Stereotactic body radiation therapy for spinal metastases: A new standard of care.

Advancements in systemic therapies for patients with metastatic cancer have improved overall survival and, hence, the number of patients living with spinal metastases. As a result, the need for more versatile and personalized treatments for spinal metastases to optimize long-term pain and local control has become increasingly important. Stereotactic body radiation therapy (SBRT) has been developed to meet this need by providing precise and conformal delivery of ablative high-dose-per-fraction radiation in few fractions while minimizing risk of toxicity. Additionally, advances in minimally invasive surgical techniques have also greatly improved care for patients with epidural disease and/or unstable spines, which may then be combined with SBRT for durable local control. In this review, we highlight the indications and controversies of SBRT along with new surgical techniques for the treatment of spinal metastases.

Management of traumatic sacral spondyloptosis: illustrative case.

BACKGROUND: Grade V spondylolisthesis, or spondyloptosis, is a complication of high-energy trauma that is most commonly reported at the lumbosacral junction. Sacral intersegmental spondyloptosis is extremely rare. The authors present a case of spondyloptosis of S1 on S2 with a comminuted fracture of S2 and complex fractures of the L4 and L5 transverse processes, resulting in severe stenosis of the lumbosacral nerve roots. OBSERVATIONS: The patient was a 70-year-old woman with a history of a fall 3 weeks prior and progressive L5 and S1 radiculopathy. Instrumentation and fusion were undertaken, extending from L3 to the pelvis because degenerative stenosis at L3-4 and L4-5 was also found. Reduction was achieved, leading to diminished pain and partial resolution of weakness. LESSONS: Traumatic sacral spondyloptosis adds a degree of difficulty to reduction, fixation, and fusion. The technique presented herein achieved sagittal realignment via a distraction maneuver of S1-2 in which rods were attached to bilateral dual S2 alar-iliac screws with reduction screws placed at S1, ultimately pulling L5 and S1 up to the rod for fixation.

Robot-assisted atlantoaxial fixation: illustrative cases.

BACKGROUND: Placing screws in the high cervical spine can be challenging because of the vital anatomical structures located in that region. Precision and accuracy with screw placement is needed. The use of robotics in the cervical spine has been described before; however, here the authors describe the use of a new robotic setup. OBSERVATIONS: The authors describe 2 cases of robot-assisted placement of C2 pars screws and C1-2 transarticular screws. The operative plans for each patient were as follows: placement of C2 pars screws with C2-4 fusion for hangman's fracture and placement of C1-2 transarticular screws for degenerative disease. Intraoperative computed tomography (CT) was used to plan and navigate the screws. Postoperative CT showed excellent placement of hardware. Both patients presented for initial postoperative clinic visits with no recurrence of prior symptoms. LESSONS: Intraoperative robotic assistance with instrumentation of the high cervical spine, particularly C2 pars and C1-2 transarticular screws, may ensure proper screw placement and help avoid injury.

Etiologies and Outcomes of Spinal Epidural Lipomatosis: Systematic Review of the Literature and Meta-Analysis of Reported Cases.

STUDY DESIGN: This was a systematic review of the literature. OBJECTIVE: The aim was to examine the contemporary demographics, etiological factors, treatment options and outcomes of spinal epidural lipomatosis (SEL) in adults. SUMMARY OF BACKGROUND DATA: SEL is primarily seen in obese patients as well as those on steroid therapy. Much regarding the etiology and treatment outcomes of SEL is unknown. METHODS: We reviewed Ovid MEDLINE, PubMed, SCOPUS, and Google Scholars databases from 1990 through August 2020 to identify cases of SEL. Data collected included patient characteristics, disease associations, level of pathology, treatment, and clinical outcomes. RESULTS: Ninety articles (145 individual cases) were included in the analysis. The median age was 54 years and 79% were males. Obesity-associated SEL constituted the largest proportion (52%) of our cohort. 22% of SEL cases were related to steroid use, while 26% cases were considered to be idiopathic. Lumbosacral SEL was the most frequently reported level of disease (68.9%), followed by the thoracic level (26.2%). The mean age of cases who underwent surgical intervention was 55 years, as compared with 48 years in those who received conservative management ( P =0.03). 95% of patients reported some degree of symptomatic improvement regardless of the treatment modality. Logistic regression suggested a possible superior outcome associated with those undergoing surgical treatment. CONCLUSION: In contrast to historical comparisons, contemporary articles support that obesity has become the major contributing factor for SEL. Logistic regression of the existing cases suggests that there may be a role for surgical intervention in select patients.

