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David B. Cohen

Infections in the spine can lead to a wide range of problems for both the patient and physician. There is perhaps no more devastating complication than the neurological consequences of a cauda equina syndrome due to spinal infection. A variety of organisms and origins can make diagnosis and treatment of spinal infection a difficult task. Both pyogenic and nonpyogenic organisms can cause vertebral involvement and can result in an epidural abscess with neurological compromise. Nonetheless, these two types of infections vary greatly in terms of associated patient demographics, clinical course, and treatments. The purpose of this paper was to review these types of infections and summarize treatment recommendations for this difficult condition.

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Alan R. Cohen, David Leifer, Marc Zechel, Daniel P. Flaningan, Jonathan S. Lewin, and W. David Lust

The purpose of this study was to elucidate the pathophysiology of hydrocephalus in a new transgenic model of mice created to overproduce the cytokine, transforming growth factor-ß1 (TGFß1), in the central nervous system (CNS).

Galbreath and colleagues generated transgenic mice that overexpressed TGFß1 in the CNS in an effort to examine the role of this cytokine in the astrocytic response to injury. Unexpectedly, the animals developed severe hydrocephalus and died. The authors perpetuated this transgenic colony to serve as a model of congenital hydrocephalus, breeding asymptomatic carrier males that were heterozygous for the transgene with wild-type females.

One hundred twelve (49.6%) of 226 mice developed clinical manifestations of hydrocephalus, which was characterized by dorsal doming of the calvaria, spasticity, limb tremors, ataxia, and ultimately death. The presence of the TGFß1 transgene was determined by performing polymerase chain reaction (PCR) analysis of sample cuts of tail. The animals with the hydrocephalic phenotype consistently carried the transgene, although some animals with the transgene did not develop hydrocephalus. Animals without the transgene did not develope hydrocephalus.

Alterations in brain structure were characterized using magnetic resonance (MR) imaging, gross and light microscopic analysis, and immunocytochemistry. Magnetic resonance imaging readily distinguished hydrocephalic animals from nonhydrocephalic controls, and it demonstrated an obstruction at the outlets of the fourth ventricle. Gross and light microscopic examination confirmed the MR findings. The results of immunofluorescent staining of brain tissue slices revealed the presence of the TGFß1 cytokine and its receptor preferentially in the meninges and subarachnoid space in both hydrocephalic and control mice. Reverse transcriptase-PCR analysis demonstrated tissue-specific expression of the TGFß1 gene in the brains of transgenic mice, and enzyme-linked immunosorbent assay confirmed the occurrence of overexpression of the TGFß1 cytokine in brain, cerebrospinal fluid, and plasma.

The transgenic murine model provides a reproducible representation of congenital hydrocephalus. The authors hypothesize that overexpression of TGFß1 in the CNS causes hyrdocephalus by altering the environment of the extracellular matrix and interfering with the circulation of cerebrospinal fluid. A model of hydrocephalus in which the genetic basis is known should be useful for evaluating hypotheses regarding the pathogenesis of this disorder and additionally, should help in the search for novel treatment strategies.

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Alan R. Cohen, David W. Leifer, Marc Zechel, Daniel P. Flaningan, Jonathan S. Lewin, and W. David Lust

Object. The purpose of this study was to elucidate the pathophysiological characteristics of hydrocephalus in a new transgenic model of mice created to overproduce the cytokine transforming growth factor—β1 (TGFβ1) in the central nervous system (CNS).

Methods. Galbreath and colleagues generated transgenic mice that overexpressed TGFβ1 in the CNS in an effort to examine the role of this cytokine in the response of astrocytes to injury. Unexpectedly, the animals developed severe hydrocephalus and died. The authors have perpetuated this transgenic colony to serve as a model of congenital hydrocephalus, breeding asymptomatic carrier males that are heterozygous for the transgene with wild-type females.

One hundred twelve (49.6%) of 226 mice developed clinical manifestations of hydrocephalus, characterized by dorsal doming of the calvaria, spasticity, limb tremors, ataxia, and, ultimately, death. The presence of the TGFβ1 transgene was determined by performing polymerase chain reaction (PCR) analysis of sample tail slices. Animals with the hydrocephalic phenotype consistently carried the transgene, although some animals with the transgene did not develop hydrocephalus. Animals without the transgene did not develop hydrocephalus.

