• Humans
• Peripheral Nervous System Diseases/diagnostic imaging
• Ultrasonography/methods
• Peripheral Nerves/diagnostic imaging
• Peripheral Nerves/pathology

• Composite Autonomic Symptom Score 31
• Hereditary transthyretin amyloidosis
• Nerve cross-sectional area
• Nerve ultrasound
• Neuropathy Impairment Score
• Quantitative sensory testing

• Humans
• Amyloid Neuropathies, Familial/genetics
• Amyloid Neuropathies, Familial/pathology
• Male
• Female
• Middle Aged
• Cross-Sectional Studies
• Mutation/genetics
• Prealbumin/genetics
• Adult
• Aged
• Quality of Life

• autonomic nerve system
• caridomyopathy
• gastrointestinal dysfunction
• hereditray transthyretin amyloidosis
• nerve sonography

• Humans
• Amyloid Neuropathies, Familial/diagnostic imaging
• Amyloid Neuropathies, Familial/complications
• Amyloid Neuropathies, Familial/physiopathology
• Male
• Female
• Aged
• Vagus Nerve/diagnostic imaging
• Vagus Nerve/physiopathology
• Ultrasonography
• Middle Aged
• Median Nerve/diagnostic imaging
• Median Nerve/physiopathology
• Autonomic Nervous System/physiopathology
• Heart/innervation
• Heart/diagnostic imaging
• Heart/physiopathology
• Case-Control Studies
• Magnetic Resonance Imaging

• 111-M0008 National Taiwan University Hospital to H.-W.H.
• 113-M0004 National Taiwan University Hospital to H.-W.H.
• 111-2320-B-002-079 National Council of Science and Technology, Taiwan Government to S-T H.

• EMG
• cerebrotendineous xanthomatosis
• nerve ultrasound
• polyneuropathy

• electrodiagnosis
• inflammatory mononeuropathy
• nerve cross‐sectional area
• peripheral nerves
• ultrasonography

• Humans
• Male
• Female
• Middle Aged
• Adult
• Ultrasonography/methods
• Aged
• Mononeuropathies/diagnostic imaging
• Mononeuropathies/physiopathology
• Peripheral Nerves/diagnostic imaging
• Peripheral Nerves/physiopathology
• Neural Conduction/physiology
• Electrodiagnosis
• Prospective Studies
• Polyneuropathies/diagnostic imaging
• Polyneuropathies/physiopathology
• Cohort Studies

• P3-0338 The Republic of Slovenia Research Agency

• Amyloidosis
• Hereditary transthyretin amyloidosis
• Muscle ultrasound
• Neuromuscular ultrasound
• Ultrasound

• Humans
• Amyloid Neuropathies, Familial/diagnostic imaging
• Male
• Female
• Middle Aged
• Ultrasonography
• Muscle, Skeletal/diagnostic imaging
• Muscle, Skeletal/pathology
• Polyneuropathies/diagnostic imaging
• Aged
• Biomarkers
• Adult

• hereditary
• immune mediated
• leprosy
• metabolic
• motor neuron disease
• polyneuropathy
• toxic
• ultrasound

• Humans
• Ultrasonography/methods
• Polyneuropathies/diagnostic imaging

• Diabetes mellitus
• Diabetic polyneuropathy
• Morphometry
• Sural nerve
• Ultrasonography

• Sural Nerve/diagnostic imaging
• Humans
• Diabetic Neuropathies/diagnostic imaging
• Ultrasonography/methods

• ATTRv
• PADO
• presymptomatic carriers
• quantitative sensory testing
• skin biopsy
• small fiber neuropathy

• Humans
• Small Fiber Neuropathy/diagnosis
• Skin/pathology
• Pain
• Polyneuropathies/pathology
• Biopsy

• Hereditary transthyretin amyloidosis
• nerve cross-sectional area
• nerve entrapments
• peripheral nerves
• ultrasonography

• Female
• Humans
• Male
• Amyloid Neuropathies, Familial/diagnostic imaging
• Amyloid Neuropathies, Familial/genetics
• Peripheral Nerves/diagnostic imaging
• Prospective Studies
• Sweden/epidemiology
• Adult
• Middle Aged
• Aged
• Aged, 80 and over

• China
• Gly83Arg
• extraocular symptoms
• ocular symptoms
• transthyretin amyloidosis

• CSA
• TTR-FAP
• transthyretin
• ultrasonography
• vagus nerve

• CIDP
• amyotrophic lateral sclerosis
• entrapment neuropathy
• hereditary neuropathy
• neuromuscular ultrasound
• peripheral neuropathy

