Common Complications in Spine Surgery: Pseudoarthrosis

Summary of Key Points

Pseudoarthrosis of the spine is defined as a failure of bony union. Symptoms include persistent pain, failure of instrumentation, and instability.
Diagnosis of pseudoarthrosis remains a challenge and requires high clinical suspicion, as well as utilization of various imaging modalities.
There are numerous patient factors, as well as surgical techniques, that can influence the risk of symptomatic pseudoarthrosis.
Treatment of symptomatic pseudoarthrosis usually requires revision surgery with more robust instrumentation, as well as use of osteoinductive, osteoconductive, and osteogenic agents.
Promising pharmaceutical agents, including antibody therapy, stem cells, and osteobiologics, show promise in reducing rates of nonunion.

Acknowledgment

Thank you to Drs. Vinay Deshmukh, Arnold B. Vardiman, Howard W. Morgan, Jr., Jad Bou Monsef, and Fernando Techy, who authored prior editions of this chapter. Their work laid the foundation for this edition.

Since its first description by Hibbs and Albee in 1911, spinal fusion has become the mainstay for the treatment of a multitude of spinal pathologies, including deformity, infection, instability, and degenerative conditions, among others. ^, Beginning with uninstrumented fusions, great strides have been made in the surgical techniques employed to achieve spinal fusion over the last century. Likewise, the evolution of osteobiologics and advancements in instrumentation have greatly increased the rates of bony fusion following spine surgery. Despite this, pseudoarthrosis remains a challenge for the modern spine surgeon, with up to 23.6% of revision lumbar surgeries performed for pseudoarthrosis. Furthermore, this number is likely to increase, as rates of spinal fusion surgery have continued to grow exponentially over the last two decades. The incidence of pseudoarthrosis will vary depending on the type and extent of procedures performed, with more surgical levels resulting in higher rates of nonunion. A recent metaanalysis reported a pseudoarthrosis rate of 12.9% for patients undergoing spinal fusion for adult spinal deformity (ASD).

A pseudoarthrosis is defined as an absence of bone formation over time across a fracture site or spinal motion segment. Clinically, one can determine a pseudoarthrosis to be present 1 year following surgical intervention in the setting of nonunion on imaging and/or clinical signs and symptoms. Despite this, Kim et al. demonstrated that 29% of pseudoarthroses may present with instrumentation failure up to 2 years postsurgery. ^, Other authors have reported symptoms such as recurrence of back pain following an asymptomatic period, progressive deformity, or “popping” sensations as signs of pseudoarthrosis as late as 7 years following surgery. Ultimately, the true incidence of pseudoarthrosis is likely underreported in the literature because of many cases being asymptomatic and not requiring further intervention. This chapter serves to review basic principles of bony fusion, as well as discuss diagnosis, risk factors, and treatment options for pseudoarthrosis.

Biology of Bone Healing

Bone is a living, dynamic tissue that undergoes constant remodeling as a result of environmental stresses in accordance with Wolff’s law. This gives it a unique capacity to repair and regenerate itself. In fact, bone is one of the few tissues in the body that does not form scar. As a result, the process of bone healing is a recapitulation of primary bone development, and thus can be considered a true regenerative process. These unique qualities are a result of its peculiar composite structure of organic and inorganic materials. Type 1 collagen comprises the organic component of bone and confers plasticity, allowing bone to deform under tension without breaking. The inorganic component, composed primarily of hydroxyapatite, precipitates around the collagen fibers in a process of nucleation and maturation of mineral crystals. The interplay between collagen and the inorganic compounds of bone gives the tissue tremendous strength in compression and bending. The cellular components of bone, which include osteoblasts, osteocytes, and osteoclasts, are connected through an intricate and well-organized system of canals known as the Haversian system.