Isthmic spondylolisthesis in adults A review of the current literature.

Isthmic spondylolisthesis can be defined as the anterior translation of a vertebral body relative to the one subjacent to it and secondary to an abnormality of the pars interarticularis. Isthmic spondylolisthesis is usually asymptomatic and discovered as an incidental radiographic finding. However, it can be symptomatic due to its biomechanical effects on the adjacent neural structures and patients may present with low back and/or radicular leg pain. Standing plain radiographs can be obtained to confirm the presence or assess the degree of isthmic spondylolisthesis. Computed tomography (CT) clearly shows the pars defect and provides a better assessment of the pathology. Magnetic resonance imaging (MRI) is indicated in patients with neurologic manifestations and can be used to assess the degree of foraminal or central stenosis. Conservative management including oral anti-inflammatory medication, physical therapy, and/or transforaminal epidural corticosteroid injections can be utilized initially. Surgery can be considered in the setting of persistent symptoms unrelieved with conservative management or significant neurologic compromise. Several surgical methods and techniques are available in the management of isthmic spondylolisthesis. There has been a significant national increase in the use of interbody fusion posteriorly for the management of isthmic spondylolisthesis. Reports have suggested that interbody fusion can be a cost-effective technique in selected patients with isthmic spondylolisthesis. Future studies are encouraged to further characterize the specific indications of various surgical modalities in patients with isthmic spondylolisthesis.

Utility of expanded anterior column resection versus decompression-alone for local control in the management of carcinomatous vertebral column metastases undergoing adjuvant stereotactic radiotherapy.

BACKGROUND CONTEXT: With improvements in adjuvant radiotherapy and minimally invasive surgical techniques, separation surgery has become the default surgical intervention for spine metastases at many centers. However, it is unclear if there is clinical benefit from anterior column resection in addition to simple epidural debulking prior to stereotactic body radiotherapy (SBRT). PURPOSE: To examine the effect of anterior column debulking versus epidural disease resection alone in the local control of metastases to the bony spine. STUDY DESIGN: Retrospective cohort study. PATIENT SAMPLE: Ninety-seven patients who underwent open surgery followed by SBRT for spinal metastases at a single comprehensive cancer center. OUTCOME MEASURES: Local tumor recurrence following surgery and SBRT. METHODS: Data were collected regarding radiation dose, cancer histology, extent of anterior column resection, and recurrence. Tumor involvement was categorized using the International Spine Radiosurgery Consortium guidelines. Univariable analyses were conducted to determine predictors of local recurrence and time to local recurrence. RESULTS: Among the 97 included patients, mean age was 60.5±11.4 years and 51% of patients were male. The most common primary tumor types were lung (20.6%), breast (17.5%), kidney (13.4%) and prostate (12.4%). Recurrence was seen in 17 patients (17.5%) and local control rates were: 85.5% (1-year), 81.1% (2-year), and 54.9% (5-year). Overall predictors of local recurrence were tumor pathology (p<.01; renal cell carcinoma and colorectal adenocarcinoma associated with poorest PFS) and undergoing anterior column debulking versus epidural decompression-alone (p=.03). Only tumor pathology predicted time to local recurrence (p<.01), though inspection of Kaplan-Meier functions showed superior long-term local control in patients with radiosensitive tumor pathologies, no previous irradiation of the metastasis, and who underwent anterior column resection versus epidural removal alone. Median time to recurrence was 288 days with 100% of lesions showing anterior column recurrence and recurrence in the epidural space. CONCLUSIONS: With the increasing shift towards surgery as a neoadjuvant to radiotherapy for patients with spinal column metastases, the role for surgical debulking has become less clear. In the present study, we find that anterior column debulking as opposed to epidural debulking-alone decreases the odds of local recurrence and improves long-term local control.

