Wild-Type Transthyretin Amyloidosis Occurring in the Ligamentum Flavum of the Cervicothoracic Spine

George, Keith M.; Dowd, Richard S.; Nail, Jayde; Yu, Anthony; Mastroianni, Michael; Wang, Andy; Arkun, Knarik; Patel, Ayan R.; Kryzanski, James; Comenzo, Raymond L.; Riesenburger, Ron I.

doi:10.1016/j.wneu.2020.06.228

Cited by 11 publications

(5 citation statements)

References 20 publications

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“…Amyloid has been detected in cervical and thoracic spinal tissue as well as in the LS. 22 Additionally, the ligamentum flavum burden as assessed pathologically is greater in patients with ATTRwt amyloid compared to non-ATTRwt patients. 23 These data coupled with the association of LSS with ATTR cardiac amyloidosis have led to the hypothesis that screening programs focused on orthopedic manifestations could identify affected subjects early in the course of their disease at a time when emerging diseasemodifying therapy may be most beneficial.…”

Section: Discussionmentioning

confidence: 98%

“…Our data add to these previous studies and further highlight that older age is a risk factor for the presence of amyloidosis in LS specimens. Amyloid has been detected in cervical and thoracic spinal tissue as well as in the LS 22 . Additionally, the ligamentum flavum burden as assessed pathologically is greater in patients with ATTRwt amyloid compared to non‐ATTRwt patients 23 .…”

Section: Discussionmentioning

confidence: 99%

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Analysis of lumbar spine stenosis specimens for identification of amyloid

Maurer

Smiley

Simsolo

et al. 2022

J American Geriatrics Society

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Background Lumbar spinal stenosis (LSS) is a common reason for spine surgery in which ligamentum flavum is resected. Transthyretin (TTR) amyloid is an often unrecognized and potentially modifiable mechanism for LSS that can also cause TTR cardiac amyloidosis. Accordingly, older adult patients undergoing lumbar spine (LS) surgery were evaluated for amyloid and if present, the precursor protein, as well as comprehensive characterization of the clinical phenotype. Methods A prospective, cohort study in 2 academic medical centers enrolled 47 subjects (age 69 ± 7 years, 53% male) undergoing clinically indicated LS decompression. The presence of amyloid was evaluated by Congo Red staining and in those with amyloid, precursor protein was determined by laser capture microdissection coupled to mass spectrometry (LCM‐MS). The phenotype was assessed by disease‐specific questionnaires (Swiss Spinal Stenosis Questionnaire and Kansas City Cardiomyopathy Questionnaire) and the 36‐question short‐form health survey, as well as biochemical measures (TTR, retinol‐binding protein, and TTR stability). Cardiac testing included technetium‐99m‐pyrophosphate scintigraphy, electrocardiograms, echocardiograms, and cardiac biomarkers as well as measures of functional capacity. Results Amyloid was detected in 16 samples (34% of participants) and was more common in those aged ≥ 75 years of age (66.7%) compared with those <75 years (22.3%, p < 0.05). LCM‐MS demonstrated TTR as the precursor protein in 62.5% of participants with amyloid while 37.5% had an indeterminant type of amyloid. Demographic, clinical, quality‐of‐life measures, electrocardiographic, echocardiographic, and biochemical measures did not differ between those with and without amyloid. Among those with TTR amyloid (n = 10), one subject had cardiac involvement by scintigraphy. Conclusions Amyloid is detected in more than a third of older adults undergoing LSS. Amyloid is more common with advancing age and is particularly common in those >75 years old. No demographic, clinical, biochemical, or cardiac parameter distinguished those with and without amyloid. In more than half of subjects with LS amyloid, the precursor protein was TTR indicating the importance of pathological assessment.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Analysis of lumbar spine stenosis specimens for identification of amyloid

Maurer

Smiley

Simsolo

et al. 2022

J American Geriatrics Society

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“…Tc-99 m PYP/DPD scintigraphy [ 19 , 20 , 24 , 29 , 37 , 39 , 41 , 42 , 45 , 51 , 58 , 60 , 63 , 64 , 66 , 68 , 69 , 73 , 77 , 78 , 80 , 95 , 96 , 109 , 110 , 118 , 120 , 122 , 132 , 137 – 139 , 148 , 152 , 165 , 166 ], a non-invasive diagnostic method which has been more commonly used during last several years to make a diagnosis of cardiac amyloidosis [ 3 ], was also used to confirm the disease in 30% of the publications included in this review (Table 2 ). Additionally, methods such as mass spectrometry were utilized to confirm that amyloid was caused by TTR [ 14 , 16 , 18 , 108 , 112 , 114 , 115 , 131 , 149 , 152 , 165 ]. Another significant limitation is that, although an association between MSK manifestations and ATTR amyloidosis is shown in the literature, it does not necessarily demonstrate causation in all cases.…”

Section: Discussionmentioning

confidence: 99%

Musculoskeletal manifestations associated with transthyretin-mediated (ATTR) amyloidosis: a systematic review

