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.

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.

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.

Studies of lipopolysaccharide effects on the induction of α-synuclein pathology by exogenous fibrils in transgenic mice.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder that is pathologically characterized by loss of dopaminergic neurons from the substantia nigra, the presence of aggregated α-synuclein (αS) and evidence of neuroinflammation. Experimental studies have shown that the cerebral injection of recombinant fibrillar αS, especially in αS transgenic mouse models, can induce the formation and spread of αS inclusion pathology. However, studies reporting this phenomenon did not consider the presence of lipopolysaccharide (LPS) in the injected αS, produced in E. coli, as a potential confound. The objectives of this study are to develop a method to remove the LPS contamination and investigate the differences in pathologies induced by αS containing LPS or αS highly purified of LPS. RESULTS AND CONCLUSIONS: We were able to remove >99.5% of the LPS contamination from the αS preparations through the addition of a cation exchange step during purification. The αS pathology induced by injection of fibrils produced from αS containing LPS or purified of LPS, showed a similar distribution pattern; however, there was less spread into the cortex of the mice injected with αS containing higher levels of LPS. As previously reported, injection of αS fibrils could induce astrogliosis, and αS inclusions were present within astrocytes in mice injected with fibrils comprised of αS with or without cation exchange purification. Furthermore, we identified the presence of αS pathology in ependymal cells in both groups of mice, which suggests the involvement of a novel mechanism for spread in this model of αS pathology.

Brain injection of α-synuclein induces multiple proteinopathies, gliosis, and a neuronal injury marker.

Intracerebral injection of amyloidogenic α-synuclein (αS) has been shown to induce αS pathology in the CNS of nontransgenic mice and αS transgenic mice, albeit with varying efficiencies. In this study, using wild-type human αS transgenic mice (line M20), we demonstrate that intracerebral injection of recombinant amyloidogenic or soluble αS induces extensive αS intracellular inclusion pathology that is associated with robust gliosis. Near the injection site, a significant portion of αS inclusions are detected in neurons but also in astrocytes and microglia. Aberrant induction of expression of the intermediate filament protein peripherin, which is associated with CNS neuronal injury, was also observed predominantly near the site of injection. In addition, many pSer129 αS-induced inclusions colocalize with the low-molecular-mass neurofilament subunit (NFL) or peripherin staining. αS inclusion pathology was also induced in brain regions distal from the injection site, predominantly in neurons. Unexpectedly, we also find prominent p62-immunoreactive, αS-, NFL-, and peripherin-negative inclusions. These findings provide evidence that exogenous αS challenge induces αS pathology but also results in the following: (1) a broader disruption of proteostasis; (2) glial activation; and (3) a marker of a neuronal injury response. Such data suggest that induction of αS pathology after exogenous seeding may involve multiple interdependent mechanisms.

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice.

It has been hypothesized that α-synuclein (αS) misfolding may begin in peripheral nerves and spread to the central nervous system (CNS), leading to Parkinson disease and related disorders. Although recent data suggest that αS pathology can spread within the mouse brain, there is no direct evidence for spread of disease from a peripheral site. In the present study, we show that hind limb intramuscular (IM) injection of αS can induce pathology in the CNS in the human Ala53Thr (M83) and wild-type (M20) αS transgenic (Tg) mouse models. Within 2-3 mo after IM injection in αS homozygous M83 Tg mice and 3-4 mo for hemizygous M83 Tg mice, these animals developed a rapid, synchronized, and predictable induction of widespread CNS αS inclusion pathology, accompanied by astrogliosis, microgliosis, and debilitating motor impairments. In M20 Tg mice, starting at 4 mo after IM injection, we observed αS inclusion pathology in the spinal cord, but motor function remained intact. Transection of the sciatic nerve in the M83 Tg mice significantly delayed the appearance of CNS pathology and motor symptoms, demonstrating the involvement of retrograde transport in inducing αS CNS inclusion pathology. Outside of scrapie-mediated prion disease, to our knowledge, this findiing is the first evidence that an entire neurodegenerative proteinopathy associated with a robust, lethal motor phenotype can be initiated by peripheral inoculation with a pathogenic protein. Furthermore, this facile, synchronized rapid-onset model of α-synucleinopathy will be highly valuable in testing disease-modifying therapies and dissecting the mechanism(s) that drive αS-induced neurodegeneration.

Amyloidogenic α-synuclein seeds do not invariably induce rapid, widespread pathology in mice.

In order to further evaluate the parameters whereby intracerebral administration of recombinant α-synuclein (αS) induces pathological phenotypes in mice, we conducted a series of studies where αS fibrils were injected into the brains of M83 (A53T) and M47 (E46K) αS transgenic (Tg) mice, and non-transgenic (nTg) mice. Using multiple markers to assess αS inclusion formation, we find that injected fibrillar human αS induced widespread cerebral αS inclusion formation in the M83 Tg mice, but in both nTg and M47 Tg mice, induced αS inclusion pathology is largely restricted to the site of injection. Furthermore, mouse αS fibrils injected into nTg mice brains also resulted in inclusion pathology restricted to the site of injection with no evidence for spread. We find no compelling evidence for extensive spread of αS pathology within white matter tracts, and we attribute previous reports of white matter tract spreading to cross-reactivity of the αS pSer129/81A antibody with phosphorylated neurofilament subunit L. These studies suggest that, with the exception of the M83 Tg mice which appear to be uniquely susceptible to induction of inclusion pathology by exogenous forms of αS, there are significant barriers in mice to widespread induction of αS pathology following intracerebral administration of amyloidogenic αS.

Induction of CNS α-synuclein pathology by fibrillar and non-amyloidogenic recombinant α-synuclein.

BACKGROUND: α-Synuclein (αS) is the major component of several types of brain inclusions including Lewy bodies, a hallmark of Parkinson's disease. Aberrant aggregation of αS also is associated with cellular demise in multiple neurologic disorders collectively referred to as synucleinopathies. Recent studies demonstrate the induction of αS pathology by a single intracerebral injection of exogenous amyloidogenic αS in adult non-transgenic and transgenic mice expressing human αS. To further investigate the mechanism of pathology induction and evaluate an experimental paradigm with potential for higher throughput, we performed similar studies in neonatal mice injected with αS. RESULTS: In non-transgenic mice, we observed limited induction of neuronal αS inclusions predominantly 8 months after brain injection of aggregated, amyloidogenic human αS. More robust inclusion pathology was induced in transgenic mice expressing wild-type human αS (line M20), and inclusion pathology was observed at earlier time points. Injection of a non-amyloidogenic (Δ71-82) deletion protein of αS was also able to induce similar pathology in a subset of M20 transgenic mice. M20 transgenic mice injected with amyloidogenic or non-amyloidogenic αS demonstrated a delayed and robust induction of brain neuroinflammation that occurs in mice with or without αS pathological inclusions implicating this mechanism in aggregate formation. CONCLUSIONS: The finding that a non-amyloidogenic Δ71-82 αS can induce pathology calls into question the simple interpretation that exogenous αS catalyzes aggregation and spread of intracellular αS pathology solely through a nucleation dependent conformational templating mechanism. These results indicate that several mechanisms may act synergistically or independently to promote the spread of αS pathology.