Background
Wild-type transthyretin amyloidosis (wtATTR) is an important cause of infiltrative cardiomyopathy in older adults, especially males. Reference Nativi-Nicolau and Maurer1,Reference Ruberg, Grogan, Hanna, Kelly and Maurer2 It results from the deposition of misfolded native (non-mutated) transthyretin (TTR) proteins in organs and tissues. Reference Nativi-Nicolau and Maurer1,Reference Ruberg, Grogan, Hanna, Kelly and Maurer2 Carpal tunnel syndrome (CTS) is one of the most common extra-cardiac manifestations of wtATTR and can predate cardiac symptoms by 5–10 years. Reference Milandri, Farioli and Gagliardi3,Reference Nakagawa, Sekijima and Yazaki4 Wild-type ATTR protein deposition commonly causes median nerve entrapment at the wrist, resulting in CTS. Reference Boyle, Sharan and Schwartz5 Bilateral CTS is more common in wtATTR than hereditary ATTR, Reference Trimarchi, Perna and Zampieri6 and the prevalence of CTS in wtATTR is thought to be higher than in light chain (AL) amyloidosis. Reference Ng, Connors, Davidoff, Skinner and Falk7 The association between CTS and wtATTR has been described in several case series; Reference Milandri, Farioli and Gagliardi3–Reference Trimarchi, Perna and Zampieri6 however, the characteristics of CTS in this population remain poorly understood.
At our centre, all patients with a new diagnosis of wtATTR are referred for comprehensive neurological screening by way of nerve conduction studies (NCS) and neurologist assessment. The purpose of our study was to evaluate the prevalence, clinical features, severity and disease course of CTS in wtATTR patients, as well as the risk of recurrence following carpal tunnel release (CTR).
Methods
Study Population
This retrospective cohort study reports findings from a single-centre experience of comprehensive neurological screening at the time of wtATTR diagnosis. Consecutive wtATTR patients followed at the University of Calgary Cardiac Amyloidosis Clinic (Calgary, Alberta, Canada) between February 2014 and December 2021 were included. A diagnosis of wtATTR was confirmed using the following criteria: [1] exclusion of AL amyloidosis by the absence of serum and urine monoclonal protein, [2] evidence of cardiac amyloidosis by either right ventricular endomyocardial biopsy or positive technetium-99 m-pyrophosphate nuclear scintigraphy, defined as a grade 2–3 myocardial uptake or heart-to-contralateral lung ratio >1.5 Reference Gillmore, Maurer and Falk8 and [3] absence of an ATTR gene mutation using genetic testing or proteomic analysis by mass spectrometry performed on biopsy tissue sample. Reference Vrana, Gamez, Madden, Theis, Bergen and Dogan9 This study was approved by the University of Calgary Research Ethics Board, and the requirement of informed patient consent was waived.
Electrodiagnostics
Neurological screening included NCS, performed in a dedicated and accredited laboratory, along with a complete history and physical examination by a neurologist at the time of electrophysiologic testing. Standard of practice at our laboratory is in keeping with the 2011 American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) monograph on electrodiagnostic evaluation of CTS. Reference Werner and Andary10 All patients had bilateral ulnar and median sensory nerve action potentials (SNAPs) and compound muscle action potentials (CMAPs) assessed, along with median versus ulnar digit 4 comparison studies. Additional median to other nerve comparison studies were done when needed, as outlined in the monograph. Recording sites, inter-electrode distance and temperature were all standardised per laboratory protocol. Testing was performed using either a Cadwell Sierra Wave machine running version 3.1.32 of Cadlink or a Natus Ultrapro S100 machine running version 22.3.0.21 of Synergy.
Data Collection and Analysis
Medical records of wtATTR patients were reviewed for a prior history of CTS and CTR; the presence of prior unilateral or bilateral disease was noted where available. This information was supplemented by patient history, taken at the time of neurologic evaluation, as prior CTS and CTR were often remote. Comorbidities commonly associated with CTS were collected, including diabetes, hypothyroidism, monoclonal gammopathy of undetermined significance, multiple myeloma, haematologic malignancy, rheumatoid arthritis, osteoarthritis, pregnancy and inherited neuropathy. The presence of CTS symptoms, including numbness, tingling, pain and weakness in the median nerve distribution, were also collected, along with abductor pollicis brevis (APB) atrophy and weakness. The presence and characteristics of bilateral disease were noted, as was New York Heart Association (NYHA) functional class for all patients. Diagnosis of CTS was based on neurologist interpretation of patient history, physical examination and electrodiagnostic data. Electrodiagnostic criteria for median neuropathy at the wrist (MNW) and electrodiagnostic severity were derived from the AANEM practice parameters. Reference Werner and Andary10 Mild CTS was defined as prolonged sensory latencies with normal motor studies, without evidence of axon loss. Reference Werner and Andary10 Abnormal median sensory latencies and prolongation of median motor distal latency without evidence of axon loss defined moderate CTS. Reference Werner and Andary10 Severe CTS was defined by any of the aforementioned abnormalities with evidence of axon loss, as defined by either: [1] an absent or low-amplitude SNAP, [2] a low-amplitude or absent thenar CMAP or [3] needle electromyography with fibrillation potentials or motor unit potential changes. Reference Werner and Andary10 Data pertaining to interventions offered were obtained, including wrist splinting, steroid injection and CTR. Recurrence after CTR was also recorded. Descriptive statistics were performed.