• ATTRv
• Polyneuropathy
• QST
• Skin biopsy
• Small fiber neuropathy

Amyloidosis caused by systemic deposition of transthyretin (TTR) is called ATTR amyloidosis and mainly includes hereditary ATTR (ATTRv) amyloidosis and wild-type ATTR (ATTRwt) amyloidosis. Until recently, ATTRv amyloidosis had been considered a disease in the field of neurology because neuropathic symptoms predominated in patients described in early reports, whereas advances in diagnostic techniques and increased recognition of this disease revealed the presence of patients with cardiomyopathy as a predominant feature. In contrast, ATTRwt amyloidosis has been considered a disease in the field of cardiology. However, recent studies have suggested that some of the patients with ATTRwt amyloidosis present tenosynovial tissue complications, particularly carpal tunnel syndrome, as an initial manifestation of amyloidosis, necessitating an awareness of this disease among neurologists and orthopedists. Although histopathological confirmation of amyloid deposits has traditionally been considered mandatory for the diagnosis of ATTR amyloidosis, the development of noninvasive imaging techniques in the field of cardiology, such as echocardiography, magnetic resonance imaging, and nuclear imaging, enabled nonbiopsy diagnosis of this disease. The mechanisms underlying characteristic cardiac imaging findings have been deciphered by histopathological studies. Novel disease-modifying therapies for ATTR amyloidosis, such as TTR stabilizers, short interfering RNA, and antisense oligonucleotides, were initially approved for ATTRv amyloidosis patients with polyneuropathy. However, the indications for the use of these disease-modifying therapies gradually widened to include ATTRv and ATTRwt amyloidosis patients with cardiomyopathy. Since the coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, occurred, the minimization of hospital visits and telemedicine have become increasingly important. As older age and cardiovascular disease are major factors associated with increased disease severity and mortality of COVID-19, many ATTR amyloidosis patients are at increased risk of disease aggravation when they are infected with SARS-CoV-2. From this viewpoint, close interspecialty communication to determine the optimal interval of evaluation is needed for the management of patients with ATTR amyloidosis.

• Amyloid angiopathy
• Cardiac amyloidosis
• Inotersen
• Patisiran
• Positron emission tomography
• Protein misfolding disease
• Red flag
• Scintigraphy
• Tafamidis
• Treatment

Backgrounds: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is frequently misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP) because of similar phenotypes in the two diseases. This study was intended to identify the role of nerve ultrasonography in evaluating TTR-FAP and CIDP.

Methods: Eighteen patients with TTR-FAP, 13 patients with CIDP, and 14 healthy controls (HC) were enrolled in this study. Consecutive ultrasonography scanning was performed in six pairs of nerves of bilateral limbs with 30 sites. The cross-sectional areas (CSAs) and CSA variability data of different groups were calculated and compared.

Results: Both TTR-FAP and CIDP showed larger CSAs at most sites of both upper and lower limbs than in HC groups. CIDP patients had larger CSAs than TTR-FAP patients at 8/15 of these sites, especially at U1-3, Sci2 sites (p < 0.01). However, the CSAs at above sites were not a credible index to differentiate TTR-FAP from CIDP with a low area under the curve (<0.8). The CSA variability of median nerves was significantly higher in CIDP than in TTR-FAP and HC groups, with high sensitivity (0.692) and specificity (0.833) to differentiate CIDP from TTR-FAP. The CSA variability of ulnar nerves was not significantly different between the three groups. For the TTR-FAP group, mean CSAs at each site were not correlated with different Coutinho stages, modified polyneuropathy disability, course of sensory motor peripheral neuropathy, Neuropathy Impairment Score, or Norfolk Quality of life-diabetic neuropathy score. The mean compound muscle action potential of ulnar nerves was negatively correlated with the mean CSAs of ulnar nerves.

Interpretation: TTR-FAP patients had milder nerve enlargement with less variability in CSAs of median nerves than those with CIDP, suggesting that nerve ultrasound can be a potential useful auxiliary tool to help differentiate the two neuropathies.

• CIDP
• TTR-FAP
• polyneuropathy
• transthyretin
• ultrasonography

• Amyloidosis
• Diagnosis
• Polyneuropathy
• Treatment
• hATTR

Background: Polyneuropathies (PNP) are a broad field of diseases affecting millions of people. While the symptoms presented are mostly similar, underlying causes are abundant. Thus, early identification of treatable causes is often difficult. Besides clinical data and basic laboratory findings, nerve conduction studies are crucial for etiological classification, yet limited. Besides Magnetic Resonance Imaging (MRI), high-resolution nerve ultrasound (HRUS) has become a noninvasive, fast, economic and available tool to help distinguish different types of nerve alterations in neuropathies. Methods: We aim to describe typical ultrasound findings in PNP and patterns of morphological changes in hereditary, immune-mediated, diabetic, metabolic and neurodegenerative PNP. Literature research was performed in PubMed using the terms ‘nerve ultrasound’, neuromuscular ultrasound, high-resolution nerve ultrasound, peripheral nerves, nerve enlargement, demyelinating, hereditary, polyneuropathies, hypertrophy’. Results: Plenty of studies over the past 20 years investigated the value of nerve ultrasound in different neuropathies. Next to nerve enlargement, patterns of nerve enlargement, echointensity, vascularization and elastography have been evaluated for diagnostic terms. Furthermore, different scores have been developed to distinguish different etiologies of PNP. Conclusions: Where morphological alterations of the nerves reflect underlying pathologies, early nerve ultrasound might enable a timely start of available treatment and also facilitate follow up of therapy success.