Alterations in brain structure were characterized using magnetic resonance (MR) imaging, gross and light microscopic analysis, and immunocytochemical studies. Magnetic resonance imaging readily distinguished hydrocephalic animals from nonhydrocephalic controls and demonstrated an obstruction at the outlets of the fourth ventricle. Gross and light microscopic examination confirmed the MR findings. The results of immunofluorescent staining of brain tissue slices revealed the presence of the TGFβ1 cytokine and its receptor preferentially in the meninges and subarachnoid space in both hydrocephalic and control mice. Reverse transcriptase—PCR analysis demonstrated tissue-specific expression of the TGFβ1 gene in the brains of transgenic mice, and enzyme-linked immunosorbent assay confirmed overexpression of the TGFβ1 cytokine in brain, cerebrospinal fluid, and plasma.

Conclusions. The transgenic murine model provides a reproducible representation of congenital hydrocephalus. The authors hypothesize that overexpression of TGFβ1 in the CNS causes hydrocephalus by altering the environment of the extracellular matrix and interfering with the circulation of cerebrospinal fluid. A model of hydrocephalus in which the genetic basis is known should be useful for evaluating hypotheses regarding the pathogenesis of this disorder and should also help in the search for new treatment strategies.

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Ryan S. Kitagawa, Robert M. Van Haren, Shoji Yokobori, David Cohen, Samuel R. Beckerman, Faiz Ahmad, and M. Ross Bullock

Object

Simultaneous traumatic brain injury (TBI) and aortic injury has been considered unsurvivable for many years because treatments such as sedation and blood pressure goals conflict for these 2 conditions. Additionally, surgical interventions for aortic injury often require full anticoagulation, which is contraindicated in patients with TBI. For these reasons, and due to the relative rarity of aortic injury/TBI, little data are available to guide treating physicians.

Methods

A retrospective review was performed on all simultaneous TBI and aortic injury cases from 2000 to 2012 at a university-affiliated, Level I trauma center. Patient demographics, imaging studies, interventions, and outcomes were analyzed. Traumatic brain injury/aortic injury cases treated with endovascular stenting were specifically studied to determine trends in procedure timing, use of anticoagulation, and neurological outcome.

Results

Thirty-three patients with concurrent TBI and aortic injury were identified over a 12-year period. The median patient age was 44 years (range 16–86 years) and the overall mortality rate after imaging diagnosis was 46%. All surviving patients were awake and neurologically functional at discharge, and 83% were discharged home or to rehabilitation facilities. Patients who died had a higher Injury Severity Scale score (p = 0.006). Severe TBI (p = 0.045) or hemodynamic instability (p = 0.015) upon arrival to the hospital was also correlated with increased mortality rates. Thirty-three percent of aortic injury/TBI patients (n = 11) underwent endovascular stenting, and 7 of these patients received intravenous anticoagulation therapy at the time of surgery. Six of these 7 anticoagulation-treated patients experienced no significant progression on postoperative brain CT, whereas 1 patient died of hemodynamic instability prior to undergoing further imaging.

Conclusions

Simultaneous TBI and aortic injury is a rare condition with a historically poor prognosis. However, these results suggest that many patients can survive with a good quality of life. Technological advances such as endovascular aortic stenting may improve patient outcome, and anticoagulation is not absolutely contraindicated after TBI.

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Mark Ren, Barry R. Bryant, Andrew B. Harris, Khaled M. Kebaish, Lee H. Riley III, David B. Cohen, Richard L. Skolasky, and Brian J. Neuman

OBJECTIVE

The objectives of the study were to determine, among patients with adult spinal deformity (ASD), the following: 1) how preoperative opioid use, dose, and duration of use are associated with long-term opioid use and dose; 2) how preoperative opioid use is associated with rates of postoperative use from 6 weeks to 2 years; and 3) how postoperative opioid use at 6 months and 1 year is associated with use at 2 years.

METHODS

Using a single-center, longitudinally maintained registry, the authors identified 87 patients who underwent ASD surgery from 2013 to 2017. Fifty-nine patients reported preoperative opioid use (37 high-dose [≥ 90 morphine milligram equivalents daily] and 22 low-dose use). The duration of preoperative use was long-term (≥ 6 months) for 44 patients and short-term for 15. The authors evaluated postoperative opioid use at 6 weeks, 3 months, 6 months, 1 year, and 2 years after surgery. Multivariate logistic regression was used to determine associations of preoperative opioid use, dose, and duration with use at each time point (alpha = 0.05).

