Essential requirement for IER3IP1 in B cell development.

In a forward genetic screen of mice with N-ethyl-N-nitrosourea-induced mutations for aberrant immune function, we identified animals with low percentages of B220+ cells in the peripheral blood. The causative mutation was in Ier3ip1, encoding immediate early response 3 interacting protein 1 (IER3IP1), an endoplasmic reticulum membrane protein mutated in an autosomal recessive neurodevelopmental disorder termed Microcephaly with simplified gyration, Epilepsy and permanent neonatal Diabetes Syndrome (MEDS) in humans. However, no immune function for IER3IP1 had previously been reported. The viable hypomorphic Ier3ip1 allele uncovered in this study, identical to a reported IER3IP1 variant in a MEDS patient, reveals an essential hematopoietic-intrinsic role for IER3IP1 in B cell development and function. We show that IER3IP1 forms a complex with the Golgi transmembrane protein 167A and limits activation of the unfolded protein response mediated by inositol-requiring enzyme-1α and X-box binding protein 1 in B cells. Our findings suggest that B cell deficiency may be a feature of MEDS.

Pathophysiology and natural history of cervical spondylotic myelopathy.

STUDY DESIGN: This study is a combination of narrative and systematic review. OBJECTIVE: Clinicians who deal with cervical spondylotic myelopathy (CSM) should be up-to-date with the emerging knowledge related to the cascade of pathobiological secondary events that take place under chronic cervical spinal cord compression. Moreover, by performing a systematic review, we aim to (1) describe the natural history and (2) determine potential risk factors that affect the progression of CSM. SUMMARY OF BACKGROUND DATA: The pathophysiology, natural history, as well as the factors associated with clinical deterioration have not been fully described in CSM. METHODS: For the first part of the study, a literature review was performed. To answer key questions 1 and 2 of the second goal, a systematic search was conducted in PubMed and the Cochrane Collaboration Library for articles published between January 1, 1956, and November 7, 2012. We included all articles that described the progression and outcomes of CSM for which no surgical intervention was given. RESULTS: By performing a narrative literature review, we found that the assumption that acute traumatic spinal cord injury and CSM share a similar series of cellular and molecular secondary injury events was made in the past. However, recent advances in basic research have shown that the chronic mechanical compression results in secondary injury mechanisms that have distinct characteristics regarding the nature and the temporal profile compared with those of spinal cord injury. For the purpose of the systematic review, 10 studies yielding 16 publications met inclusion criteria for key questions 2 and 3. Moderate-strength evidence related to the natural history of CSM suggests that 20% to 60% of patients will deteriorate neurologically over time without surgical intervention. Finally, there is low-strength evidence indicating that the area of circumferential compression is associated with deteriorating neurological symptoms. CONCLUSION: CSM has unique pathobiological mechanisms that mainly remain unexplored. Although the natural history of CSM can be mixed, surgical intervention eliminates the chances of the neurological deterioration. EVIDENCE-BASED CLINICAL RECOMMENDATIONS: RECOMMENDATION: Evidence concerning the natural history of CSM suggests that 20% to 60% of patients will deteriorate neurologically over time without surgical intervention. Therefore, we recommend that patients with mild CSM be counseled regarding the natural history of CSM and have the option of surgical decompression explained. OVERALL STRENGTH OF EVIDENCE: Moderate. STRENGTH OF RECOMMENDATION: Strong. SUMMARY STATEMENTS: Chronic compression of the spinal cord results in progressive neural cell loss related to secondary mechanisms including apoptosis, neuroinflammation, and vascular disruption.

Nonoperative management of cervical myelopathy: a systematic review.

