Longitudinal multimodal assessment of peripheral nerve involvement in wild-type transthyretin amyloidosis.

Pathological intra-epidermal nerve fiber density (IENFD) was significantly more common in ATTRwt patients than in healthy controls.

• Pathological IENFD occurred in 47.8% of patients versus 4.3% of controls (p=0.002).
• IENFD from skin biopsies was used to assess small fiber involvement.
• 23 patients with ATTRwt cardiomyopathy were included and compared to healthy controls.
• This finding indicates significant small fiber neuropathy involvement in ATTRwt.

Sensory-predominant axonal polyneuropathy was present in the majority of ATTRwt patients.

• Sensory-predominant axonal polyneuropathy was present in 82.6% of ATTRwt patients.
• Patients with polyneuropathy had higher Neuropathy Impairment Score Lower Limb (NIS-LL) and greater symptom burden (p<0.001).
• Nerve conduction studies were used to characterize the neuropathy.
• The neuropathy was classified as a mixed fiber neuropathy affecting both large and small fibers.

All quantitative sensory testing (QST) parameters were abnormal in ATTRwt patients except cold detection.

• QST was used as part of a multimodal neurological assessment battery.
• Cold detection was the only QST parameter that did not show abnormality in ATTRwt patients.
• Abnormal QST parameters indicate involvement of both large and small sensory nerve fibers.
• This pattern of QST abnormality is consistent with a mixed fiber neuropathy.

Carpal tunnel syndrome (CTS) was highly frequent in ATTRwt patients, and the combination of polyneuropathy with CTS was more common in ATTRwt than in controls.

• Carpal tunnel syndrome was present in 82.7% of ATTRwt patients.
• Polyneuropathy with CTS was more common in ATTRwt patients compared to controls (p=0.025).
• The co-occurrence of polyneuropathy and CTS is suggested as a clinical red flag for ATTRwt.
• CTS is an entrapment neuropathy that may reflect amyloid deposition in the carpal tunnel.

Serum neurofilament light chain (sNfL) levels were similar between ATTRwt patients and healthy controls.

• sNfL was measured as a biomarker of neuroaxonal injury.
• No significant difference in sNfL was found between ATTRwt patients and controls.
• This finding contrasts with the structural and functional nerve abnormalities detected by other modalities.
• The lack of elevated sNfL may suggest relatively low ongoing neuroaxonal damage despite detectable neuropathy.

At 13-month follow-up, no significant clinical or electrophysiological progression of neuropathy was observed, and no new cases of polyneuropathy were diagnosed.

• Patients were evaluated prospectively at baseline and after approximately 1 year (13 months).
• No newly diagnosed cases of polyneuropathy were identified at follow-up.
• The authors describe the progression as 'subtle clinical progression over 13 months.'
• No electrophysiological progression was detected on nerve conduction studies at follow-up.

Patients with ATTRwt had higher symptom burden as measured by Norfolk Quality of Life-Diabetic Neuropathy questionnaire and Chalder Fatigue scale.

• Symptoms were assessed using the Norfolk-QoL-DN questionnaire and the Chalder Fatigue scale.
• Higher NIS-LL scores and greater symptom burden were found in ATTRwt patients with polyneuropathy (p<0.001).
• Both neuropathy-specific quality of life and fatigue were assessed as part of the multimodal evaluation.
• The study prospectively evaluated 23 patients with ATTRwt cardiomyopathy alongside healthy controls.