Nerve Root Sparing En Bloc Resection of Sacral Chondrosarcoma: Technical Note and Review of the Literature.

BACKGROUND: Total en bloc sacrectomy provides the best long-term local control for large primary bony sacral tumors, but often requires lumbosacral nerve root sacrifice leading to loss of ambulation and/or bowel, bladder, and/or sexual dysfunction. Nerve-sparing techniques may be an option for some patients that avoid these outcomes and accordingly improve postoperative quality of life. OBJECTIVE: To describe the technique for a posterior-only en bloc hemisacrectomy with maximal nerve root preservation and to summarize the available literature. METHODS: A 38-yr-old woman with a 7.7 × 5.4 × 4.5 cm biopsy-proven grade 2 chondrosarcoma involving the left L5-S2 posterior elements underwent a posterior-only left hemisacrectomy tri-rod L3-pelvis fusion. A systematic review of the English literature was also conducted to identify other descriptions of high sacrectomy with distal sacral nerve root preservation. RESULTS: Computer-aided navigation facilitated an extracapsular resection that allowed preservation of the left-sided L5 and S3-Co roots. Negative margins were achieved and postoperatively the patient retained ambulation and good bowel/bladder function. Imaging at 9-mo follow-up showed no evidence of recurrence. The systematic review identified 4 prior publications describing 6 total patients who underwent nerve-sparing sacral resection. Enneking-appropriate resection was only obtained in 1 case though. CONCLUSION: Here we describe a technique for distal sacral nerve root preservation during en bloc hemisacrectomy for a primary sacral tumor. Few prior descriptions exist, and the present technique may help to reduce the neurological morbidity of sacral tumor surgery.

Sacroplasty Augmentation of Instrumented Pelvic Reconstruction After High Sacrectomy: A Technical Case Report.

BACKGROUND AND IMPORTANCE: En bloc resection of sacral tumors is the most effective treatment to help prevent recurrence. Sacrectomy, however, can be destabilizing, depending on the extent of resection. Various surgical techniques for improving stability and enabling early ambulation have been proposed. CLINICAL PRESENTATION: Here, we report a case in which we use PMMA (poly[methyl methacrylate]) to augment pelvic instrumentation to improve mechanical stability after sacrectomy for en bloc resection of a solitary fibrous tumor. CONCLUSION: We highlight the use of sacroplasty augmentation of pelvic ring reconstruction to provide biomechanical stability without the need for fusion of any mobile spine segments, which allowed for early patient ambulation and no appreciable loss of range of motion or mobility.

Does Myelopathy Increase the Morbidity and Mortality of Elective Single-Level Anterior Cervical Discectomy and Fusion? An Updated Propensity-Matched Analysis of 3938 Patients From the American College of Surgeons National Surgical Quality Improvement Program Database.

