1 Introduction

Amyloidosis refers to a cluster of potentially life-threatening protein-folding and deposition disorders that have long been implicated in cardiac and other organ pathologies, primarily including polyneuropathy, restrictive cardiomyopathy, and nephropathy.¹ However, there is increasing recognition of amyloidotic involvement in musculoskeletal tissues. This is believed to contribute to common orthopaedic pathologies including carpal tunnel syndrome (CTS) and spinal stenosis (SS)—and is associated with unique disease presentation, progression, and comorbidities.²

Amyloidosis is an entity defined by the extracellular deposition of misfolded proteins, which form plaques called amyloid fibrils.³ Several classes of amyloid protein have been identified in orthopaedic pathologies—with Transthyretin (TTR) amyloidosis being most common. Cases of TTR amyloidosis (ATTR) are classified as hereditary amyloidosis (hATTR) or wild-type amyloidosis (ATTRwt).⁴ While ATTRwt is related to age-dependent defects in protein formation, hATTR is hereditary.³ Both ATTRwt and hATTR have been implicated the development of various orthopaedic conditions.^5,6 In practice, the advanced age of many orthopaedic patients with suspected ATTR amyloidosis has been used as a pseudo-diagnostic criterion for ATTRwt amyloidosis, the more common of the two variants.⁷

Amyloid fibrils can accumulate in many tissues, threatening their functions and integrity as well as those of surrounding tissues via mass effect. Cardiac amyloidosis (CA)—which leads to cardiomyopathy—is one of the most reported and severe complications of amyloid deposition.⁴ However, the ligamentum flavum (LF) is another common site of amyloidotic accumulation and is associated with LF hypertrophy (LFH).⁶ LFH decreases the diameter of the vertebral canal, leading to SS with ischemia and myelopathy. Several recent studies propose ATTRwt as a leading cause of SS in older individuals.^8–12 hATTR, while less common, offers an explanation for recurrent LFH and SS in younger individuals—especially in the presence of comorbidities such as CTS and cardiomyopathy.¹³

Importantly, the presence of either form of ATTR amyloidosis in one site is correlated with an increased instance of systemic amyloid deposition.^14–16Therefore, identifying ATTR involvement in LFH during spinal surgery could be used to inform additional screening and treatment. Furthermore, several emerging treatments targeting amyloid formation have been shown to be effective in treating systemic amyloidosis.^1,17,18 This creates a potentially groundbreaking opportunity for spine surgeons to identify and treat patients at risk of developing both systemic amyloidosis and subsequent orthopaedic pathology.

This article is a comprehensive, systematic review of case reports, case series, retrospective analyses, and prospective studies regarding ATTR involvement in SS with LFH. The reports here included scope over more than three decades, making this the most comprehensive and recent review on the subject to date.

2 Methods

3 Results

Using the search criteria outlined above, 67 articles were yielded. After evaluating the literature utilizing our inclusion and exclusion criteria, a total of 18 articles were included in this review (Fig. 1). We reviewed each of the articles and obtained the following data: country, study type, sample size, amyloidosis type, amyloidosis subtype confirmation, spinal level, systemic symptoms, treatment, patient outcomes, and conclusion of the authors (Table 1).

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Fig. 1 PRIMSA Flowchart.

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A total of 1045 patients with spinal stenosis were reviewed, of which 329 (31.5%) had detectable amyloid deposition in the LF. Several studies included different analyses on the same patient population—accordingly, each patient population was counted only once for the purpose of these analyses. Among patients with detectable LF amyloid deposition, ATTR was the most represented amyloidosis subtype observed, with 277 reported cases (84.2%). Of the patients with ATTR, there were 273 reported cases of ATTRwt (98.6%) and 4 cases of confirmed hATTR (1.4%). Two cases of AL amyloid (0.6%) and 65 cases of amyloid of indeterminate subtype (19.8%) were also found among the patient population with detectable LF amyloid deposition. Various analytical methods were used to identify amyloid subtypes including genetic sequencing, immunohistochemistry, and liquid chromatography with mass spectrometry.

SS with LFH and confirmed amyloid deposition was observed across all spinal regions. Amyloid deposition was most frequently observed in the lumbar spine, being found in a total of 309 (93.9%) of SS patients with amyloid deposition. Cervical amyloidosis was found in 7 patients (2.1%), and 4 patients (1.2%) were observed to harbor amyloid in the LF of the thoracic spine. Spinal region was not reported in 11 cases (3.3%) of ATTRwt SS. Notably, there was a small number of individuals with amyloidosis in more than one spinal region.

Pertinent medical history among patients sampled included systemic amyloidosis (laryngeal, cardiac, polyneuropathy), CTS, lumbar disc herniation, and congestive heart failure. Cardiac amyloidosis was the most frequently recorded comorbidity and was observed in 11 studies (61.1%) of the 18 reports eligible for review. CTS was also frequently reported and was observed in 10 studies (55.5%). It should be noted that cardiac pathologies appeared infrequently, even in those studies where they were observed.

The most common surgical intervention during which LF samples were harvested was laminectomy, decompression, and fusion. Although a small number of LF samples were also harvested during discectomies and laser microdissections.

