Mohammed F. Shamji

Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues

OBJECTIVE Prior reports document macrophage and lymphocyte infiltration with proinflammatory cytokine expression in pathologic intervertebral disc (IVD) tissues. Nevertheless, the role of the Th17 lymphocyte lineage in mediating disc disease remains uninvestigated. We undertook this study to evaluate the immunophenotype of pathologic IVD specimens, including interleukin-17 (IL-17) expression, from surgically obtained IVD tissue and from nondegenerated autopsy control tissue. METHODS Surgical IVD tissues were procured from patients with degenerative disc disease (n = 25) or herniated IVDs (n = 12); nondegenerated autopsy control tissue was also obtained (n = 8) from the anulus fibrosus and nucleus pulposus regions. Immunohistochemistry was performed for cell surface antigens (CD68 for macrophages, CD4 for lymphocytes) and various cytokines, with differences in cellularity and target immunoreactivity scores analyzed between surgical tissue groups and between autopsy control tissue regions. RESULTS Immunoreactivity for IL-4, IL-6, IL-12, and interferon-gamma (IFNgamma) was modest in surgical IVD tissue, although expression was higher in herniated IVD samples and virtually nonexistent in control samples. The Th17 lymphocyte product IL-17 was present in >70% of surgical tissue fields, and among control samples was detected rarely in anulus fibrosus regions and modestly in nucleus pulposus regions. Macrophages were prevalent in surgical tissues, particularly herniated IVD samples, and lymphocytes were expectedly scarce. Control tissue revealed lesser infiltration by macrophages and a near absence of lymphocytes. CONCLUSION Greater IFNgamma positivity, macrophage presence, and cellularity in herniated IVDs suggests a pattern of Th1 lymphocyte activation in this pathology. Remarkable pathologic IVD tissue expression of IL-17 is a novel finding that contrasts markedly with low levels of IL-17 in autopsy control tissue. These findings suggest involvement of Th17 lymphocytes in the pathomechanism of disc degeneration.

Brain tumors and epilepsy: pathophysiology of peritumoral changes.

Epilepsy commonly develops among patients with brain tumors, frequently even as the presenting symptom, and such patients consequently experience substantial morbidity from both the seizures and the underlying disease. At clinical presentation, these seizures are most commonly focal with secondary generalization and conventional medical management is often met with less efficacy. The molecular pathophysiology of these seizures is being elucidated with findings that both the tumoral and peritumoral microenvironments may exhibit epileptogenic phenotypes owing to disordered neuronal connectivity and regulation, impaired glial cell function, and the presence of altered vascular supply and permeability. Neoplastic tissue can itself be the initiation site of seizure activity, particularly for tumors arising from neuronal cell lines, such as gangliogliomas or dysembryoblastic neuroepithelial tumors. Conversely, a growing intracranial lesion can both structurally and functionally alter the surrounding brain tissue with edema, vascular insufficiency, inflammation, and release of metabolically active molecules, hence also promoting seizure activity. The involved mechanisms are certain to be multifactorial and depend on specific tumor histology, integrity of the blood brain barrier, and characteristics of the peritumoral environment. Understanding these changes that underlie tumor-related epilepsy may have roles in both optimal medical management for the seizure symptom and optimal surgical objective and management of the underlying disease.

Impact of surgical approach on complications and resource utilization of cervical spine fusion: a nationwide perspective to the surgical treatment of diffuse cervical spondylosis

