DOI: 10.31038/JCRM.2019225

Abstract

Lipidology as super-specialty is evolving both in terms of risk prediction but also to uncover the hidden mysteries within humans suffering from atherosclerotic cardiovascular disease (ASCVD) associated complication with apparently similar LDL concentration and particle size. Over decades since LDL discovery in 1950, the science has covered miles to allow us to learn more about the villainous nature of LDL lipoprotein i.e., ApoB, size wise fractions of LDL particles especially the small dense and large buoyant LDL types and oxidized LDLs. However, the recent evidence suggest exploring the morphology of LDLp within plaques suggest the varying concentration of sphingolipids to phosphatidylcholine in LDL-aggregates. This discovery has allowed newer insights into the pathophysiological mechanisms leading to plaque instability and rupture though an accelerated atherosclerotic mechanistic phenomena. This newer development will also allow us to segregate individuals with similar LDL phenotypes in terms of concentration and particle size to end up with ASCVD related complications. This brief communication discusses briefly discusses the recent LDL-plaque relationship and highlights new lipid biomarkers to further allow personalized segregation of cardiovascular disease (CVD) risk.

Key words

LDL-cholesterol (LDLc), small dense LDL-cholesterol (sdLDLc), Large buoyant LDL-cholesterol (lbLDLc), LDL-aggregates, Oxidized LDL, Lipoprotein associated phospholipase A2 (Lp-LPA2), ApoB

1. Introduction

While cholesterol was acknowledged as one of the components being present in the blood from 16^th century onwards, it was Oncley et al in 1950 who isolated the beta globulin from fraction-III by means of ultracentrifugation. [1] Since then it was realized that the increasing LDL lipoprotein concentration emerged strongly as a risk for various atherosclerotic cardiovascular diseases (ASCVD) and was thus included as a primary prevention target parameter. [2] Though multiple studies have highlighted LDL lipoprotein concentration as the culprit, but later research further dissected LDL fractions to identify particle size to be more related with ASCVD. [3] Down the line researchers were able to segregate LDL particles between two broad categories including small dense LDL particles (sdLDc) and large buoyant LDL particles (lbLDLc), where the former category is associated with more atherogenicity and ASCVD. [4] Guidelines followed the initial research and quickly adopted the concept of particle size and some labs even marketed the LDL-particle size as of now. [5] The traditional concept of LDL cholesterol concentration measurements is still, however in vogue across the world and evolved from calculation based methods to directly measuring techniques which have improved at least the precision of LDL measurement. [6] Form the point of view developing and under developed economies the strategy still remains the most cost-effective, well-understood in terms of data interpretation and feasibility in terms of instrument availability. While the reliance on conventional lipid profile data currently seem to be the logical option for many set ups across the globe still, there are gaps with this “LDL concentration approach” to predict ASCVD risk. [7] LDL Lipoprotein structure has more to offer, than just the cholesterol content as the origin from VLDL to movement within circulation and with dumping down physiologically through LDL receptors into liver and pathologically into vasculature is highly variable between subjects. [8] Data suggest simple LDL concentration measures does not provide optimal appraisal of ASCVD in many subjects. Ramasamy et al in his very recent publication has clearly highlighted the limitations in lipid measurement technologies to highlight the need to develop biomarkers to better predict cardio vascular disease (CVD) risk. [7] Lawler et al using Nuclear Magnetic Resonance (NMR) Spectroscopy evaluated different fractions of LDL particles and concluded that small LDL particle was associated with CVD risk.[9] Finally literature at least now clearly acknowledges the LDL sub-fractions to be differently linked with ASCVD, and the whole lipoprotein risk evaluation using traditional lipid markers are poorly equated with future CVD prediction. [10]

2. Emerging biomarkers in Lipidology

a. Small dense LDL-cholesterol (sdLDLc)