RESULTS

The following preoperative factors were associated with opioid use 2 years postoperatively: any opioid use (adjusted odds ratio [aOR] 14, 95% CI 2.5–82), high-dose use (aOR 7.3, 95% CI 1.1–48), and long-term use (aOR 17, 95% CI 2.2–123). All patients who reported high-dose opioid use at the 2-year follow-up examination had also reported preoperative opioid use. Preoperative high-dose use (aOR 247, 95% CI 5.8–10,546) but not long-term use (aOR 4.0, 95% CI 0.18–91) was associated with high-dose use at the 2-year follow-up visit. Compared with patients who reported no preoperative use, those who reported preoperative opioid use had higher rates of use at each postoperative time point (from 94% vs 62% at 6 weeks to 54% vs 7.1% at 2 years) (all p < 0.001). Opioid use at 2 years was independently associated with use at 1 year (aOR 33, 95% CI 6.8–261) but not at 6 months (aOR 4.3, 95% CI 0.95–24).

CONCLUSIONS

Patients’ preoperative opioid use, dose, and duration of use are associated with long-term use after ASD surgery, and a high preoperative dose is also associated with high-dose opioid use at the 2-year follow-up visit. Patients using opioids 1 year after ASD surgery may be at risk for long-term use.

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Micheal Raad, Andrew B. Harris, Varun Puvanesarajah, Mostafa H. El Dafrawy, Floreana N. Kebaish, Brian J. Neuman, Richard L. Skolasky, David B. Cohen, and Khaled M. Kebaish

OBJECTIVE

Patients’ expectations for pain relief are associated with patient-reported outcomes after treatment, although this has not been examined in patients with adult spinal deformity (ASD). The aim of this study was to identify associations between patients’ preoperative expectations for pain relief after ASD surgery and patient-reported pain at the 2-year follow-up.

METHODS

The authors analyzed surgically treated ASD patients at a single institution who completed a survey question about expectations for back pain relief. Five ordinal answer choices to “I expect my back pain to improve” were used to categorize patients as having low or high expectations. Back pain was measured using the 10-point numeric rating scale (NRS) and Scoliosis Research Society–22r (SRS-22r) patient survey. Preoperative and postoperative pain were compared using analysis of covariance.

RESULTS

Of 140 ASD patients eligible for 2-year follow-up, 105 patients (77 women) had pre- and postoperative data on patient expectations, 85 of whom had high expectations. The mean patient age was 59 ± 12 years, and 46 patients (44%) had undergone previous spine surgery. The high-expectations and low-expectations groups had similar baseline demographic and clinical characteristics (p > 0.05), except for lower SRS-22r mental health scores in those with low expectations. After controlling for baseline characteristics and mental health, the mean postoperative NRS score was significantly better (lower) in the high-expectations group (3.5 ± 3.5) than in the low-expectations group (5.4 ± 3.7) (p = 0.049). The mean postoperative SRS-22r pain score was significantly better (higher) in the high-expectations group (3.3 ± 1.1) than in the low-expectations group (2.6 ± 0.94) (p = 0.019).

CONCLUSIONS

Despite similar baseline characteristics, patients with high preoperative expectations for back pain relief reported less pain 2 years after ASD surgery than patients with low preoperative expectations.

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Rafa Rahman, Alvaro Ibaseta, Jay S. Reidler, Nicholas S. Andrade, Richard L. Skolasky, Lee H. Riley III, David B. Cohen, Daniel M. Sciubba, Khaled M. Kebaish, and Brian J. Neuman

OBJECTIVE

The authors conducted a study to analyze associations between changes in depression/anxiety before and 12 months after spine surgery, as well as changes in scores using the Patient-Reported Outcomes Measurement Information System (PROMIS) at the same time points.

METHODS

Preoperatively and 12 months postoperatively, the authors assessed PROMIS scores for depression, anxiety, pain, physical function, sleep disturbance, and satisfaction with participation in social roles among 206 patients undergoing spine surgery for deformity correction or degenerative disease. Patients were stratified according to preoperative/postoperative changes in depression and anxiety, which were categorized as persistent, improved, newly developed postoperatively, or absent. Multivariate regression was used to control for confounders and to compare changes in patient-reported outcomes (PROs).

RESULTS

Fifty patients (24%) had preoperative depression, which improved in 26 (52%). Ninety-four patients (46%) had preoperative anxiety, which improved in 70 (74%). Household income was the only preoperative characteristic that differed significantly between patients whose depression persisted and those whose depression improved. Compared with the no-depression group, patients with persistent depression had less improvement in all 4 domains, and patients with postoperatively developed depression had less improvement in pain, physical function, and satisfaction with social roles. Compared with the group of patients with postoperatively improved depression, patients with persistent depression had less improvement in pain and physical function, and patients with postoperatively developed depression had less improvement in pain. Compared with patients with no anxiety, those with persistent anxiety had less improvement in physical function, sleep disturbance, and satisfaction with social roles, and patients with postoperatively developed anxiety had less improvement in pain, physical function, and satisfaction with social roles. Compared with patients with postoperatively improved anxiety, patients with persistent anxiety had less improvement in pain, physical function, and satisfaction with social roles, and those with postoperatively developed anxiety had less improvement in pain, physical function, and satisfaction with social roles. All reported differences were significant at p < 0.05.