Several common themes emerged among the included articles. Five articles recommended consideration of routine harvest and analysis of LF specimens during spinal surgery as an adjunct screening method for systemic amyloidoses.^8,12,19–21 Two studies demonstrated no correlation between the presence of amyloid and other spinal disorders including disc degeneration and lumbar disc herniation.^10,22 Three articles found that amyloid burden was correlated with degree of SS and LFH.^6,7,23 Three articles that included cases of spinal involvement in hATTR reported significant, unique complications associated with hereditary etiology.^24–26

4 Discussion

The value of predicting and preventing debilitating disease cannot be overstated. Historically, predicting the development of amyloidosis has mainly been possible only in the context of hereditary etiology within families.^5,19,24,27 Correspondingly, treatment for wild-type amyloidosis has typically been employed only reactionarily in cases of actively progressing systemic pathology cardiomyopathy.²⁸ This pattern is likely due in large part to the difficulty, invasiveness, and cost of screening for amyloidotic cardiomyopathy in its early stages.²⁹ With the emerging, widespread identification of ATTR amyloid fibrils in common orthopaedic pathologies, including SS and CTS, it may soon be possible to reliably predict the development of this devastating condition in patients with degenerative etiologies. Therefore, characterizing the relationship between orthopaedic amyloidosis and cardiac amyloidosis is an essential step in identifying and developing methods for detection, prediction, and prophylaxis of amyloidosis in both medical and orthopaedic patients.

Some studies have attempted to elucidate the relationship between amyloid deposition in orthopaedic pathologies, such as SS, and systemic pathologies including cardiomyopathy.^8,12 Reports on orthopaedic amyloidosis have indicated that at the time of SS intervention, patients with amyloidotic LFH are only marginally more likely to exhibit cardiac amyloidosis than their peers without pathological ATTR deposition.¹¹ Additionally, however, a significant increase in non-pathological amyloid deposition in adjacent tissues has been noted in patients at the time of ATTR-positive SS presentation.¹² Therefore, it is likely that amyloidotic cardiomyopathy represents a later finding in the progression of widespread amyloidosis. This indicates that the LF could be understood as a sentinel site that predicts later systemic amyloid deposition. Indeed, it has been proposed that amyloid deposition in CTS could similarly predict the development of systemic amyloidosis.¹⁴ Further study is necessary to determine if individuals exhibiting orthopaedic amyloid deposition are at greater risk of developing cardiac amyloidosis or pathological accumulation in other orthopaedically relevant locations long term.

Should additional investigations indicate that patients with a history of ATTRwt-related SS with LFH or ATTR-positive CTS are at greater risk for future amyloidotic cardiomyopathy, it may be possible to initiate prophylactic measures against the development of cardiac and other orthopaedic amyloidosis in high-risk individuals. Several pharmacological interventions have proven effective in treating individuals with hATTR and wtATTR.^17,18,30 Notably, new classes of pharmaceuticals that include Patisiran and Tafamidis have also been shown to limit the progression of ATTR polyneuropathy and cardiomyopathy.^18,30 The development of these agents represents a substantial improvement over traditional, highly toxic chemotherapeutic agents typically employed in amyloidosis treatment regimens and could preclude the necessity for heart transplantation and additional high-cost, high-risk interventions.^31,32 The long-term prophylactic value of these agents in cardiac and orthopaedic amyloidosis has yet to be investigated, but could offer a proactive alternative to watchful waiting in high risk cardiac and orthopaedic patient populations.

Furthermore, at the current time, the definitive value of adding ATTRwt detection through histologic analysis of specimens obtained during spinal decompression surgery to the standard of care is yet to be fully characterized. Undeniably, perioperative biopsy analysis can provide valuable epidemiological and disease progression data. For example, a report showed that 2 of 324 patients undergoing laminectomy for SS had signs of cardiac amyloidosis at the time of SS intervention.¹¹ However, there is little evidence these analyses yield medically actionable results for most patients in the short term. Therefore, more study is needed to determine if standardizing perioperative biopsy with screening for amyloidosis is an effective means of identifying patients at risk of disease progression. Thus, routine intraoperative biopsy of the LF remains useful mainly in the context of clinical research.

5 Conclusion

In conclusion, spinal stenosis associated with amyloid deposition in the ligamentum flavum is an underreported cause of spinal stenosis around the world. The early presentation of spinal stenosis presents an opportunity to identify at-risk patients for systemic amyloid disease and potential cardiac involvement. Given recent advancements in the treatment of amyloidosis, these patients may be able to be treated if accurately identified. Orthopaedic practitioners should be aware of this association and recognize it as an opportunity to improve care for this subset of patients.

Ethical statement

This study was performed in accordance with the professional and ethical standards set by University of Utah and the American Medical Association.

Funding statement

No institutional or other funds were used in the execution of this project and subsequent drafting.

Guardian/parent consent

N/A.

CRediT authorship contribution statement

Zachary J. Moore: Formal analysis, Investigation, Writing – original draft, Visualization. James M. Rizkalla: Conceptualization, Methodology, Writing – review & editing. Brian Karamian: Validation, Writing – review & editing, Supervision. Brandon Lawrence: Supervision, Project administration.