The initial search comes in through discovery of LDL-fractions where an initial broader categorization was made as to segregate LDL particles into two categories i.e., sdLDLc and large buoyant LDL cholesterol (lbLDLc). sdLDLc in current research has been considered as risk for CVD. [11] However, lbLDLc were not considered atherogenic which clearly challenges the use of LDLc in clinics for identifying ASCVD risk.

b. ApoB measurements

Alongside the protein components within lipoprotein also entered clinical market as ApoA as surrogate for HDLc and ApoB for LDLc. The Insulin Resistance Atherosclerosis Study (IRAS) have graded ApoB measurements to be more predicative than LDLc.[12] However, research shows ApoB not to provide any additional information than conventional LDLc. [13,14]

c. Lipoprotein associated phospholipase A2 (Lp-LPA2)

This enzyme is found mainly in LDLc where it helps contributes to atherosclerosis but confers some anti-atherogenic advantages to HDLc as well. Lp-PLA(2) studies collaboration group have identified a strong association of enzyme activity and mass with various ASCVD adverse outcomes like stroke, heart diseases and hypertension. Similarly, Anderson J et al have demonstrated Lp-LPA2 as an independent risk factor for predicting coronary artery disease (CAD). [16] Though appealing in terms of its role to cleave oxidized phospholipids and acting as a chemo-attractant to bring inflammatory proteins and cells to unstable plaque, still large trials like JUPITER and HPS have not found additional benefit of its utilization for both primary and secondary prevention of ASCVD than conventional LDLc. [17,18] Another issues haunting Lp-PLA(2) is the measurement variability due to assay formats, which stands mandatory before its clinical use in routine. [19] So it seems that Lp-PLA(2) use in clinical arena is bound to face delays or may never be used due to incoming better markers.

d. LDL Particles

Over the last 2 decades LDL particles have been found to have multiple sizes, where the literature has identified varying atherogenic potential for LDL-sub particles. Gourgari et al have identified in a study LDL-particle size to be higher in polycystic ovarian syndrome subjects (PCOS) in comparison to controls which was related with markers of inflammation and insulin resistance. [20] Similarly others have highlighted LDL particles to be more related with ASCVD. [3] However, the contrasting evidence highlighted in the Multi-Ethnic Study of Atherosclerosis(MESA) observed slightly greater benefit by using LDLp/HDLp ratio but identified this risk prediction for coronary heart disease (CHD) to get attenuated after adjustment of standard lipid variables. [21]

e. Oxidized LDL

For some time researchers did thrive on the concept of LDL concentration and particle size, but emerging evidence from kinetic studies identified various post-translational modifications like oxidative changes. [22, 23] These oxidized LDL (oxLDLc) are considered to result in certain “damage associated molecular patterns” (DAMP), which are later to result in vascular inflammation. [22] So oxLDLc within vessel walls can act as new LDL biomarkers; however, no standardized lipid lowering therapy is yet available to prevent this oxidative damage in LDL.[23]

f. LDL-aggregates

Within vessel wall it has been demonstrated that LDL particles aggregate. [24] These aggregates of LDL particles within arterial walls are quite atherogenic and can cause changes like conversion of macrophages into foam cells and accumulation within smooth muscles to cause accelerated atherosclerosis and plaque formation by the enzyme sphingomyelinase (SMase). [24, 23] LDL-aggregates, though not in correlation with conventional lipid and inflammatory markers but still have been observed to change with lifestyle modifications, use of PCSK9 inhibitors and other treatment modalities. These LDL-aggregates are distinguished by the fact that they have increase sphingolipids to phospatidylcholine ratio, which accelerates the process of atherosclerosis and in turn predispose plaques to rupture.Therefore, LDL-aggregates may emerge as powerful diagnostic and monitoring tool in future. [23–25]

3. Futuristic incorporation in lipid clinic care pathways

While current clinical market poses both economic issues and lack of quality research, still visibility is now here that conventional lipid markers are not able to predict ASCVD in multiple cases and the need is ever appreciated for advance lipid biomarkers to address both personalized medicine and health economics. The below mentioned algorithm is meant for a dedicated lipid clinic where an individualized diagnosis of lipid pathology could be diagnosed to avoid pan-medical trials and to provide specific interventional approached to reduce ASCVD risk for the patients and genetic solutions for the family members.