Osteoblasts are derived from mesenchymal stem cells from the bone marrow and periosteum. Osteoblasts form bone in response to many stimuli and under different conditions, such as growth, physiological remodeling, fracture healing, and heterotopic ossification. Researchers have shown that new bone is formed in response to tumors and infections. An investigation has shown that osteoblasts have the ability to form bone during distraction osteogenesis, when substituting the void initially filled by autologous or allogeneic bone graft, demineralized bone matrix (DBM), or synthetic bone substitutes. The mature osteoblast produces proteins such as type I collagen, osteocalcin, and alkaline phosphatase, a key enzyme in bone mineralization. Osteoblasts become entrapped in their own osteoid matrix and develop long cytoplasmic processes to remain in contact with surrounding cells. They then begin expressing a whole new set of genes to continue bone turnover and mineral homeostasis. These cells are now considered osteocytes (mature bone cells). Osteoclasts are derived from hematopoietic stem cells. They exit the circulation close to the site to be remodeled and are responsible for bone resorption. ^,

Similar to fracture healing, the formation of a spinal fusion mass is a combination of both intramembranous and endochondral ossification. Using a rabbit model, Boden described three distinct phases of spinal fusion mass formation: (1) the inflammatory phase, (2) the reparative phase, and lastly (3) the remodeling phase. The early, or inflammatory phase, typically occurs 1 to 3 weeks following surgery. It is marked by an increase in proinflammatory cytokines such as tumor necrosis factor, platelet-derived growth factor, transforming growth factor (TGF), and fibroblast growth factor. Bone morphogenetic proteins (BMPs), which are members of the TGF-β superfamily, are also produced during this time. This inflammatory response leads to vascular dilation and formation of a hematoma. Eventually, vascular ingrowth and primary intramembranous bone formation occur at the site of decortication, followed by endochondral bone formation across a cartilage scaffold. Healing will typically begin at the edges of the fusion mass, called the outer zone, ending with fusion across the middle, termed the central zone. This explains why nonunions will typically occur at the centroid of two bony structures. The reparative phase usually occurs 4 to 5 weeks after surgery. It is characterized by resorption of necrotic tissue, increased vascularization of the immature bone, and differentiation of pluripotent cells into chondroblasts and osteoblasts. This phase is also marked by calcification of the cartilaginous scaffold, leading to formation of immature bone. The remodeling phase begins after week 6 and is notable for remodeling of immature bone into mature lamellar bone. This process is typically complete by 12 weeks following surgery in a rabbit model. However, it is vital to note that bone remodeling will occur years following surgery, with best estimates for complete fusion in humans occurring between 6 and 18 months.

Although the general sequence of inflammation, repair, and remodeling that occurs in long bone fracture healing also occurs with bone graft repair, there are some distinct differences. Autograft bone used in spinal fusion is initially deprived of blood supply, although a robust nonspecific inflammatory response occurs as a result of preparation of the graft recipient bed. The collection of coagulated blood around the graft is somewhat analogous to the hematoma of an acute fracture, with the complex processes of inflammation ongoing within this milieu. Although some of the periosteum, endosteum, mesenchymal cells, and osteocytes within 0.2 to 0.3 mm of the borders survive transplant, most of the transplanted bone cells, separated from their blood supply, die. The cancellous portion of the bone graft may be revascularized within 2 weeks, and cortical bone is revascularized within 1 to 2 months. Cancellous bone is more rapidly remodeled and is initially strengthened during the remodeling phase, because osteoblasts are first laid down over the trabeculae. Cortical bone is weakened during initial remodeling, and the process is slower than in cancellous bone. Bone graft is gradually replaced with new bone in a process called creeping substitution. Osteoclasts that act as cutting cones bore into the graft from the margins of host bone, followed by osteoblasts that lay down new bone. This process of healing and remodeling may leave as much as 50% to 90% of the original matrix intact, even after many years. ^, The strength of cortical autograft is halved during the first 6 months after fusion but is gradually restored over 1 to 2 years. Autograft bone provides some living bone cells with the ability to make bone (i.e., osteogenic properties). It contains BMP and other substances capable of inducing cellular differentiation (i.e., it has osteoinductive properties), and it provides a scaffolding for bone growth (i.e., it has osteoconductive properties).