BACKGROUND CONTEXT Cervical spine fusion is performed for various indications in patient populations ranging from young and healthy to aged and frail. The choice of surgical approach is affected not only by disease pathoanatomy, but also by age, medical comorbidities, and the number of involved levels. Anterior fusion is more common for single-level pathology in relatively young, healthy patients; and posterior fusion is typically performed on older, more comorbid patients with multilevel disease. Consequently, retrospective comparisons of surgical approaches for cervical fusion will be impacted by this bias, and the optimal management of multilevel cervical spine pathology remains ambiguous with surgeon preference and experience playing a significant role in choice of procedures. PURPOSE To define the complications and resource utilization related to multilevel cervical spine fusion surgery, and to evaluate the impact of surgical approach on these outcomes. STUDY DESIGN/SETTING A retrospective nationwide database study of inpatient perioperative complications. PATIENT SAMPLE All patients undergoing multilevel (four to eight levels) cervical spine fusion for degenerative disease between 2003 and 2005 at institutions represented in the Nationwide Inpatient Sample database. OUTCOME MEASURES Measures of patient periprocedural mortality, selected specific morbidities, and resource utilization were evaluated. Resource utilization included length of hospitalization, inflation-adjusted cost, and likelihood of nonroutine discharge to assisted living. METHODS Data for 8,548 patients who underwent cervical fusion of four to eight levels were collected from the Nationwide Inpatient Sample database (2003-2005), and subjects were grouped by surgical approach (anterior vs. posterior). Descriptive statistics compared baseline characteristics, and bivariate analysis and logistic regression modeling evaluated the effect of surgical approach on mortality, selected postoperative complications, length of stay, hospitalization cost, and discharge disposition. All tests were performed at the 0.05 level of significance. RESULTS This observational study indicates that a posterior approach to multilevel cervical fusion is associated with more respiratory complications, postoperative infections, symptomatic hematomas, and transfusions when compared with an anterior approach. Resource utilization was nearly double for those undergoing a posterior approach, including hospital length of stay, inflation-adjusted cost, and likelihood of discharge to an assisted-living facility. Not surprisingly, this study confirms that patients fused posteriorly had a lower incidence of symptomatic postoperative dysphagia. CONCLUSIONS This nationwide study defines the incidence of mortality and the frequency of inpatient complications encountered during multilevel cervical fusion. The results suggest that immediate morbidity from anterior approaches is less than those undergoing posterior fusion. Prospective analysis is required to evaluate if these findings remain significant in a randomized study population. Further, these results represent only perioperative complications. However, based on the data presented herein, when confronted with the patient requiring a four-level cervical fusion, the anterior approach may offer a less risky and less costly option.

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

Interleukin-17 synergizes with IFNγ or TNFα to promote inflammatory mediator release and intercellular adhesion molecule-1 (ICAM-1) expression in human intervertebral disc cells

Interleukin‐17 (IL‐17) is a cytokine recently shown to be elevated, along with interferon‐γ (IFNγ) and tumor necrosis factor (TNFα), in degenerated and herniated intervertebral disc (IVD) tissues, suggesting a role for these cytokines in intervertebral disc disease. The objective of our study was to investigate the involvement of IL‐17 and costimulants IFNγ and TNFα in intervertebral disc pathology. Cells were isolated from anulus fibrosus and nucleus pulposus tissues of patients undergoing surgery for intervertebral disc degeneration or scoliosis. The production of inflammatory mediators, nitric oxide (NOx), prostaglandin E2 (PGE2) and interleukin‐6 (IL‐6), as well as intercellular adhesion molecule (ICAM‐1) expression, were quantified for cultured cells following exposure to IL‐17, IFNγ, and TNFα. Intervertebral disc cells exposed to IL‐17, IFNγ, or TNFα showed a remarkable increase in inflammatory mediator release and ICAM‐1 expression (GLM and ANOVA, p < 0.05). Addition of IFNγ or TNFα to IL‐17 demonstrated a synergistic increase in inflammatory mediator release, and a marked increase in ICAM‐1 expression. These findings suggest that IVD cells not only respond with a catabolic phenotype to IL‐17 and costimulants IFNγ and TNFα, but also express surface ligands with consequent potential to recruit additional lymphocytes and immune cells to the IVD microenvironment. IL‐17 may be an important regulator of inflammation in the IVD pathologies.

Impact of body habitus on perioperative morbidity associated with fusion of the thoracolumbar and lumbar spine.