• demyelinating polyneuropathies
• hereditary polyneuropathies
• high-resolution nerve ultrasound
• peripheral nerve imaging

• Chronic inflammatory demyelinating polyneuropathy
• High-resolution nerve ultrasonography
• Nerve enlargement
• Transthyretin familial amyloid polyneuropathy

• Amyloid Neuropathies, Familial
• Diagnosis, Differential
• Humans
• Polyneuropathies
• Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnostic imaging
• Ultrasonography

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.

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.

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).

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).

• ATTRv
• Amyloidotic polyneuropathy
• Carpal tunnel syndrome
• Nerve ultrasound
• Transthyretin amyloidosis

Neuromuscular ultrasound (NMUS) is a rapidly evolving technique used in neuromuscular medicine to provide complimentary information to standard electrodiagnostic studies. NMUS provides a dynamic, real time assessment of anatomy which can alter both diagnostic and management pathways in peripheral nerve disorders. This review describes the current and future techniques used in NMUS and details the applications and developments in the diagnosis and monitoring of compressive, hereditary, immune-mediated and axonal peripheral nerve disorders, and motor neuron diseases. Technological advances have allowed the increased utilisation of ultrasound for management of peripheral nerve disorders; however, several practical considerations need to be taken into account to facilitate the widespread uptake of this technique.

• Neuromuscular ultrasound
• Peripheral neuropathy
• Polyneuropathy
• Entrapment neuropathy
• Immune-mediated neuropathy
• Hereditary neuropathy

Familial amyloid polyneuropathy with the substitution of methionine for valine at position 30 in the TTR gene is the most common type of hereditary transthyretin amyloidosis. Although several authors have previously reported a size-dependent fibre loss, predominantly involving unmyelinated and small-diameter myelinated fibres, the mechanisms of nerve fibre loss have not been fully understood. In this study, we establish the morphometric pattern of peripheral neuropathy in patients with familial amyloid polyneuropathy and asymptomatic mutation carriers in the biopsies from our archive and correlated the pathological findings with clinical features. A total of 98 patients with familial amyloid polyneuropathy and 37 asymptomatic mutation carriers (TTR Val30Met mutation), aged between 17 and 84 years, who underwent sural nerve biopsy between 1981 and 2017 at Centro Hospitalar Universitário do Porto were studied. Thirty-one controls were included for comparison. The median age at nerve biopsy was 26.0 [interquartile range = 23.5–39.5] years for asymptomatic mutation carriers, 45.0 [35.0–60.0] years for patients with familial amyloid polyneuropathy and 44.0 [30.0–63.0] years for controls. The median duration between nerve biopsy and symptoms’ onset was 7.0 [3.3–11.8] years (range: 1–27 years) in the asymptomatic carriers. Most patients were in an earlier disease stage (93% with a polyneuropathy disability scale ≤2). Patients had loss of small and myelinated fibres compared with both asymptomatic carriers and controls (P < 0.001), whereas asymptomatic carriers showed loss of small myelinated fibres when compared with controls (P < 0.05). The loss of myelinated fibres increased with disease progression (P < 0.001), and patients in more advanced clinical stage showed more frequent amyloid deposition in the nerve (P = 0.001). There was a positive correlation between large myelinated fibre density and time to symptoms’ onset in the asymptomatic carriers that developed early-onset form of the disease (r = 0.52, P < 0.01). In addition, asymptomatic carriers with amyloid deposition already present in sural nerve biopsies developed symptoms earlier than those with no amyloid (P < 0.01). In conclusion, this study confirms that the loss of small fibre size is an initial event in familial amyloid polyneuropathy, already present in asymptomatic gene carriers, starting several years before the onset of symptoms. We show for the first time that large myelinated fibres’ loss and amyloid deposition are pathological features that correlate independently with short period to the onset of symptoms for asymptomatic carriers that developed early-onset form of the disease. These findings are therapeutically relevant, as it would allow for a better interpretation of the role of disease-modifying agents in transthyretin familial amyloid polyneuropathy.

• familial amyloid neuropathy
• pathology
• sural serve
• transthyretin

• amyloid cardiomyopathy
• transthyretin
• transthyretin family amyloid polyneuropathy

• Diaphragm
• Electromyography
• Motor neuron disease
• Myopathy
• Nerve conduction studies
• Neuropathy