This data, albeit discussed recently in literature replies to the critical question raised in the clinics that “why ASCVD prevalence did not correspond with LDL concentration and particle size?” Deeper insight intoLDLp interaction within plaque, ratio of sphingolipid / phosphatidylcholine as prevails within LDLp and the activity of sphingomyelinase (SMase) all finally converge towards plaque progression, rupture and thus the acute consequences resulting from the ASCVD. It is anticipated that SMase activity and genetic alterations in LDL aggregation will probably follow these phenotypic changes to clarify the mutations and polymorphisms underlying the varying development of plaques and onward ASCVD risk among individuals.

4. Closing remarks

Incorporation overtime to address one of the crucial villains to cause ASCVD would require additional biomarker arsenal to allow meaningful data to segregate risk prediction among individuals with similarities baseline LDL phenotypes i.e., Aggregation-prone LDLp and Aggregation-resistant LDLp. In this regard advanced lipid clinics can extend help to incorporate LDL particle measurements, phenotyping of LDL classes, functional assays to asses to learn LDL aggregation and oxidized LDL types. Molecular diagnostics can also be added to specifically diagnose the underlying genetic pathology. A one-time assessment can help predict risk for ASCVD related morbidity and mortality along with avoiding people with unnecessary lifelong medication, concerns and as a very powerful primary prevention tool. Perhaps larger tertiary care set ups in country should develop tools and arsenals to perform advanced lipid testing within dedicated lipid clinics to address the multifactorial pathogenesis of ASCVD to address the pushing needs to “personalized medicine”, cost-effective care provision and finally to segregate .patients who need lipid lowering treatment or otherwise.

Consent for publication: Not applicable (No individual data was presented)

Competing interests: The author has no competing interests to declare.

Data funding: There are no funding sources to disclose.

Figure 1. The process of LDLp entry into carotid intima, to changeswithin the plaque resulting in plaque instability and onward rupture.

Figure 2. Evolution LDL biomarkers for predicting adverse ASCVD consequences

References

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DOI: 10.31038/JCRM.2019224

Abstract

Patients with brain tumors are frequently treated with combination chemotherapy and radiation therapy. Alkylating agents, such as Temozolomide, have known carcinogenic effects and are associated with secondary malignancies. This case illustrates the FDG PET / CT findings of an astrocytoma patient treated with Temozolomide presenting with an unknown mediastinal mass, with lymphoma being the most likely diagnosis.

Keywords

Temozolomide, brain tumor, astrocytoma, secondary malignancy, Fluorodeoxyglucose (FDG) PET / CT, lymphoma

Case Report

Figure 1. A 41-year-old male with a history of brain tumor and prior chemotherapy presented with numerous symptoms including back pain. He underwent tumor resection resulting in a pathologic diagnosis of transformed astrocytoma and also received Temozolomide therapy (50 mg/m2) over approximately 4 years. Upon presentation, an MRI revealed leptomeningeal spread, and additionally, a posterior mediastinal mass. Subsequently, a PET/CT was obtained following intravenous administration of 14.2 mCi of fluorine-18 fluorodeoxyglucose (18F-FDG). This study demonstrated intense uptake in the mediastinal mass (Figure 1; A-transaxial CT; B- transaxial FDG PET; C-transaxial fused PET / CT; D-maximum intensity projection FDG PET).

Figure 1.

Biopsy confirmed lymphoid malignancy suspicious for Hodgkin’s disease. Brain tumor therapies with radiation and Temozolomide have demonstrated clinical efficacy [1]. The differential diagnosis for a secondary malignancy in patients with brain malignancies treated with Temozolomide includes hematologic malignancies, however, the only solid malignancy previously reported is lymphoma [2–10]. A recent literature review demonstrated 5 reported cases of lymphoma [7]. All of the other 12 patients either had myelodysplasia or aplastic anemia [7].

