Nerve ultrasound able to spot silent damage in hATTR, study finds
Noninvasive testing may help monitor nerve damage before symptoms start
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Nerve ultrasound — a scan that uses high-frequency sound waves to create real-time images of the body’s nerves — may be used to monitor signs of polyneuropathy, or widespread damage, in people who carry disease-causing TTR mutations but have not yet developed symptoms of hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN).
That is the finding of a new study into the technique, used to detect damage to peripheral nerves, which are those outside the brain and spinal cord. Known as polyneuropathy, damage to multiple peripheral nerves can lead to symptoms such as muscle weakness, sensory changes, and pain.
Given this finding, the scientists suggest that such testing could be used to keep an eye on asymptomatic TTR carriers — people carrying TTR mutations that cause hATTR-PN but who have not yet developed signs of the inherited condition.
“As a noninvasive, inexpensive, and sensitive assessment, nerve ultrasound should be considered to be added to the established follow up program for … asymptomatic TTR carriers,” the team wrote.
Their study, “Nerve ultrasound in asymptomatic hereditary transthyretin amyloidosis carriers,” was published in the journal Clinical Neurophysiology by researchers in Europe.
Also known as familial amyloid polyneuropathy (FAP), hATTR-PN is caused by mutations in the TTR gene that result in the production of a misfolded transthyretin protein that is prone to form toxic clumps, called amyloid fibrils. In hATTR-PN patients, these clumps accumulate mainly in peripheral nerves.
Testing high resolution nerve ultrasound as a diagnostic tool
Now, a research team from Switzerland and Bulgaria evaluated whether high-resolution nerve ultrasound, or HRUS, could be used as a complementary diagnostic tool for the early detection of amyloid fibrils in the peripheral nerves of people with TTR mutations but no signs of the disease. Their study involved 21 asymptomatic TTR mutation carriers from Bulgaria.
All participants — 11 men and 10 women — carried p.Glu89Gln, the most common hATTR-PN-causing mutation in Bulgaria. This mutation is associated with an average age at disease onset of 51.7 years, with polyneuropathy as the main initial symptom.
None of the participants, who ranged in age from 23 to 54, had symptoms suggesting polyneuropathy. They also tested normal on nerve conduction studies, which measure the speed and strength of electrical signals in motor and sensory nerves, as well as in tests assessing the function of the autonomic nervous system, which controls involuntary bodily functions.
HRUS results were presented as an ultrasound pattern sum score (UPSS), which measures nerve cross-sectional area, representing nerve enlargement that can be caused by damage.
UPSS scores were abnormal in 70% of the participants, the data showed. Although the men in the study were younger than the women (31.1 vs. 34.3 years), they more frequently had abnormal scores (81.8% vs. 50%). The men also had a higher median UPSS score (3.4 vs. 1.6), indicating more pronounced nerve swelling.
More nerve abnormalities found in men than women
A total of 13 carriers (61.9%) had an abnormal UPSA subscore, which measures the cross-sectional area of the nerves that control motor and sensory function in the limbs. These are the median and ulnar nerves in the arms and the tibial and peroneal nerves in the legs.
Specifically, motor nerves in the arm were normal in all women, but median nerves were enlarged in six men at the elbow region and in four men at the upper arm region. Ulnar nerves were normal for all participants in the upper arm, and for all but one man in the forearm.
Mild enlargement of the median nerve at the wrist region was also detected in 13 participants — eight men and five women.
Regarding nerves in the leg, the tibial nerve in the region behind the knee was normal in women, but showed slight enlargement in four men. In the ankle region, the tibial nerve was enlarged in four men and three women.
The peroneal nerve was slightly enlarged in two men and one woman behind the knee, and in five women and two men at the outer knee bone, the researchers found.
As early diagnosis of peripheral nerve involvement is crucial for administration of disease modifying therapy, we suggest that nerve ultrasound may be added to the routine screening protocols of TTR carriers.
The UPSC subscore, which assesses the enlargement in nerves that control sensations to the limbs, was abnormal in eight participants, specifically five men and three women. The researchers found that six participants had an enlargement of the superficial peroneal nerve in the lower leg. In five, the radial nerve in the upper arm was enlarged.
“The most frequent abnormalities were found in the UPSA subscore with CSA [cross-sectional area] increase of tibial nerve at the ankle as the most frequent finding independent of the sex,” the researchers wrote. “When considering the male carriers only, the most frequently observed abnormality was increased CSA of the median nerve at the elbow.”
These findings shed new light on early signs of nerve damage in people with hATTR-PN, and highlight the potential of nerve ultrasound as a helpful diagnostic and monitoring tool, according to the researchers.
“As early diagnosis of peripheral nerve involvement is crucial for administration of disease modifying therapy, we suggest that nerve ultrasound may be added to the routine screening protocols of TTR carriers and may be considered as an additional test finding to the minimum criteria to establish disease onset,” the team wrote.