BACKGROUND: Myelopathy is thought to be associated with higher morbidity and mortality after anterior cervical discectomy and fusion (ACDF); however, the literature investigating this association has limitations. OBJECTIVE: To investigate the influence of myelopathy on early perioperative complications of elective single-level ACDF. METHODS: Patients who underwent ACDF between 2016 and 2018 were reviewed from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. Propensity score matching analysis was used. RESULTS: Twenty percent of the cohort was myelopathic. These patients were significantly older, had more comorbidities, more likely to be functionally dependent, and to undergo emergency surgery when compared to the nonmyelopathic cohort. When 1969 myelopathic patients were 1:1 propensity matched with nonmyelopathic patients, there was no difference between the myelopathic and nonmyelopathic patients in incidence of postoperative intensive care unit admission or death. Patients in the myelopathic group were significantly more likely to have a nonhome discharge and less likely to be discharged on the first postoperative day. Myelopathic patients had a higher rate of return to operating room within the same admission (2.2%) as well as a higher unplanned readmission rate (4.2%). The total operation time (143 min) and average length of hospital stay (52 h) were significantly higher in the myelopathic group when compared to the nonmyelopathic group (117 min) and (33 h), respectively. CONCLUSION: Patients with myelopathy who undergo elective single-level ACDF have higher risks of several perioperative events including longer operative time, longer hospital stay, higher return to operating room, and unplanned readmission rates, when compared to nonmyelopathic patients. On the other hand, myelopathic patients did not exhibit higher mortality rate.

Fragile X-associated tremor ataxia syndrome with co-occurrent progressive supranuclear palsy-like neuropathology.

Co-occurrence of multiple neuropathologic changes is a common phenomenon, most prominently seen in Alzheimer's disease (AD) and Parkinson's disease (PD), complicating clinical diagnosis and patient management. Reports of co-occurring pathological processes are emerging in the group of genetically defined repeat-associated non-AUG (RAN)-translation related diseases. Here we report a case of Fragile X-associated tremor-ataxia syndrome (FXTAS) with widespread and abundant nuclear inclusions of the RAN-translation related FMRpolyG-peptide. In addition, we describe prominent neuronal and glial tau pathology representing changes seen in progressive supranuclear palsy (PSP). The highest abundance of the respective pathological changes was seen in distinct brain regions indicating an incidental, rather than causal correlation.

Comparative analyses of the in vivo induction and transmission of α-synuclein pathology in transgenic mice by MSA brain lysate and recombinant α-synuclein fibrils.

α-synuclein (αS) is the major component of several types of brain pathological inclusions that define neurodegenerative diseases termed synucleinopathies. Central nervous system (CNS) inoculation studies using either in vitro polymerized αS fibrils or in vivo derived lysates containing αS aggregates to induce the progressive spread of αS inclusion pathology in animal disease models have supported the notion that αS mediated progressive neurodegeneration can occur by a prion-like mechanism. We have previously shown that neonatal brain inoculation with preformed αS fibrils in hemizygous M20+/- transgenic mice expressing wild type human αS and to a lesser extent in non-transgenic mice can result in a concentration-dependent progressive induction of CNS αS pathology. Recent studies using brain lysates from patients with multiple system atrophy (MSA), characterized by αS inclusion pathology in oligodendrocytes, indicate that these may be uniquely potent at inducing αS pathology with prion-like strain specificity. We demonstrate here that brain lysates from MSA patients, but not control individuals, can induce αS pathology following neonatal brain inoculation in transgenic mice expressing A53T human αS (M83 line), but not in transgenic expressing wild type human αS (M20 line) or non-transgenic mice within the timeframe of the study design. Further, we show that neuroanatomical and immunohistochemical properties of the pathology induced by MSA brain lysates is very similar to what is produced by the neonatal brain injection of preformed human αS fibrils in hemizygous M83+/- transgenic mice. Collectively, these findings reinforce the idea that the intrinsic traits of the M83 mouse model dominates over any putative prion-like strain properties of MSA αS seeds that can induce pathology.

Critical Care Management of Acute Spinal Cord Injury-Part II: Intensive Care to Rehabilitation.