OBJECTIVESpinal fusion is performed in patients ranging from young and healthy to aged and frail. Although recent population trends in the United States are toward obesity, no large-scale study has evaluated how body habitus affects mortality, complications, and resource utilization for lumbar spine fusion. Such information is important for patient selection and to confirm the safety of such procedures in this population. METHODSData for 244 170 patients who underwent thoracolumbar or lumbar spine fusion for degenerative disease between 1988 and 2004 were collected from the Nationwide Inpatient Sample database, and subjects were grouped by surgical approach and body habitus. Multivariate logistic regression evaluated group effects on selected postoperative complications, length of stay, resource utilization, and discharge disposition. RESULTSThis study confirms that body habitus affects perioperative morbidity sustained by patients undergoing thoracolumbar or lumbar spine fusion. Demographic heterogeneity exists for race, geography, and number of diseased levels among body habitus groups, prompting application of multivariate logistic regression for outcomes. For all approaches, higher body mass index associated with increased transfusion requirements and likelihood of discharge to assisted living. Furthermore, morbidly obese patients undergoing posterior fusion sustained more wound complications and postoperative infections. CONCLUSIONThis nationwide study describes inpatient complications encountered during fusion surgery in patients who are obese. For a given surgical approach, patients with higher body mass index sustain increased transfusion requirements and utilize more resources during thoracolumbar and lumbar spine fusion. Nevertheless, the findings of equivalent mortality, length of stay, and other complication rates suggest that patients who are obese remain safe surgical candidates.

Fusion order controls expression level and activity of elastin-like polypeptide fusion proteins

We have previously developed a method to purify recombinant proteins, termed inverse transition cycling (ITC) that eliminates the need for column chromatography. ITC exploits the inverse solubility phase transition of an elastin‐like polypeptide (ELP) that is fused to a protein of interest. In ITC, a recombinant ELP fusion protein is cycled through its phase transition, resulting in separation of the ELP fusion protein from other Escherichia coli contaminants. Herein, we examine the role of the position of the ELP in the fusion protein on the expression levels and yields of purified protein for four recombinant ELP fusion proteins. Placing the ELP at the C‐terminus of the target protein (protein‐ELP) results in a higher expression level for the four ELP fusion proteins, which also translates to a greater yield of purified protein. The position of the fusion protein also has a significant impact on its specific activity, as ELP‐protein constructs have a lower specific activity than protein‐ELP constructs for three out of the four proteins. Our results show no difference in mRNA levels between protein‐ELP and ELP‐protein fusion constructs. Instead, we suggest two possible explanations for these results: first, the translational efficiency of mRNA may differ between the fusion protein in the two orientations and second, the lower level of protein expression and lower specific activity is consistent with a scenario that placement of the ELP at the N‐terminus of the fusion protein increases the fraction of misfolded, and less active conformers, which are also preferentially degraded compared to fusion proteins in which the ELP is present at the C‐terminal end of the protein.

Minimally invasive interbody fusion for revision lumbar surgery: technical feasibility and safety.

Study Design Retrospective chart review of one surgeons practice. Objective We evaluate the perioperative morbidity of 43 patients undergoing minimally invasive lumbar interbody fusion to differentiate risks between primary and revision surgery candidates. Summary of Background Data Minimally invasive approaches to the lumbar spine have rapidly evolved and the technical feasibility and safety of minimally invasive interbody fusion is well established. Revision surgery is technically more challenging and may cause avoidance of such approaches because of altered anatomy and absent bony landmarks. Description of minimally invasive surgery approaches among revision patients and the feasibility of such techniques demands clarification. Methods Forty-three consecutive minimally invasive transforaminal lumbar interbody fusions (TLIFs) and posterior lumbar interbody fusions (PLIFs) were reviewed. Estimated blood loss, operative time, and complication rates were compared between primary and revision patients using Student t tests. Results Seventeen revision surgery cases (40%) were compared with 26 primary surgeries (60%) to elucidate differences in operative time, estimated blood loss, and complications. Demographic variables were similar in both groups. Estimated blood loss trended higher among the PLIF group and among revision cases, though no statistical significance was observed. A higher rate of complications, most notably incidental durotomy, was observed among revision cases in both PLIF and TLIF patients. One patient undergoing primary surgery had an intraoperative pedicle fracture, and 1 patient undergoing revision surgery had an asymptomatic screw malposition. No patients had a major complication, nerve injury, infection, or conversion to an open procedure. Conclusions Minimally invasive lumbar interbody fusion by revision surgery is technically feasible and is not associated with more blood loss or neurologic morbidity. However, revision surgery has a higher minor perioperative complication rate, particularly of incidental durotomy. These outcomes demand significant experience before attempting minimally invasive revision surgery in the lumbar spine.