Metastatic disease from primary brain tumors outside of the nervous system is extremely uncommon occurring in <2% of the cases; this is attributed to physical barriers including the dura mater and the thickened basement membrane of the blood vessels [11]. In the clinical context of a brain tumor previously treated with Temozolomide, and a suspected extracranial malignant tumor by FDG PET / CT, lymphoma is the primary diagnostic consideration.

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5. Van Ginderachter L, Cox T, Drijkoningen R, Achten R, Joosens E, Maes A, Theunissen K, Mebis J. Non-hodgkin lymphoma after treatment with extended dosing temozolomide and radiotherapy for a glioblastoma: A case report. Case reports in oncology. 2013; 6: 45- 49
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DOI: 10.31038/JCRM.2019223

Abstract

OBJECTIVE: Complex spinal deformities requiring ≥5 fusion levels is challenging, and significantly impacts the quality of life for the patients. Patient reported pain scores are becoming increasingly important as it sheds insight into the patient’s perception of health stat, as well as serving as a proxy of satisfaction for patients with spine deformity undergoing corrective surgery. However, with an aging population, the impact of age on perception of pain before and after undergoing complex deformity correction is understudied. The aim of this study was to evaluate whether there was an association between age and patient-reported pain scores after complex spinal fusions.

METHODS: The medical records of 92 adult (≥18 years old) spine deformity patients undergoing elective, primary complex spinal fusion (≥5 levels) for deformity correction at a major academic institution from 2010 to 2015 were reviewed. Patients were grouped by age: young (<65 years old) and older (≥65 years old). We identified 43 (46.7%) patients ≥65 years old and 49 (53.3%) <65 years old (Elderly: n = 43 vs. Young: n = 49). Patient demographics, comorbidities, intraoperative and postoperative complication rates were collected for each patient. Inpatient patient-reported pain scores and ambulatory status were also collected. The primary outcome of this study was patient-reported pain scores.

RESULTS: Patient demographics and comorbidities were slightly different between both cohorts, with the Elderly cohort having a greater proportion of patients with hypertension, hyperlipidemia, and osteoarthritis, Table 1. The median number of fusion levels operated, length of surgery, estimated blood loss, and complication rates were similar between both cohorts, Table 2. Moreover, the post-operative complication profiles between the cohorts were also similar, except for the Elderly having a higher rate of post-operative delirium (16.3% vs. 0.0%), Table 3. Baseline (p = 0.1885), First-(p = 0.3331) and Last-(p = 0.1990) post-operative patient reported pain scores were similar between cohorts, Table 4. However, the Elderly cohort trended to have a greater reduction of pain from baseline to Last pain score, compared to the Young cohort (Elderly: -2.4 ± 4.1 vs. Young: -0.69 ± 4.5, p = 0.0556), Table 4. While ambulation immediately before discharge was similar in both groups, the Elderly cohort had significantly fewer ambulatory steps on the first post-operative ambulatory day compared to Young cohort (Elderly: 40.2 ± 63.4 vs. Young: 106.0 ± 134.6, p = 0.0042), Table 4.

CONCLUSIONS: Our study suggests that age may have an impact in patient perception of pain and improvement after complex spinal fusions (≥5 levels). Consideration of patients’ age may facilitate tailored pain management and physical therapy regimens in deformity patients undergoing correction surgery.

