Ultrasound may help assess FAP peripheral nerve malfunction

Standard nerve conduction tests missed damage in about half of patients studied

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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An ultrasound of the peripheral nerves could help monitor disease progression in people with early-stage familial amyloid polyneuropathy (FAP) who carry V30M, the most common disease-causing mutation.

That’s according to a study in Sweden that also showed that while about half of patients analyzed showed no signs of peripheral nerve damage in standard nerve conduction studies, an ultrasound analysis revealed significantly enlarged nerves in the legs. Peripheral nerves are those outside the brain and spinal cord.

“The present study emphasizes the importance of early introducing US [ultrasound] of peripheral nerves in the clinical investigation of ATTRv patients as significantly increased CSA [cross-sectional area, or size] was found within patients, despite having short disease duration,” the researchers wrote in “Enlarged cross-sectional area in peripheral nerves in Swedish patients with hereditary V30M transthyretin amyloidosis,” which was published in Annals of Medicine.

A feature of FAP, also known as hereditary transthyretin amyloidosis with polyneuropathy, is damage to the peripheral nerves caused by mutations in the TTR gene, which result in an abnormal version of the transthyretin protein accumulating to toxic levels in cells.

Nerve conduction studies (NCS), which measure the strength and speed of a nerve’s electrical signal transmission, and electromyography (EMG), which assesses the health of muscles and the nerves controlling them, are two standard tests to diagnose and monitor FAP.

Both “can be perceived as unpleasant for the patients, as weak electric current is given to the patients [in NCS], and thin needles are inserted in muscles during the examination procedure [in EMG],” the researchers wrote. Also, they may miss damage to smaller nerve fibers, those most commonly affected in the disease’s early stage.

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Ultrasound differences between FAP patients, healthy people

Ultrasonography is a noninvasive and nonpainful imaging technique that uses ultrasound to capture live images from inside the body. It can detect nerve enlargement, which in FAP may be caused by transthyretin clumps in the layer surrounding nerves, making them “more vulnerable to stretching around bone structures,” the researchers wrote.

Researchers at Umeå University, Sweden evaluated the use of ultrasound in 13 Swedish FAP patients (10 men, three women) who were referred for a first-time neurophysiology evaluation at the university’s hospital between November 2021 and April 2023, and underwent nerve conduction studies and an ultrasound exam of the peripheral nerves.

The patients’ age ranged from 30-88, and their median age at the onset of disease was 66. All carried V30M, the most most common FAP-causing mutation. Most patients had late-onset disease, with symptoms appearing after age 50. Only two patients had early-onset, before their 50s.

Most patients had discrete symptoms, often tingling feet, and were at a relatively early stage of the disease, with nine (69.2%) living with the disease for fewer than 1.5 years. A matched group of healthy people, eight men and six women between the ages 26-74, were included in the study, serving as controls.

An ultrasound evaluation of a nerve cross-sectional area, a classic measure of structural nerve abnormalities, was conducted at 11 peripheral nerve sites in the legs and arms, except for three late-onset patients, on whom not all nerve sites were evaluated.

Results from healthy controls showed no significant differences between body sides in any of the tested sites nor between younger (below 50) and older (over 50) people.

While “no significant differences were found between sides at any of the analyzed CSA nerve sites” in FAP patients, there were significant CSA differences between the FAP and control groups.

FAP patients showed a significantly enlarged CSA in lower extremity nerves, including the tibial nerve at the ankle, the sural nerve — which provides sensation to the back of the lower leg and foot — and the peroneal nerve behind the knee joint. The ulnar nerve at the middle upper arm was also significantly enlarged.

Comparing late-onset patients with healthy controls older than 50 showed similar results. No significant differences were seen in the other tested nerve sites.

Seven patients (53.8%) had no signs of peripheral nerve damage in standard NCS, but “significantly enlarged CSA in the lower extremities at all three nerve sites compared with controls” were found, the researchers wrote.

Patients with type A fibrils — the most common type of transthyretin clumps in late-onset FAP patients — showed a significantly larger CSA at the median nerve of the wrist than those with type B fibrils (more common in early-onset FAP). The wrist’s median nerve is affected in carpal tunnel syndrome, a common symptom of FAP.

“This study confirms previous findings, reporting thickening of peripheral nerves in [FAP] patients, but those studies differed in aspects that other mutation besides V30M were included,” the researchers wrote. “Our study is unique in one aspect since only those with a V30M mutation were randomly included.”

Evaluating the peripheral nerves with ultrasound “could be a valuable tool in disease evaluation and could facilitate monitoring of disease progression,” they said.