Spinal cord injury is devastating to those affected due to the loss of motor and sensory function, and, in some cases, cardiovascular collapse, ventilatory failure, and bowel and bladder dysfunction. Primary trauma to the spinal cord is exacerbated by secondary insult from the inflammatory response to injury. Specialized intensive care of patients with acute spinal cord injury involves the management of multiple systems and incorporates evidence-based practices to reduce secondary injury to the spinal cord. Patients greatly benefit from early multidisciplinary rehabilitation for neurologic and functional recovery. Treatment of acute spinal cord injury may soon incorporate novel molecular agents currently undergoing clinical investigation to assist in neuroprotection and neuroregeneration.

Early Management of Acute Spinal Cord Injury-Part I: Initial Injury to Surgery.

Acute spinal cord injury is a devastating event associated with substantial morbidity worldwide. The pathophysiology of spinal cord injury involves the initial mechanical trauma and the subsequent inflammatory response, which may worsen the severity of neurologic dysfunction. Interventions have been studied to reduce the extent of primary injury to the spinal cord through preventive measures and to mitigate secondary insult through early specialized care. Management, therefore, is multifold, interdisciplinary, and begins immediately at the time of injury. It includes the trauma triage, acute management of the circulatory and respiratory systems, and definitive treatment, mainly with surgical decompression and stabilization.

Motor neuron loss and neuroinflammation in a model of α-synuclein-induced neurodegeneration.

Mechanisms underlying α-synuclein (αSyn) mediated neurodegeneration are poorly understood. Intramuscular (IM) injection of αSyn fibrils in human A53T transgenic M83+/- mice produce a rapid model of α-synucleinopathy with highly predictable onset of motor impairment. Using varying doses of αSyn seeds, we show that αSyn-induced phenotype is largely dose-independent. We utilized the synchrony of this IM model to explore the temporal sequence of αSyn pathology, neurodegeneration and neuroinflammation. Longitudinal tracking showed that while motor neuron death and αSyn pathology occur within 2 months post IM, astrogliosis appears at a later timepoint, implying neuroinflammation is a consequence, rather than a trigger, in this prionoid model of synucleinopathy. Initiating at 3 months post IM, immune activation dominates the pathologic landscape in terminal IM-seeded M83+/- mice, as revealed by unbiased transcriptomic analyses. Our findings provide insights into the role of neuroinflammation in αSyn mediated proteostasis and neurodegeneration, which will be key in designing potential therapies.

Proteolysis of α-synuclein fibrils in the lysosomal pathway limits induction of inclusion pathology.

Progression of α-synuclein inclusion pathology may occur through cycles of release and uptake of α-synuclein aggregates, which induce additional intracellular α-synuclein inclusion pathology. This process may explain (i) the presence of α-synuclein inclusion pathology in grafted cells in human brains, and (ii) the slowly progressive nature of most human α-synucleinopathies. It also provides a rationale for therapeutic targeting of extracellular aggregates to limit pathology spread. We investigated the cellular mechanisms underlying intraneuronal α-synuclein aggregation following exposure to exogenous preformed α-synuclein amyloid fibrils. Exogenous α-synuclein fibrils efficiently attached to cell membranes and were subsequently internalized and degraded within the endosomal/lysosomal system. However, internalized α-synuclein amyloid fibrils can apparently overwhelm the endosomal/lysosomal machinery leading to the induction of intraneuronal α-synuclein inclusions comprised of endogenous α-synuclein. Furthermore, the efficiency of inclusion formation was relatively low in these studies compared to studies using primary neuronal-glial cultures over-expressing α-synuclein. Our study indicates that under physiologic conditions, endosomal/lysosomal function acts as an endogenous barrier to the induction of α-synuclein inclusion pathology, but when compromised, it may lower the threshold for pathology induction/transmission. Cover Image for this issue: doi: 10.1111/jnc.13787.

Early Surgical Intervention for a Large Newborn Cephalohematoma.