Results
Patient Population and Characteristics
A total of 124 wtATTR patients were eligible for inclusion. Seventy-nine underwent neurological screening. The remaining 45 patients either declined screening or were awaiting screening at the time of data collection. Patient demographics, NYHA functional class, comorbidities commonly associated with CTS, presence of pre-existing CTS and prior CTR are presented in Table 1.
Table 1: Baseline patient characteristics
CTS, carpal tunnel syndrome; IQR, interquartile range; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; NYHA, New York Heart Association; wtATTR, wild-type transthyretin amyloidosis.
Neurologic Evaluation
Prevalence and characteristics of MNW at the time of neurological screening are outlined in Table 2. The presence of CTS symptoms and physical examination findings in patients with MNW at the time of screening are also shown, along with electrodiagnostic severity and rate of recurrence following CTR.
Table 2: Characteristics of MNW in wtATTR patients on neurological screening
APB, abductor pollicis brevis; CTR, carpal tunnel release; CTS, carpal tunnel syndrome; EDX, electrodiagnostic; MNW, median neuropathy at the wrist; wtATTR, wild-type transthyretin amyloidosis.
Seventy-four (94%) wtATTR patients had electrodiagnostic findings of MNW, 37 (50%) of which had a prior diagnosis of CTS and 37 (50%) had a new diagnosis of MNW on testing. Three (4%) wtATTR patients with MNW had CTR prior to screening, resulting in complete resolution of CTS symptoms at the time of screening. Over half of wtATTR patients (42, 53%) were found to have bilateral MNW on electrophysiologic testing. The majority of wtATTR patients with pre-existing CTS had bilateral disease (28, 76%) and underwent bilateral CTR (23, 62%) prior to screening. Most wtATTR patients that met electrodiagnostic criteria for MNW were symptomatic (53, 72%) at the time of screening. Thirty-two (43%) wtATTR patients with MNW had APB weakness on examination, and 27 (36%) had APB atrophy. Twenty-one (19%) wrists had mild MNW, 43 (38%) moderate and 49 (43%) severe on electrophysiologic testing. Twenty-one (28%) wtATTR patients with MNW were asymptomatic, 10 of which (48%) had moderate disease and 11 (52%) had mild disease. Nineteen (36%) wtATTR patients with symptomatic MNW on screening had recurrent disease despite previous CTR.
The prevalence of MNW and recurrent MNW following CTR according to NYHA functional class in wtATTR patients is presented in Figure 1.
Figure 1: Frequency of median neuropathy at the wrist (MNW) diagnosed on neuropathy screening among patients with wild-type transthyretin amyloidosis (wtATTR) according to New York Heart Association (NYHA) functional class. The proportion of patients with recurrent MNW on neuropathy screening, following carpal tunnel release, is also shown.
Regarding NYHA functional class, 39 (49%) wtATTR patients had class III heart failure symptoms, 30 (38%) class II, 9 (11%) class I and 1 (1%) class IV. MNW in wtATTR patients was severe in the majority (49, 43%) of wrists examined, compared to moderate (43, 38%) and mild (21, 19%) disease. The rate of severe MNW was similar across NYHA functional classes.
Interventions
As a result of screening, a total of 19 (36%) wtATTR patients with symptomatic MNW were prescribed wrist splinting, 3 (6%) steroid injection and 36 (68%) were referred for CTR following screening (Figure 2). Some wtATTR patients were prescribed more than one intervention. Those wtATTR patients with MNW that did not receive treatment recommendations (27, 36%) were either asymptomatic (18, 67%) or minimally symptomatic (9, 33%).
Figure 2: Proportion of wild-type transthyretin amyloidosis (wtATTR) patients prescribed interventions for median neuropathy at the wrist (MNW). Patients that did not receive treatment recommendations were either asymptomatic or minimally symptomatic. Type and frequency of interventions prescribed are also represented. Some patients were prescribed more than one intervention.
Discussion
This study shows that CTS is very common in patients with newly diagnosed wtATTR. We observed that MNW was seen in the vast majority of wtATTR patients at the time of electrophysiologic testing; half had a pre-existing history of CTS and half had a new diagnosis of MNW on screening. Many with pre-existing CTS had bilateral disease and prior CTR. At the time of electrophysiologic testing, most wtATTR patients with MNW were symptomatic and over half had bilateral involvement. APB weakness and atrophy were seen in some patients. MNW was severe in the majority of wrists examined, compared to mild and moderate disease. Recurrence after CTR was common. Nearly half of wtATTR patients had NYHA class III heart failure at the time of screening. The prevalence of MNW and recurrent disease following CTR was similar across wtATTR patients with NYHA class I, II and III heart failure. Nearly half of asymptomatic patients with MNW on screening had moderate disease.