STUDY DESIGN: Systematic review. OBJECTIVE: To conduct a systematic review investigating the evidence of (1) efficacy, effectiveness, and safety of nonoperative treatment of patients with cervical myelopathy; (2) whether the severity of myelopathy affects outcomes of nonoperative treatment; and (3) whether specific activities or minor injuries are associated with neurological deterioration in patients with myelopathy or asymptomatic stenosis being treated nonoperatively. SUMMARY OF BACKGROUND DATA: Little is known about the appropriate role of nonoperative treatment in the management of cervical myelopathy, which is typically considered a surgical disorder. METHODS: A systematic search was conducted in PubMed and the Cochrane Collaboration Library for articles published between January 1, 1956, and November 20, 2012. We included all articles that compared nonoperative treatments or observation with surgery for patients with cervical myelopathy or asymptomatic cervical cord compression to determine their effects on clinical outcomes, including myelopathy scales (Japanese Orthopaedic Association, Nurick), general health scores (36-Item Short Form Health Survey), and pain (neck and arm). Nonoperative treatments included physical therapy, medications, injections, orthoses, and traction. We also searched for articles evaluating the effect of specific activities or minor trauma in neurological outcomes. Case reports and studies with less than 10 patients in the exposure group were excluded. RESULTS: Of 54 citations identified from our search, 5 studies reported in 6 articles met inclusion criteria. In 1 randomized controlled study, there was low evidence that nonoperative treatment may yield equivalent or better outcomes than surgery in those with mild myelopathy. For moderate to severe myelopathy, nonoperative treatment had inferior outcomes versus surgery in 2 cohort studies, despite the fact that surgically treated patients were worse at baseline. There was insufficient evidence to determine whether specific activities or minor trauma is a risk factor for neurological deterioration in those with myelopathy or asymptomatic cord compression. CONCLUSION: There is a paucity of evidence for nonoperative treatment of cervical myelopathy, and further studies are needed to determine its role more definitively. In particular, for the patient with milder degrees of myelopathy, randomized studies comparing nonoperative with surgical treatment would be particularly helpful, as would trials comparing specific types of nonoperative treatments with the natural history of myelopathy. EVIDENCE-BASED CLINICAL RECOMMENDATIONS: RECOMMENDATION 1: Because myelopathy is known to be a typically progressive disorder and there is little evidence that nonoperative treatment halts or reverses its progression, we recommend not routinely prescribing nonoperative treatment as the primary modality in patients with moderate to severe myelopathy. OVERALL STRENGTH OF EVIDENCE: Low. STRENGTH OF RECOMMENDATION: Strong. RECOMMENDATION 2: If there is a role for nonoperative treatment as a primary treatment modality, it may be in the patient with mild myelopathy. However, it is not clear which specific forms of nonoperative treatment provide any benefit compared with the natural history. If nonoperative treatment is selected, we suggest care be taken to observe for neurological deterioration. OVERALL STRENGTH OF EVIDENCE: Low. STRENGTH OF RECOMMENDATION: Weak. RECOMMENDATION 3: In those with asymptomatic spondylotic cord compression but no clinical myelopathy, the available literature neither supports nor refutes the notion that minor trauma is a risk factor for neurological deterioration. We suggest that patients should be counseled about this uncertainty. OVERALL STRENGTH OF EVIDENCE: Low. STRENGTH OF RECOMMENDATION: Weak. Recommendation 4: In those with a clinical diagnosis of cervical spondylotic myelopathy but no ossification of the posterior longitudinal ligament, the available studies did not specifically address the issue of neurological deterioration secondary to minor trauma. However, in those with underlying ossification of the posterior longitudinal ligament, trauma may be more likely to cause worsening of existing myelopathy or even initiate symptoms in those who were previously asymptomatic. We suggest that patients should be counseled about these possibilities. OVERALL STRENGTH OF EVIDENCE: Low. STRENGTH OF RECOMMENDATION: Weak.

Effectiveness of EMG use in pedicle screw placement for thoracic spinal deformities.