INTRODUCTION

In the last decade, patient-reported outcomes (PRO) measures have grown to be a significant proxy for overall quality of care [1]. In spine surgery, many hospitals use a variety of PRO metrics as a mean to qualify surgical effectiveness and satisfaction [2,3]. One particular PRO that has been shown to have the greatest influence on patients’ functional status and satisfaction has been pain scores. Pain is the driving factor for most patients to undergo elective deformity correction surgery. In a study by author et al. of xx patients undergoing deformity surgery, demonstrated that 80% of patients presenting to clinic have pain as a driving factor. Complex spine surgery involving 5-levels and greater impact patients significantly, however it has provided tremendous quality of life, functionality and pain reduction. Identifying risk factors that influence perception of pain after deformity correction surgery is necessary to better overall quality of care.

With an aging population, there has been an expansion of patients presenting with adult spine deformity (ASD) [4,5]. Elderly patients undergoing complex spine deformity surgery have unique surgical challenges due to increasing medical comorbidities, fragility and physiological changes associated with age. Similarly, geriatric patients present with a varying perception of pain, functionality and disability. Previous studies have demonstrated mixed associations with age and pain scores, with some demonstrating a negative correlated with age [6,7], greater pain with increasing age[8–10], and even no correlation at all [11–13]. However, previous studies have mostly looked at spinal fusions involving less than 3 levels, with a paucity of data in complex spinal fusion (≥5 levels) patients.

The aim of this study was to evaluate whether there was an association between age and patient-reported pain scores after complex spinal fusions.

METHODS

The medical records of 92 adult (≥18 years old) spine deformity patients undergoing elective, primary complex spinal fusion (≥5 levels) for deformity correction at a major academic institution from 2010 to 2015 were reviewed. Institutional review board approval was obtained prior to study initiation. Inclusion criteria included patients with 1) available demographics and treatment; 2) who underwent an elective, primary complex spinal fusion (≥5 levels) for deformity correction; and 3) who had baseline and post-operative patient reported pain scores. Patients were grouped by age: young (<65 years old) and older (≥65 years old). We identified 43 patients (46.7%) ≥65 years old and 49 patients (53.3%) <65 years old (Elderly: n = 43 vs. Young: n = 49). Patient demographics, comorbidities, intraoperative and postoperative complication rates were collected for each patient. Inpatient patient-reported pain scores and ambulatory status were also collected. The primary outcome of this study was the difference in patient-reported pain scores between elderly and young patients undergoing complex spine deformity surgery.

Baseline characteristics and demographic variables evaluated included patient age, sex, and body mass index (BMI). Comorbidities included depression, anxiety, chronic obstructive pulmonary disease (COPD), diabetes, congestive heart failure (CHF), coronary artery disease (CAD), atrial fibrillation (A-Fib), prior myocardial infarction (MI), hypertension (HTN), hyperlipidemia (HLD), and osteoarthritis. Other preoperative variables collected included alcohol use, smoking status, and home narcotic use.

Intraoperative variables included number of fusion levels, operative time, estimated blood loss (EBL), administration of packed red blood cell (PRBC) or cell-saver transfusions, and whether an osteotomy was performed. Other operative variables assessed included use of somatosensory stimulus evoked potentials (SSEP), transcranial motor evoked potentials (TcMEP), electromyography (EMG), and fluoroscopy. Additionally, whether patients received bone graft and intra-operative drain placement were also collected. Intraoperative complications collected included spinal cord injury, nerve root injury, and incidental durotomy.

Postoperative complications included length of stay in hospital (LOS), ICU transfer rate, delirium, urinary tract infection (UTI), fever, ileus, deep and superficial surgical site infection (SSI), wound dehiscence, draining wounds, pneumonia, hypertension (HTN), hypotension, hematoma, anemia, MI, weakness, sensory deficit, and urinary retention.

Baseline and post-operative inpatient patient-reported pain scores and ambulatory status were also collected. Pain scores were recorded on a scale from 0 to 10 first post-operative day and prior to discharge. Ambulatory status included the number of days from the operating room to ambulation, the number of steps of first ambulatory steps, and the number of steps of last ambulatory steps.