Cephalohematomas in newborns are often managed nonsurgically and resolve within the first month of life. In cases of large hematomas (>7 cm) with delayed resorption and persistence over 4 weeks, these masses can often lead to complications of calcification, infection, or hyperbilirubinemia. We report a case of a 14-day-old child with a persistent, large, noncalcified cephalohematoma. After observation alone showed that the cephalohematoma increased in size, 100 ml of old blood was surgically evacuated on day 15 of life. The procedure required a small 1-cm incision and, unlike most large cephalohematomas evacuated after 1 month of observation, there were no signs of skull-deforming calcification observed. This case report presents the earliest evacuation of large noncalcified cephalohematomas in newborns ever reported in the literature, and suggests benefits of early surgical evacuation before 1 month of life.

Novel Application of a Reverse Triage Protocol Providing Increased Access to Care in an Outpatient, Primary Care Clinic Setting.

BACKGROUND AND OBJECTIVES: As the number of patients with access to care increases, outpatient clinics will need to implement innovative strategies to maintain or enhance clinic efficiency. One viable alternative involves reverse triage. METHODS: A reverse triage protocol was implemented during a student-run free clinic. Each patient's chief complaint(s) were obtained at the beginning of the clinic session and ranked by increasing complexity. "Complexity" was defined as the subjective amount of time required to provide a full, thorough evaluation of a patient. Less complex cases were prioritized first since they could be expedited through clinic processing and allow for more time and resources to be dedicated to complex cases. Descriptive statistics were used to characterize and summarize the data obtained. Categorical variables were analyzed using chi-square. A time series analysis of the outcome versus centered time in weeks was also conducted. RESULTS: The average number of patients seen per clinic session increased by 35% (9.5 versus 12.8) from pre-implementation of the reverse triage protocol to 6 months after the implementation of the protocol. CONCLUSIONS: The implementation of a reverse triage in an outpatient setting significantly increased clinic efficiency as noted by a significant increase in the number of patients seen during a clinic session.

Viral expression of ALS-linked ubiquilin-2 mutants causes inclusion pathology and behavioral deficits in mice.

BACKGROUND: UBQLN2 mutations have recently been associated with familial forms of amyotrophic lateral sclerosis (ALS) and ALS-dementia. UBQLN2 encodes for ubiquilin-2, a member of the ubiquitin-like protein family which facilitates delivery of ubiquitinated proteins to the proteasome for degradation. To study the potential role of ubiquilin-2 in ALS, we used recombinant adeno-associated viral (rAAV) vectors to express UBQLN2 and three of the identified ALS-linked mutants (P497H, P497S, and P506T) in primary neuroglial cultures and in developing neonatal mouse brains. RESULTS: In primary cultures rAAV2/8-mediated expression of UBQLN2 mutants resulted in inclusion bodies and insoluble aggregates. Intracerebroventricular injection of FVB mice at post-natal day 0 with rAAV2/8 expressing wild type or mutant UBQLN2 resulted in widespread, sustained expression of ubiquilin-2 in brain. In contrast to wild type, mutant UBQLN2 expression induced significant pathology with large neuronal, cytoplasmic inclusions and ubiquilin-2-positive aggregates in surrounding neuropil. Ubiquilin-2 inclusions co-localized with ubiquitin, p62/SQSTM, optineurin, and occasionally TDP-43, but were negative for α-synuclein, neurofilament, tau, and FUS. Mutant UBLQN2 expression also resulted in Thioflavin-S-positive inclusions/aggregates. Mice expressing mutant forms of UBQLN2 variably developed a motor phenotype at 3-4 months, including nonspecific clasping and rotarod deficits. CONCLUSIONS: These findings demonstrate that UBQLN2 mutants (P497H, P497S, and P506T) induce proteinopathy and cause behavioral deficits, supporting a "toxic" gain-of-function, which may contribute to ALS pathology. These data establish also that our rAAV model can be used to rapidly assess the pathological consequences of various UBQLN2 mutations and provides an agile system to further interrogate the molecular mechanisms of ubiquilins in neurodegeneration.