STUDY DESIGN: Systematic review. OBJECTIVE: To determine the effectiveness of using electromyography (EMG) during intraoperative pedicle screw placement in patients with thoracic deformity. METHODS: A systematic review of the English-language literature was undertaken for articles published between 1970 and July 2011. For our first question, we identified all articles that were designed to evaluate the diagnostic test characteristics (ie, measures of validity such as sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV]) of EMG for thoracic deformities in adolescent and adult patients. For our second question, we attempted to identify all articles that reported complication rates (pedicle wall breach or new neurological event) after pedicle screw placement in the same population comparing patients who did and did not undergo intraoperative EMG. Articles were excluded if they did not report or give raw data to calculate at least one of the four primary diagnostic test characteristics: sensitivity, specificity, PPV, or NPV for study question one. Articles were excluded if they did not have a "no EMG" control group for study question two. Other exclusions were reviews, editorials, case reports, non-English written studies, and animal studies. We rated the overall body of evidence with respect to each key question using a modified Grades of Recommendation Assessment, Development and Evaluation (GRADE) system for diagnostic and therapeutic studies. RESULTS: The overall strength of evidence evaluating the diagnostic characteristics was low due to inconsistent findings between studies and uncertainty of the impact of false-negatives. The fairly low sensitivity may lead to a high-false negative rate. It is unclear what the impact of false-negatives would be since no neurological injuries were identified in the studies summarized. A higher specificity would suggest a fairly low false-positive rate; however, the rates could be as high as 30%. If sudden changes in treatment are required in the absence of any adverse event, this could be considered a limitation of such testing. The overall strength of evidence for evaluating the efficacy of EMG compared with no EMG was insufficient because of literature shortage on this topic. CONCLUSION: The overall strength of evidence evaluating the diagnostic characteristics was low due to inconsistent findings between studies and uncertainty of the impact of false-negatives. Given the low sensitivity and potential high rate of false-negatives, pedicle wall breaches may occur, without EMG notification. These undetected breaches may lead to loose or weak screw position which may lead to neurovascular complications during or after a translation-rotation maneuver, especially in rigid deformities. The higher sensitivity would suggest a lower rate of false-positives. We recommend considering the use of intraoperative EMG-monitoring method to help identify potential complications based upon available technology, personal experiences and preferences; however, surgeons should keep in mind that false-positive results may lead to increased surgery time and increased blood loss. The surgeon should not depend solely on EMG since it can also render false-negatives.

Indication for spinal fusion and the risk of adjacent segment pathology: does reason for fusion affect risk? A systematic review.

STUDY DESIGN: A systematic review. OBJECTIVE: To determine whether different indications or reasons for spinal fusion are associated with different risks of subsequent adjacent segment pathology (ASP) in the lumbar and cervical spine. SUMMARY OF BACKGROUND DATA: Pre-existing degeneration at levels adjacent to an arthrodesis may play a role in the development of symptomatic adjacent segment pathology. Although most spinal arthrodeses occur in patients with degenerative spinal disease, spinal fusion occurs in the pediatric and trauma population, and also congenitally. Evaluating the risk of ASP in these populations may shed light on its etiology. METHODS: A systematic search was conducted in PubMed and the Cochrane Library for articles published between January 1, 1990, and December 31, 2011. We included all articles that described the risk of radiographical adjacent segment pathology (RASP) following surgical fusion for degenerative disease, for trauma, or for conditions requiring fusion in pediatrics in the lumbar or cervical spine. In addition, we included studies recording ASP in patients with congenital fusion. RESULTS: Nineteen studies met our inclusion criteria. In patients who underwent fusion in the lumbar spine for degenerative reasons, the RASP rate averaged 12.4% during an average of 5.6-year follow-up. For patients who underwent fusion in the cervical spine for degenerative reasons, the average RASP rate was 25.3% during a 2.3-year follow-up. For patients with Klippel-Feil syndrome and congenital fusion, the RASP rate averaged 49.7% during an average of 23.5-years of follow-up. In patients who were fused for scoliosis, the average RASP rate was 20.3% of 3.9-year follow-up. However there is significant variation between studies in patient population, follow-up, and definition of RASP. CONCLUSION: In the cervical spine, the rate of RASP in patients with fusion for degenerative reasons indications is greater than the rate of RASP in patients with congenital fusion suggesting that the pre-existing health and status of the adjacent level at the time of fusion may play a contributory role in the development of ASP. There is insufficient evidence in the literature to determine whether the indication/reason for fusion affects the risk of RASP in the lumbar spine CONSENSUS STATEMENT: In the cervical spine, the rate of RASP in patients with fusion for degenerative reasons indications is greater than the rate of RASP in patients with congenital fusion suggesting that the pre-existing health and status of the adjacent level at the time of fusion may play a contributory role in the development of ASP. Strength of Statement: Weak.

The risk of adjacent-level ossification development after surgery in the cervical spine: are there factors that affect the risk? A systematic review.