CONCLUSIONS

Many spine surgery patients experienced postoperative improvements in depression/anxiety. Improvements in 12-month PROs were smaller among patients with persistent or postoperatively developed depression/anxiety compared with patients who had no depression or anxiety before or after surgery and those whose depression/anxiety improved after surgery. Postoperative changes in depression/anxiety may have a greater effect than preoperative depression/anxiety on changes in PROs after spine surgery. Addressing the mental health of spine surgery patients may improve postoperative PROs.

CLASSIFICATION OF EVIDENCE Type of question: causation; study design: prospective cohort study; evidence: class III.

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David J. Bonda, Sunil Manjila, Prachi Mehndiratta, Fahd Khan, Benjamin R. Miller, Kaine Onwuzulike, Gianfranco Puoti, Mark L. Cohen, Lawrence B. Schonberger, and Ignazio Cali

The human prion diseases, or transmissible spongiform encephalopathies, have captivated our imaginations since their discovery in the Fore linguistic group in Papua New Guinea in the 1950s. The mysterious and poorly understood “infectious protein” has become somewhat of a household name in many regions across the globe. From bovine spongiform encephalopathy (BSE), commonly identified as mad cow disease, to endocannibalism, media outlets have capitalized on these devastatingly fatal neurological conditions. Interestingly, since their discovery, there have been more than 492 incidents of iatrogenic transmission of prion diseases, largely resulting from prion-contaminated growth hormone and dura mater grafts. Although fewer than 9 cases of probable iatrogenic neurosurgical cases of Creutzfeldt-Jakob disease (CJD) have been reported worldwide, the likelihood of some missed cases and the potential for prion transmission by neurosurgery create considerable concern. Laboratory studies indicate that standard decontamination and sterilization procedures may be insufficient to completely remove infectivity from prion-contaminated instruments. In this unfortunate event, the instruments may transmit the prion disease to others. Much caution therefore should be taken in the absence of strong evidence against the presence of a prion disease in a neurosurgical patient. While the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have devised risk assessment and decontamination protocols for the prevention of iatrogenic transmission of the prion diseases, incidents of possible exposure to prions have unfortunately occurred in the United States. In this article, the authors outline the historical discoveries that led from kuru to the identification and isolation of the pathological prion proteins in addition to providing a brief description of human prion diseases and iatrogenic forms of CJD, a brief history of prion disease nosocomial transmission, and a summary of the CDC and WHO guidelines for prevention of prion disease transmission and decontamination of prion-contaminated neurosurgical instruments.

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Gregory E. Plautz, Gene H. Barnett, David W. Miller, Bruce H. Cohen, Richard A. Prayson, John C. Krauss, Mark Luciano, Debra B. Kangisser, and Suyu Shu

Object. To determine the feasibility, toxicity, and potential therapeutic benefits of systemic adoptive immunotherapy, 10 patients with progressive primary or recurrent malignant glioma received this treatment. Adoptive immunotherapy, the transfer of immune T lymphocytes, is capable of mediating the regression of experimental brain tumors in animal models. In animal models, lymph nodes (LNs) that drain the tumor vaccine site are a rich source of tumor-immune T cells.

Methods. In this clinical study, patients were inoculated intradermally with irradiated autologous tumor cells and granulocyte macrophage-colony stimulating factor as an adjuvant. Cells from draining inguinal LNs, surgically resected 7 days after vaccination, were stimulated sequentially with staphylococcal enterotoxin A and anti-CD3, and a low dose of interleukin-2 (60 IU/ml) was used to expand the stimulated cells. The maximum cell proliferation was 350-fold over 10 days of culture. The activated cells were virtually all T cells consisting of various proportions of CD4 and CD8 cells. These cells were given to patients by intravenous infusion at doses ranging from 9 × 108 to 1.5 × 1011. There were no Grade 3 or 4 toxicities associated with the treatment. Following T-cell transfer therapy, radiographic regression that lasted at least 6 months was demonstrated in two patients with recurrent tumors. One patient demonstrated stable disease that has lasted for more than 17 months. The remaining patients had progressive disease; however, four of the eight patients with recurrent tumor remain alive more than 1 year after surgery for recurrence. Three patients required intervention with corticosteroid agents or additional surgery approximately 1 month following cell transfer.

Conclusions. These intriguing clinical observations warrant further trials to determine whether this approach can provide therapeutic benefits and improve survival.