Nerve ultrasound in hereditary transthyretin amyloidosis: red flags and possible progression biomarkers

Abstract

Background Diagnostic delay of hereditary transthyretin amyloidosis (ATTRv, v for variant) prevents timely treatment and, therefore, concurs to the mortality of the disease. The aim of the present study was to explore with nerve ultrasound (US) possible red flags for early diagnosis in ATTRv patients with carpal tunnel syndrome (CTS) and/or polyneuropathy and in pre-symptomatic carriers. Methods Patients and pre-symptomatic carriers with a TTR gene mutation were enrolled from seven Italian centers. Severity of CTS was assessed with neurophysiology and clinical evaluation. Median nerve cross-section area (CSA) was measured with US in ATTRv carriers with CTS (TTR-CTS). One thousand one hundred ninety-six idiopathic CTS were used as controls. Nerve US was also performed in several nerve trunks (median, ulnar, radial, brachial plexi, tibial, peroneal, sciatic, sural) in ATTRv patients with polyneuropathy and in pre-symptomatic carriers. Results Sixty-two subjects (34 men, 28 women, mean age 59.8 years ± 12) with TTR gene mutation were recruited. With regard to CTS, while in idiopathic CTS there was a direct correlation between CTS severity and median nerve CSA ( r = 0.55, p < 0.01), in the subgroup of TTR-CTS subjects (16 subjects, 5 with bilateral CTS) CSA did not significantly correlate with CTS severity ( r = − 0.473). ATTRv patients with polyneuropathy showed larger CSA than pre-symptomatic carriers in several nerve sites, more pronounced at brachial plexi ( p < 0.001). Conclusions The present study identifies nerve morphological US patterns that may help in the early diagnosis (morpho-functional dissociation of median nerve in CTS) and monitoring of pre-symptomatic TTR carriers (larger nerve CSA at proximal nerve sites, especially at brachial plexi).

Nerve Ultrasound Comparison Between Transthyretin Familial Amyloid Polyneuropathy and Chronic Inflammatory Demyelinating Polyneuropathy

“…The CSAs at proximal sites of measurable nerves (median nerves, ulnar nerves and sciatic nerves) were significantly higher than those of healthy controls, compared with distal sites in a same nerve. All this was compatible with the findings of previous studies for nerve ultrasound and magnetic resonance neurography in TTR-FAP patients (7,8,15). Moreover, prominent enlargement of peripheral nerves at proximal sites was not common in most axonal neuropathies (17,18), which could help distinguish TTR-FAP from other axonal neuropathies.…”

“…Moreover, prominent enlargement of peripheral nerves at proximal sites was not common in most axonal neuropathies (17,18), which could help distinguish TTR-FAP from other axonal neuropathies. For note, distal enlargement of median nerves was also observed in our study, which might associate with carpal tunnel syndrome in these TTR-FAP patients (8).…”

“…Nerve ultrasound is a painless tool for quick evaluation of peripheral nerve morphology. Several nerve ultrasound studies showed nerve enlargement in TTR-FAP (6)(7)(8). The cross-sectional areas (CSAs) of peripheral nerves in cases of TTR-FAP are significantly larger than those of controls, most are in the proximal nerve segments (7).…”

“…The cross-sectional areas (CSAs) of peripheral nerves in cases of TTR-FAP are significantly larger than those of controls, most are in the proximal nerve segments (7). Nerve ultrasound patterns can facilitate the evaluation of asymptomatic carriers, presenting as larger nerve CSAs at proximal nerve sites (8). Nerve ultrasound can also serve as a useful complementary diagnostic tool for the identification of treatment-responsive inflammatory neuropathies (9)(10)(11).…”

Nerve Ultrasound as Helpful Tool in Polyneuropathies

“…Further, this nerve enlargement can also be seen by ultrasound, particularly at entrapment sites ( Figure 2 C,D) [ 54 ]. Podnar et al found that besides common entrapment sites, a pronounced nerve enlargement in a larger cohort of ATTR patients was also seen in proximal segments and plexus [ 55 ], and even of presymptomatic carriers [ 56 ]. This finding suggests ultrasound as an important tool to enable early treatment.…”