STUDY DESIGN: Systematic review. OBJECTIVE: To answer the following clinical questions: (1) What is the risk of adjacent-level ossification development (ALOD) in patients receiving noninstrumented cervical fusion, instrumented cervical fusion with a plate, or cervical total disc arthroplasty?; (2) What are the risk factors for ALOD?; (3) What is the time course for the development of ALOD?; and (4) Does ALOD affect outcomes and rates of reoperation? SUMMARY OF BACKGROUND DATA: Anterior cervical plating, total disc arthroplasty, and noninstrumented fusion have all been used in the treatment of cervical disc disease. There are numerous reports that identify ALOD, a form of heterotopic ossification, as a major risk factor after performing these procedures. Few studies have compared these 3 procedures to evaluate the risk, timing, and outcomes related to postoperation ALOD. METHODS: A systematic search was conducted in PubMed and the Cochrane Library for articles published between January 1, 1990, and December 31, 2011. We included all articles that described the risk of or risk factors for ALOD after surgical treatment of the cervical spine. Studies with patients older than 18 years or those treated for tumor or trauma were excluded from the study. In addition, those with posterior fusions, case reports, and case series with less than 10 patients were excluded. RESULTS: A total of 5 studies met the inclusion criteria for our systematic review. The risk of ALOD with anterior cervical discectomy and fusion ranged from 41% to 64%, whereas the risk of ALOD after total disc replacement ranged from 6% to 24%. When ALOD did occur, there was a 2-fold higher risk of development at the cranial adjacent segment. The most important risk factor for the development of ALOD was the use of instrumentation and the plate-to-disc distance, although the surgical procedure type (corpectomy vs. discectomy and fusion) neared but did not reach statistical significance. Insufficient evidence was available to delineate the time course for its development and how ALOD affected outcomes. CONCLUSION: The current body of literature suggests that ALOD will develop with the use of instrumentation and especially so if anterior instrumentation is placed within 5 mm of the adjacent cranial disc segment. In addition, total disc replacement showed lower rates for the development of ALOD compared with anterior cervical discectomy and fusion at both short- and long-term follow-up. CONSENSUS STATEMENT: We recommend that the surgeon make every effort to keep the plate as far away from the adjacent disc as possible. Strength of Statement: Strong.

Frequency, risk factors, and treatment of distal adjacent segment pathology after long thoracolumbar fusion: a systematic review.

STUDY DESIGN: Systematic review. OBJECTIVE: To systematically review the literature related to distal adjacent segment pathology (ASP) after long thoracolumbar fusions for deformity including frequency, risk factors, frequency differences between adolescents and adults, surgical approach for revision, and revision complications. SUMMARY OF BACKGROUND DATA: Spinal deformity surgery complications include ASP. Although ASP at the rostral end of instrumented fusions has been well described, substantially less has been documented about distal ASP. METHODS: A systematic search was conducted in Medline and the Cochrane Collaboration Library for articles published between January 1, 1983, and March 15, 2012. We included all articles that described distal ASP after long thoracolumbar fusion for deformity. Radiographical ASP (RASP) was defined as evidence of ASP based on imaging, and clinical ASP (CASP) was defined as symptomatic ASP. RESULTS: Seven retrospective cohort studies met inclusion criteria. Distal CASP developed in 17.7% at 2- 6-year follow-up and 19.8% at 9-year follow-up, whereas reoperation due to CASP was reported in 15.6% at 2 to 6 years and 14.4% at 9 years. Distal RASP was more frequent (44.7%-65.5%). Preoperative sagittal imbalance was associated with increased risk of distal ASP. There was increased risk of CASP in patients with higher postoperative fractional curve and increased risk of RASP in younger patients and those with preoperative disc degeneration, longer fusions, circumferential procedures, and postoperative L5-S1 disc space narrowing. No studies meeting inclusion criteria compared distal ASP in adults and adolescents or defined the best approach or complications for distal ASP revision. CONCLUSION: Low-quality evidence suggests a cumulative rate of 18% to 20% for CASP and 45% to 65% for RASP after long thoracolumbar fusion for spinal deformity during 9-year follow-up. Low-quality evidence suggests an association between preoperative sagittal imbalance and distal ASP, with greater risk of distal ASP in patients with sagittal imbalance. Low-quality evidence suggests increased risk of CASP in patients with higher postoperative fractional curve and increased risk of RASP in younger patients and those with preoperative disc degeneration, longer fusions, circumferential procedures, and postoperative L5-S1 disc space narrowing. CONSENSUS STATEMENT: 1. The risk of developing new symptoms secondary to distal adjacent segment pathology following long thoracolumbar fusion for deformity is approximately 18­20% during a period of 9 years follow up, and most of these patients will require revision surgery. Strength of Statement: Weak. 2. The risk of developing distal adjacent segment pathology may be higher in those with preoperative sagittal imbalance, preoperative disc degeneration, longer fusions, circumferential procedures, and postoperative L5­S1 disc space narrowing. Strength of Statement: Weak.