Aldinc,

Campbell,

Gustafsson

et al. 2023

BMC Musculoskelet Disord

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Background Hereditary and wild-type transthyretin-mediated (ATTRv and ATTRwt) amyloidoses result from the misfolding of transthyretin and aggregation of amyloid plaques in multiple organ systems. Diagnosis of ATTR amyloidosis is often delayed due to its heterogenous and non-specific presentation. This review investigates the association of musculoskeletal (MSK) manifestations with ATTR amyloidosis and the delay from the onset of these manifestations to the diagnosis of ATTR amyloidosis. Methods This systematic review utilized Medline and EMBASE databases. Search criteria were outlined using a pre-specified patient, intervention, comparator, outcome, time, study (PICOTS) criteria and included: amyloidosis, ATTR, and MSK manifestations. Publication quality was assessed utilizing Joanna Briggs Institute (JBI) critical appraisal checklists. The search initially identified 7,139 publications, 164 of which were included. PICOTS criteria led to the inclusion of epidemiology, clinical burden and practice, pathophysiology, and temporality of MSK manifestations associated with ATTR amyloidosis. 163 publications reported on ATTR amyloidosis and MSK manifestations, and 13 publications reported on the delay in ATTR amyloidosis diagnosis following the onset of MSK manifestations. Results The MSK manifestation most frequently associated with ATTR amyloidosis was carpal tunnel syndrome (CTS); spinal stenosis (SS) and osteoarthritis (OA), among others, were also identified. The exact prevalence of different MSK manifestations in patients with ATTR amyloidosis remains unclear, as a broad range of prevalence estimates were reported. Moreover, the reported prevalence of MSK manifestations showed no clear trend or distinction in association between ATTRv and ATTRwt amyloidosis. MSK manifestations precede the diagnosis of ATTR amyloidosis by years, and there was substantial variation in the reported delay to ATTR amyloidosis diagnosis. Reports do suggest a longer diagnostic delay in patients with ATTRv amyloidosis, with 2 to 12 years delay in ATTRv versus 1.3 to 1.9 years delay in ATTRwt amyloidosis. Conclusion These findings suggest that orthopedic surgeons may play a role in the early diagnosis of and treatment referrals for ATTR amyloidosis. Detection of MSK manifestations may enable earlier diagnosis and administration of effective treatments before disease progression occurs.

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“…Both ATTRv and ATTRwt are also associated with amyloid deposits in connective tissue with secondary neurologic manifestations and high prevalence of carpal tunnel syndrome, while spinal stenosis is also common in ATTRwt (7,18,19,(21)(22)(23)(24)(25)(26)(27)(28). While ATTRwt deposits are found in muscle tendons and ligaments, heart muscle and other types of tissue (Figure 1) (29,30), overall multisystemic manifestations of ATTRwt are not as prominent as in ATTRv (25).…”

Section: Introductionmentioning

confidence: 99%

Neuromuscular manifestations of wild type transthyretin amyloidosis: a review and single center’s experience

Živković,

Lacomis,

Soman

2024

Front. Cardiovasc. Med.

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Transthyretin amyloidosis (ATTR) is a condition defined by accumulation of insoluble transthyretin amyloid deposits in multiple organs, especially in the peripheral nerve and heart muscle. ATTR may result from transthyretin mutations (variant ATTR or ATTRv) or may occur with normal transthyretin genotype (wild type ATTR or ATTRwt). ATTRwt was previously known as “senile amyloidosis” and causes cardiomyopathy which may lead to heart failure with a preserved ejection fraction, affecting predominantly elderly men. The exact prevalence of ATTRwt in the general population remains unclear, but its occurrence may be underestimated in women. It was observed that a proportion of ATTRwt cardiomyopathy patients may develop slowly progressing neuropathy that is milder and indolent in comparison with typical progressive neuropathy associated with ATTRv. Furthermore, the causality of neuropathy is often uncertain in patients with ATTRwt. Neuropathy symptoms, including distal sensory loss, unsteadiness and (neuropathic) pain are common in elderly patients with multiple potential causes, and as ATTRwt patients are typically older, relatively high prevalence of peripheral neuropathy is expected with frequent comorbidities. Relatively high prevalence of ATTRwt in elderly population contrasts few documented cases of neuropathy caused by ATTRwt, and there is uncertainty whether ATTRwt neuropathy is an infrequent occurrence or a significant manifestation of multisystemic ATTRwt. We review neurologic and musculoskeletal manifestations of ATTRwt and present clinical features of a single center cohort of ATTRwt patients with suspected peripheral neuropathy.

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Wild-Type Transthyretin Amyloidosis Occurring in the Ligamentum Flavum of the Cervicothoracic Spine

Cited by 11 publications

References 20 publications

Analysis of lumbar spine stenosis specimens for identification of amyloid

Analysis of lumbar spine stenosis specimens for identification of amyloid

Musculoskeletal manifestations associated with transthyretin-mediated (ATTR) amyloidosis: a systematic review

Neuromuscular manifestations of wild type transthyretin amyloidosis: a review and single center’s experience

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