Parametric data were expressed as means ± standard deviation (SD) and compared using the Student’s t-test. Nonparametric data were expressed as median [interquartile range] and compared via the Mann-Whitney U test. Nominal data were compared with the χ² test. A multivariate nominal logistic regression was used to assess the association between age and patient-reported pain scores. All tests were two-sided and were statistically significant if the p-value was less than 0.05. Statistical analysis was performed using JMP®, Version 13. SAS Institute Inc., Cary, NC, 1989–2007.

RESULTS

Patient Demographics and Preoperative Variables

There were 92 adults (≥18 years old) who met the inclusion criteria of this study (Elderly: n = 43; Young: n = 49), Table 1. Overall, the average age for the Elderly cohort was 71.6 ± 4.7 years and for the Young cohort was 41.4 ± 16.8 years. There were no significant differences in gender or BMI between the cohorts (Elderly: 26.8 ± 4.3 kg/m² vs. Young: 41.4 ± 16.8 kg/m², p = 0.7759), Table 1. The prevalence of some comorbidities between the cohorts were similar, including depression (p = 0. 5103), anxiety (0. 7253), COPD (p = 0. 3116), diabetes (p = 0. 3733), CHF (p = 0. 3729), CAD (p = 0. 0656), A-Fib (p = 0. 1253), and prior MI (p = 0. 3116). The Elderly cohort had a higher rate of HTN (Elderly: 72.1% vs. Young: 34.7%, p = 0.0003), HLD (Elderly: 55.8% vs. Young: 24.5%, p = 0.0021), and osteoarthritis (Elderly: 53.5% vs. Young: 16.3%, p = 0.0002) but a lower percentage of alcohol use (Elderly: 41.9% vs. Young: 20.4%, p = 0. 0257). Current smoking (p = 0.4929) and pre-operative narcotic use (p = 0. 2971) did not differ between the cohorts, Table 1.

Table 1. Demographic and Comorbidities

Intraoperative Variable and Complications

The median number of fusion levels (Elderly: 9 [7–10] vs. Young: 9 [7–13], p = 0.2844) and operative time (Elderly: 339.3 ± 147.0 mins vs. Young: 312.7 ± 103.1, p = 0.3232) were similar between cohorts, Table 2. The Young cohort had a higher rate of SSEP (Elderly: 25.0% vs. Young: 46.5%, p = 0.0415) and TcMEP (Elderly: 7.5% vs. Young: 34.9%, p = 0.0025), but the utilization of EMG (p = 0.8070) and fluoroscopy (p = 0.1064) were similar between cohorts, Table 2. The Elderly cohort also had a higher rate of PRBC Transfusions (Elderly: 70.0% vs. Young: 38.8%, p = 0.0030), Table 2. There were no significant differences in the other surgical variables, including intra-operative EBL (Elderly: 1544.8 ± 1265.0 mL vs. Young: 1384.2 ± 1521.1 mL, p = 0.5819), cell-saver transfusions (Elderly: 76.7% vs. Young: 67.4%, p = 0.3179), and the performance of osteotomy (Elderly: 18.6% vs. Young: 14.3%, p = 0.5758) between the cohorts, Table 2. There were also no significant differences in nerve root/spinal cord injuries (p = 0.000) or incidental durotomy (p = 0.5854), Table 2. The proportion of patients receiving bone graft (p = 0.1732) and having a drain placement (p = 0.8986) were also similar between the cohorts, Table 2.

