes in (1) the distribution of parvalbumin-expressing GABAergic cortical interneurons in the medial prefrontal cortex, (2) GABA-mediated synaptic transmission that resulted in an inhibitory/excitatory synaptic imbalance, and (3) behavioral flexibility. These findings alert women of child-bearing age that fetal alcohol spectrum disorders can be rooted very early in fetal brain development, and reinforce evidence-based counseling against binge drinking even at the earliest stages of pregnancy.