Diagnosis of Pseudoarthrosis

Despite great advances in the technology and tools available to modern spine surgeons, diagnosis of pseudoarthrosis remains a challenge. This is the result in part of inherent conflict between radiographic and clinical success. For example, patients may demonstrate pain reduction, improved function, and increased satisfaction despite an absence of bony union. Conversely, patients may complain of persistent pain and disability in the setting of fusion. Kim et al., in their series of 40 patients, showed that only 23% of patients diagnosed with pseudoarthrosis between 5 and 10 years following ASD surgery exhibited clear radiographic signs of nonunion. In all instances, it is important to rule out infection, instrumentation failure, and adjacent segment disease as the cause of recurrent symptoms. Classic signs or symptoms of pseudoarthrosis include recurrent pain following an asymptomatic period, progressive deformity, or a “popping” sensation with and without pain. To date, the gold standard for diagnosis remains surgical exploration and direct palpation of the fusion mass. However, in the clinical setting this method has both limitations and risks, and is open to bias. As a result, numerous noninvasive imaging modalities have been developed to aid in the diagnosis of pseudoarthrosis.

Standard Radiography

At the initial evaluation for pseudoarthrosis, plain radiographs are commonly taken, given their relatively lower cost, lower radiation exposure, and greater availability. The most important radiographic marker for union is bridging trabecular bone across the vertebral segments. Conversely, signs of pseudoarthrosis on plain films include graft resorption, implant subsidence or migration, change in implant integrity, and the presence of deformity under physiological load ( Fig. 88.1 ). Although bridging bone can be seen on static radiography, the reliability of this method is questionable, particularly when applied to the lumbar and thoracic spine. Moreover, orthogonal views may fail to show pseudoarthroses that are tangential to the coronal and sagittal views. ^,

Fig. 88.1, Instrumentation failure, including broken rods, is a hallmark for the presence of pseudoarthrosis.

To date, few studies have examined the efficacy of static radiography alone in diagnosing pseudoarthrosis. Tuli et al. found high variability in using plain radiographs to identify the presence or absence of fusion in 57 patients undergoing anterior cervical discectomy and fusion (ACDF). Newton et al. attempted to classify interbody fusion through a four-grade system with fair intra- and interobserver reliability. The reliability was improved when further defining the fusion as either greater than or less than 50% of disc space, with the greatest limitation being visualization in the thoracic spine. Blumenthal and Gill compared intraoperative palpation to plain films in the diagnosis of interbody and posterolateral fusion, finding only 69% overall agreement between the two methods. Kant likewise showed that almost one-quarter of patients who were thought to be fused on plain radiographs had pseudoarthrosis on surgical exploration. Likewise, Santos et al. showed that plain radiographs identified only four of 15 nonunions seen on computed tomography (CT) scan. As a result, there is a clear consensus that plain radiography overestimates the rates of successful fusion when compared with CT scan. ^, It is therefore recommended that, in instances of clinical suspicion for pseudoarthrosis, more reliable modalities including advanced imaging be employed.

Dynamic Radiography

The goal of dynamic radiography is to detect motion in a region previously subject to attempted arthrodesis. In most basic terms, if motion is seen on dynamic radiography, it is unlikely that a fusion was achieved. Despite this straightforward premise, identifying and measuring motion on radiographs carries challenges and is highly dependent on the rater. As a result, multiple motion parameters have been proposed in an attempt to define pseudoarthrosis. Authors have proposed motion of greater than 1 to 2 mm between the spinous processes on flexion/extension radiography to be indicative of pseudoarthrosis. ^, However, Cannada et al. showed that this method has limitations, with a specificity of 89% and a sensitivity of 91% compared with the gold standard of surgical exploration. According to the U.S. Food and Drug Administration, radiographic guidelines for successful fusion are defined as less than 3 mm of translational motion and less than 5 degrees of angular motion. Other authors have advocated for the criteria of greater than 2-degree change in Cobb measurement on lateral flexion/extension views. However, this method was likewise found to have shortcomings, with only 39% specificity and 82% sensitivity. Furthermore, Bono et al. demonstrated wide variations in motion on flexion/extension radiography based not only on the presence of fusion but also on the type. Solid but incomplete interbody and spinous process fusions can result in up to 5 degrees of motion on flexion/extension. This is particularly true in the lumbar spine, where there is a tendency to overestimate the presence of successful arthrodesis.