Impact of preoperative neurological status on perioperative morbidity associated with anterior and posterior cervical fusion

OBJECT Cervical spine fusion is performed for various indications in patient populations ranging from young and healthy to aged and frail. Whereas disease pathoanatomy dictates the surgical approach, preoperative neurological status does not necessarily implicate a specific technique. Although one expects anterior decompression to be performed over fewer segments in healthier patients who experience fewer complications and faster recovery, the impact of pre-operative myelopathy on perioperative complications remains unclear. No large-scale study has evaluated rates of common complications for cervical fusion or their association with surgical approach and neurological status. METHODS Data for 96,773 patients who underwent cervical fusion for degenerative disease between 1988 and 2003 were collected from the Nationwide Inpatient Sample database. Patients were grouped according to surgical approach (anterior versus posterior) and preoperative neurological status (myelopathic versus nonmyelopathic). Multivariate regression was used to evaluate group effects on selected postoperative complications, length of stay, and disposition at the time of hospital discharge. Although this technique can control for the observed covariates, the absence of key information such as the number of fused levels precludes statistical comparison between patients who underwent anterior or posterior approaches. RESULTS In this study the authors confirmed that preoperative neurological status impacts perioperative morbidity. For example, patients who were nonmyelopathic and underwent an anterior approach were 7 years younger than the rest of the cohort, and they had a mortality rate of 0.05%. Transfusion was required in 0.34%, and venous thromboembolism occurred in 0.04%. Conversely, these rates were > 13-fold higher in patients with myelopathy who underwent a posterior approach. Furthermore, independent of approach, preoperative myelopathy is highly prognostic of death, pneumonia, transfusion, infection, length of stay, and posthospital disposition. These outcomes at least doubled, with some increasing > 10-fold. CONCLUSIONS This nationwide study clarifies the frequency and associations of inpatient complications encountered when treating cervical spine disease. Whereas immediate complications due to anterior approaches are limited, patients with myelopathy who undergo a posterior approach have a more sobering outlook. This study shows that clinical myelopathy augments rates of complication during cervical fusion, regardless of the approach. The exclusion of pathoanatomical data from the Nationwide Inpatient Sample database, of key importance in guiding the surgical approach, prevents any conclusions being drawn about the merits and disadvantages of anterior versus posterior surgery.

Circulation of the spinal cord: An important consideration for thoracic surgeons

The spinal cord has significant thoracic arterial watershed areas rendering it vulnerable to intraoperative ischemic damage, clearly mandating a need for postoperative neurologic monitoring. Mechanisms of hypoperfusion include aortic cross-clamping, rib retraction, intercostal artery interruption, and costovertebral junction bleeding. We report cases of primary lung cancer resection, resection of pulmonary metastasis adherent to the thoracic aorta, resection of cartilaginous tumor with chest wall invasion, and esophagomyotomy for achalasia-all complicated by postoperative paraplegia. We review spinal cord circulation, describe mechanisms and patterns of neurologic dysfunction of susceptible watershed areas, and outline roles of preoperative spinal angiography and intraoperative evoked potentials.