Table 2. Intraoperative Variables and Complications

SSEP = Sensory Stimulus Evoked Potentials; TcMEP = Transcranial Motor Evoked Potentials;

Postoperative Complications

There were no significant differences in overall LOS between the cohorts (Elderly: 8.3 ± 5.4 days vs. Young: 6.4 ± 3.1 days, p = 0.0525) or ICU transfer (Elderly: 56.1% vs. Young: 50.0%, p = 0.5657), Table 3. Compared to the Elderly group, the Elderly cohort experienced a significantly higher incidence of post-operative delirium (Elderly: 16.3% vs. Young: 0.0%, p = 0.0033) and anemia (Elderly: 58.1% vs. Young: 29.2%, p = 0.0053), Table 3. There were no significant differences in the incidence of other post-operative complications, including UTI (p = 0.1314), fever (p = 0.2102), ileus (p = 0.4929), Deep SSI (0.2437), wound dehiscence (p = 0.5053), draining wounds (p = 0.1349), superficial SSI (p = 0.3476), pneumonia (p = 0.3412), HTN (p = 0.0670), hypotension (p = 0.8379), hematoma (p = 0.9373), MI (p = 0.1308), weakness (p = 0.8084), sensory deficits (p = 0.000), and urinary retention (p = 0.2093), Table 3.

Table 3. Postoperative Complications

Pre- and Post-Operative Patient Reported Pain Scores and Ambulatory Status

Baseline pain scores (Elderly: 6.0 ± 2.7 vs. Young: 5.1 ± 3.5, p = 0.1885) as well as the first pain score (Elderly: 6.4 ± 3.0 vs. Young: 5.8 ± 2.7, p = 0.3331) and the last pain score (Elderly: 3.5 ± 3.5 vs. Young: 4.4 ± 3.1, p = 0. 1990) were similar between both cohorts, Table 4. There were no significant differences between the change from baseline to first pain score (Elderly: +0.44 ± 3.4 vs. Young: +0.71 ± 3.8, p = 0.7180), but the elderly trended to have a greater reduction of pain (Elderly: -2.4 ± 4.1 vs. Young: -0.69 ± 4.5, p = 0.0556), Table 4. Additionally, there were no significant differences in the number of days from the operating room to ambulation (p = 0.9904) or the number of steps of last ambulatory steps (p = 0.0789), Table 4. However, the Elderly cohort had significantly fewer ambulatory steps on the first post-operative ambulatory day compared to Young cohort (Elderly: 40.2 ± 63.4 vs. Young: 106.0 ± 134.6, p = 0.0042), Table 4.

Table 4. Pre- and Post-Operative Patient Reported Pain Scores and Ambulatory Status

DISCUSSION

In this retrospective study, we show that elderly patients (≥65 years old) had a greater pain reduction compared to younger patients after complex spinal fusions (≥5 levels) for adult deformity correction.

Previous studies have demonstrated associations between age and complications after adult deformity correction surgery. In a retrospective review of 206 patients undergoing spinal fusion for scoliosis correction, Smith et al. found that total perioperative complications were significantly higher in the 65–85 year age range than in 25–44 and 44–85 year age ranges [10]. Similarly, in another retrospective analysis of 46 patients who underwent a thoracic or lumbar arthrodesis (≥5 spinal levels), Daubs et al. demonstrated that patients older than age 69 years had a 9-fold greater likelihood to have a major complication [12]. In another retrospective review of a prospective multicenter study of 480 patients who underwent spinal surgery for deformity correction, Soroceanu et al. demonstrated that older age trended to be a predictor for a higher medical complication rate [14]. Analogous to the aforementioned studies, our study showed that elderly patients had increasing rates of post-operative anemia and incidences of delirium compared to the younger cohort.

Along with complication rates, previous studies have explored the impact age has on PROs after deformity correction surgery. In the Smith et al. study of 206 patients, the authors showed that elderly patients had initial greater disability and greater neck and back pain [10]. In a retrospective study of 55 patients who underwent ≥5 levels of spinal fusion to the sacrum with iliac fixation, Elsamadicy et al. found no significant difference in pain scores between young and elderly cohorts after surgery[13]. Similarly, in the retrospective analysis of 46 patients who underwent a thoracic or lumbar arthrodesis (≥5 spinal levels), Daubs et al. reported that age had no impact on disability (ODI) scores [12]. Our study showed that elderly patients trended to have worse pain scores before spinal fusion, but the surgery brought a greater improvement of pain than the younger cohort by their last day in the hospital. This suggests that elderly people have better patient-reported outcomes and that spinal surgery may be more beneficial for them than the younger cohort.