At our centre, routine comprehensive neurological screening by way of NCS and neurologist assessment led to the diagnosis of mild and moderate MNW in many wtATTR patients. This included a proportion of wtATTR patients with MNW that were asymptomatic at the time of electrodiagnostic evaluation. Diagnosis of MNW at mild and moderate stages facilitated early intervention for symptomatic patients. The majority (64%) of wtATTR patients were prescribed a therapeutic intervention; most were referred for CTR surgery. Early decompression of the median nerve results in a more timely and complete improvement in pain, sensory abnormalities and hand function compared to delayed CTR. Reference Musad, Rashid, Malik, Khan and Sarwar11
In our study of 79 patients, 94% had MNW on electrophysiologic testing, an exceptionally high proportion which has not been reported previously. We observed that CTS affected 67% of our patients with newly diagnosed wtATTR, which is in keeping with the prevalence reported in prior studies, ranging from 41 to 68%. Reference Nakagawa, Sekijima and Yazaki4,Reference Trimarchi, Perna and Zampieri6,Reference Ng, Connors, Davidoff, Skinner and Falk7,Reference Russell, Hahn, Chhibber, Korngut and Fine12 Half of our wtATTR patients with MNW on screening had a prior history of CTS, and many had bilateral disease and prior CTR. This supports the understanding that CTS is often an early clinical manifestation of wtATTR that predates cardiac symptoms. Reference Milandri, Farioli and Gagliardi3,Reference Nakagawa, Sekijima and Yazaki4 Our study also supports the notion that CTS is relatively aggressive in patients with wtATTR, as it is often bilateral and rapidly progressive with a higher rate of recurrence compared to patients without wtATTR. Reference Elzinga, Khayambashi, Hahn, Mahe and Fine13 At the time of wtATTR diagnosis, most of our patients had severe MNW and over half had bilateral disease. In comparison, patients with diabetes often have mild to moderate CTS at the time of diagnosis. Reference Yurdakul, Bodur and Cakmak14 Recurrence after CTR was seen in 36% of our wtATTR patients with symptomatic MNW at the time of screening, which is higher than the rate of recurrence in the general population, estimated at 3–20%. Reference Osiak, Elnazir, Walocha and Pasternak15 For this reason, it has been suggested that a history of bilateral recurrent CTS should prompt consideration of tissue biopsy at the time of repeat CTR. Reference Elzinga, Khayambashi, Hahn, Mahe and Fine13 Tenosynovium and transverse carpal ligament biopsies should also be considered in men with bilateral CTS and concurrent left ventricular hypertrophy, as the rate of wtATTR is 33% in this population, according to one study. Reference Elzinga, Khayambashi, Hahn, Mahe and Fine13 Lastly, we found that wtATTR patients with NYHA class I, II and III heart failure had similar rates of MNW and recurrence following CTR on electrophysiologic testing. Severe MNW was more common than mild or moderate disease across these NYHA functional classes. Collectively, these are novel observations.
Limitations
Limitations of this study include the retrospective single-centre cohort design and small sample size; therefore, the presence of bias cannot be excluded. Neurologists were not blinded to clinical data. Information collected pertaining to pre-existing CTS was largely based on history, as detailed neurologic data prior to their wtATTR diagnosis were not available in most patients. Histopathological confirmation of amyloid neuropathy was not collected as tenosynovial biopsy was not routinely pursued at our centre. The prevalence of comorbidities commonly associated with CTS in some wtATTR patients included in this study confounds the ability to determine causality for the findings reported. Our sample size precludes controlling for these comorbidities.
Conclusions
Our study shows that CTS affects the majority of wtATTR patients and often predates wtATTR diagnosis, which is in keeping with prior studies. We observed that MNW is very common in patients at the time of wtATTR diagnosis, affecting 94% of our patients on screening. Twenty-eight percent of our patients were asymptomatic despite more than half of those having moderate severity MNW on NCS. We also observed that most wtATTR patients had severe MNW and bilateral MNW on electrophysiologic testing, with a rate of recurrence after CTR that was higher than the general population. This supports that CTS is relatively aggressive in wtATTR. Our results demonstrate the importance of routine comprehensive neurological screening by way of NCS and neurologist assessment at the time of wtATTR diagnosis. This facilitated early diagnosis of MNW in our wtATTR patients and early intervention in symptomatic patients.
Acknowledgements
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Statement of authorship
AR participated in study design, data collection and analysis, and manuscript preparation. CH, NMF, SC, and SK participated in study design, data analysis and manuscript preparation.
Competing interests
Dr. Chhibber has received honoraria from Alexion. Dr. Fine has received consulting fees and research support from Pfizer, Akcea and Alnylam. Dr. Hahn has received consulting fees from Pfizer, Akcea and Alnylam. Dr. Khayambashi has received honoraria from Alnylam. Dr. Russell has no conflicts of interest to declare.
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