Computed Tomography

CT scans offer distinct advantages over plain films in their ability to detect bridging trabecular bone. Chafetz et al. first used CT scans to assess the presence of bony fusion in the 1980s. Although limitations with earlier generation scans produced high degrees of inaccuracy, modern tomography with thin slices, helical acquisition, multiplanar reconstructions, and artifact reduction has dramatically increased the ability to identify pseudoarthrosis. ^, With respect to the cervical spine, there is conflicting literature on the superiority of CT scan to dynamic radiography. Ploumis et al. showed an overestimation of fusion when using dynamic radiography compared with CT scan for patients undergoing ACDF. Conversely, Ghiselli et al. demonstrated equivalence when comparing CT scan to flexion/extension radiography, especially when using computer software to detect motion. ( Fig. 88.2 ).

Fig. 88.2, An example of dynamic flexion/extension radiography for the diagnosis of pseudoarthrosis in the cervical spine.

CT scans show clear superiority to plain films and dynamic radiography in the diagnosis of pseudoarthrosis in the lumbar spine. When compared with the gold standard of surgical exploration, fine-cut CT scans have shown 89% accuracy in diagnosing pseudoarthrosis in the lumbar spine versus 68% with plain radiography. ^, Dimar et al. performed a prospective study of 194 patients undergoing single-level posterolateral fusion. Arthrodesis rates were determined to be 89.3% when using dynamic radiography, but dropped to 83.9% when fine-cut CT was employed ( Fig. 88.3 ). Additionally, CT scan has been shown to have superior rates of intra- and interrater reliability compared with plain and dynamic radiography. According to Kanemura et al., a radiolucent zone of 1mm around the entire interbody cage on CT at 1 year is a significant predictor for permanent pseudoarthrosis ( Fig. 88.4 ).

Fig. 88.3, A and B, Despite the presence of instrumentation, there is gross motion at L4‒L5 indicative of nonunion.

Fig. 88.4, A and B, Screw “haloing” seen on computed tomography may be indicative of pseudoarthrosis.

CT scans are not without limitations, and carry added risks over radiography. Although levels of radiation can vary, one CT scan is roughly equivalent to 240 chest radiographs. Moreover, a CT scan carries a 1 in 3,300 chance of inducing a fatal cancer per examination. Furthermore, CT scan sensitivity and specificity are affected by the presence of metal devices, including screws, rods, and interbodies, despite advances in artifact reduction software and thin cuts.

Magnetic Resonance Imaging

Despite the commonplace use of MRI as a preoperative diagnostic modality, its efficacy for the diagnosis of pseudoarthrosis is not clear in the literature. Kroner et al. used MRI to demonstrate bony trabecular bridging in 49 patients who underwent posterior lumbar interbody fusion. However, the study had shortcomings because it did not use a surgical- or CT-based control. Another study that looked at patients who underwent ACDF found MRI to have fair interobserver reliability but to be inferior to CT scan for the identification of nonunion. There was likewise only moderate agreement with the findings from surgical exploration. Furthermore, MRI imaging is particularly susceptible to metal artifact, limiting its efficacy in areas of instrumentation. This has become paradoxically exacerbated as the magnetic strength of MRI scanners has continued to increase. Lastly, MRI is more time-consuming and more expensive compared with CT, despite offering the distinct advantage of postoperative evaluation of neural elements.

Bone Scan

The use of bone scan for the diagnosis of pseudoarthrosis remains controversial. In theory, technetium-99m with single-photon emission CT provides information on bone turnover and metabolic activity that may be suggestive of nonunion. However, historically this modality has been shown to have low sensitivity and positive predictive value. This was supported by Albert et al., who showed a sensitivity of 50% and specificity of 58% for detecting pseudoarthrosis compared with the gold standard of surgical exploration. Furthermore, the efficacy of bone scans is heavily dependent on timing, as studies performed within 6 months of surgery carry a false positive rate of as high as 50%.

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