Previous studies have also looked at the impact of age on long-term patient-reported outcomes collected during follow-up. In a retrospective review of 374 patients who had undergone a 3-column pedicle subtraction osteotomy, Scheer et al. showed that the older patients had greater improvement in 2-year disability and Scoliosis Research Society-22 questionnaire (SRS) total scores [9]. Furthermore, disability scores and leg pain at 2-year follow up were significantly more improved among elderly patients than younger ones [9]. In contrast, in a multicenter prospective study of 56 patients who underwent primary spinal deformity surgery for scoliosis, Birdwell et al. found that age had no effect on rates of improvement in pain in a 2-year follow-up [11]. In a prospective study of 40 patients with posterior reconstruction with an instrumented fusion from the thoracic spine to the sacrum, Crawford et al. demonstrated that the elderly cohort had worse Physical Component Score (PCS) but higher MCS scores at baseline [17]. However, at two-year follow-up, there were no significant differences in any of the scores [17].

In an era of trying to reduce medical costs, a few studies have looked at the impact of age and pain on cost following surgery. In a retrospective analysis of 76 US patients undergoing spinal fusion (≥5 levels) for deformity correction, Yagi et al. reported that direct hospital costs for the initial surgery averaged to $71,638 ± 23,246 and 2-year follow up costs came out to be $44,479 ± 10,943 [18]. In a retrospective study of a prospective, consecutive, multicenter database of 514 patients who underwent surgery for adult spinal deformity, Fischer et al. demonstrated that age greater than 55 years was associated with cost-effectiveness, as measured by cost/QALY [19]. Two important factors that affect cost are pain medication use and hospital length of stay. In a retrospective study of 78 postoperative patients requiring morphine, Macintyre et al. found that the strongest correlator with increased morphine requirement was increasing age [8]. In a prospective longitudinal study of 752 patients who underwent an elective laminectomy and fusion for degenerative lumbar conditions, Sivaganesan et al. found that the average 90-day cost of surgery was $29,295, and the amount of preop and postop opioid use was a significant driver of that cost [20]. Concerning length of stay, in a retrospective study of 55 patients who underwent ≥5 levels of spinal fusion to the sacrum with iliac fixation, Elsamadicy et al. found no difference length of stay between young and elderly cohorts [13]. In contrast, in a prospective cohort study of 411 patients admitted to a New York hospital with a hip fracture, Morrison et al. found that greater pain is associated with longer length of stay and long-term functional impairment, both of which increases costs [21]. Analogously, in the Romano et al. study of 10,416 patients, the authors reported that patients older than 70 years of age were had a 1.8 times longer length of stay those 31–40 years of age [16]. In a retrospective study of 480 patients undergoing surgery for adult spinal deformity, McCarthy et al. found that a 1-year increase in patient age increased index costs by $2,600, and an extra day in the hospital increased index costs by $4,600 [22]. Thus, reducing pain, and therefore pain medication use, and hospital length of stay would help drive down the costs of complex spinal surgery.

This study has limitations with potential implications for study interpretation. Although all variables were recorded pre-, peri-, and postoperatively, they were reviewed retrospectively and, as such, are limited by the weaknesses inherent to retrospective analyses. Furthermore, a relatively small patient sample size from only one academic center was used, making broad conclusions difficult and potentially biasing our results for particular patient population or treatment paradigms. Despite these limitations, this study has demonstrated that an elderly age is associated with a greater reduction in pain after complex spinal fusion (≥5 levels) for deformity correction.

CONCLUSIONS

Our study suggests that age may have an impact in patient perception of pain and improvement after complex spinal fusions (≥5 levels). Consideration of patients’ age may facilitate tailored pain management and physical therapy regimens in deformity patients undergoing correction surgery.

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