# Description of peripheral nervous system involvement in wild-type transthyretin amyloidosis: A clinical and electrophysiological study.

R. Barriol, Bruno Lemarchant, F. Cassim, Jean-Baptiste Davion, Luc Defebvre, Jean-Baptiste Gibier, Nicolas Lamblin, Celine Tard

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## To cite this version:

R. Barriol, Bruno Lemarchant, F. Cassim, Jean-Baptiste Davion, Luc Defebvre, et al., Description of peripheral nervous system involvement in wild-type transthyretin amyloidosis: A clinical and electrophysiological study., Revue Neurologique, 2025, Rev Neurol (Paris), 10.1016/j.neurol.2025.06.007. hal-05303124

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Original article

# Description of peripheral nervous system involvement in wild-type transthyretin amyloidosis: A clinical and electrophysiological study*

<figure><img src="image_3.png" /></figure>

R. Barriol*, B. Lemarchant, F. Cassim, J.-B. Davion, L. Defebvre, J.-B. Gibier

AmyloLille<fnref n="1" />, N. Lamblin, C. Tard

Lille University Hospital, rue Émile-Laine, 59037 Lille, France

## INFO ARTICLE

Article history:

Received 10 December 2024

Received in revised form

4 May 2025

Accepted 2 June 2025

Available online 15 July 2025

Keywords:

Transthyretin amyloidosis

Polyneuropathy

TTR

Electroneuromyography

## ABSTRACT

**Introduction.** – Wild-type transthyretin amyloidosis (ATTRwt) is not clearly known to be associated with peripheral neurological complications. The aim of our study was to characterize neurological involvement in ATTRwt, as well as its evolution over time, using clinical and electrodiagnostic (EDX) data.

**Methods.** – We prospectively included patients diagnosed with ATTRwt who were addressed by cardiologists. All patients underwent neurological evaluation, including examination (neuropathy impairment score) and an EDX study including electrochemical skin conductance and/or sympathetic skin response testing. Motor, sensory, and small fiber composite sum scores were calculated based on the EDX data. Clinical and EDX scores were then reassessed during the follow-up period.

**Results.** – Fifty-two patients were included, 94% of whom were treated with tafamidis. At inclusion 98% of patients presented peripheral nerve involvement at EDX, the most common being carpal tunnel syndrome (88%), polyneuropathy (67%), and ulnar tunnel syndrome (21%). Twenty-nine patients were reevaluated and mean follow-up was 16.7 months with no significant change of clinical or neurophysiological data.

**Discussion.** – In our cohort, a large majority of ATTRwt patients showed peripheral nerve involvement, generally expressed as the combination of different neurological syndromes (entrapment syndromes, large and/or small fiber polyneuropathy, radicular impairment). Polyneuropathy in ATTRwt seemed stable over our follow-up period. Clinical and EDX screening should be conducted in ATTRwt patients with symptoms suggestive of neurological involvement in order not to oversee these frequent complications which could affect therapeutic decision making.

© 2025 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

<footnote>* Given his role as a member of the Scientific Advisory Board, the author Luc Defebvre was not involved in the peer-review process of this article, nor did he have access to any information regarding this process. He did not participate in the decision-making regarding the article.</footnote>

<footnote>* Corresponding author. 406, rue Léon-Gambetta, 59000 Lille, France.</footnote>

<footnote>E-mail address: romain.barriol@chu-lille.fr (R. Barriol).</footnote>

<footnote n="1">¹ The complete list of AmyloLille collaborators is available in the Supplementary material. https://doi.org/10.1016/j.neurol.2025.06.007</footnote>

<footnote>0035-3787/© 2025 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</footnote>
# 1. Introduction

Transthyretin amyloidosis (ATTR) is a systemic gain-of-toxic-function disease caused by amyloidogenic transthyretin (TTR) deposition in affected organs, including the heart and the peripheral nervous system. The two major forms of ATTR amyloidosis are hereditary ATTR (ATTRv) and wild-type ATTR (ATTRwt) [1]. ATTRv is an inherited disorder related to a mutation in the TTR gene, leading to the production of an unstable transthyretin variant, resulting in tetramer dissociation and subsequent aggregation into amyloid fibrils. To date, more than 120 pathogenic TTR gene mutations have been reported in ATTRv, with an autosomal dominant transmission [2]. On the other hand, ATTRwt is a sporadic disorder occurring in older individuals in whom tetramer instability and TTR aggregation also occur, but without a pathogenic mutation in the TTR gene [1].

Neurological impairment in ATTRv has been well characterized. ATTRv-related polyneuropathy (PN), referred to as familial amyloid polyneuropathy (FAP), is a hallmark of ATTRv amyloidosis and generally presents as a progressive, symmetric, axonal, sensory, autonomic, and/or motor neuropathy. Small fiber neuropathy is predominant and autonomic functions can be impaired from the onset of FAP [3,4]. Neuropathy phenotypes may vary depending on the type of amyloidogenic mutation or other environmental factors. In France for instance, the prevalent phenotypes are demyelinating peripheral neuropathies which can mimic chronic inflammatory demyelinating neuropathy, or non-length dependent neuropathies with upper limb onset [5,6]. ATTRv can also lead to the involvement of other organs, such as the heart and the eye. Particular gene mutations responsible for ATTRv may also induce familial leptomeningeal amyloidosis, characterized by amyloid deposition in the media and adventitia of arteries, arterioles and veins of the cortex and leptomeninges [2,7].

The classical hallmark of ATTRwt amyloidosis is a cardiomyopathy prevalent in elderly individuals, principally affecting men and frequently associated with carpal tunnel syndrome (CTS) at diagnosis [8]. However, recent evidence suggests that this disorder may induce other neurological impairments such as large and small fiber peripheral neuropathies and spinal nerve root involvement. In 2021, a study found that 44% of a cohort of 23 ATTRwt patients suffered from axonal neuropathy as well as small fiber neuropathy, without other coexisting causes of neuropathy. Furthermore, skin biopsies showed reduced intraepidermal nerve fiber density in over 80% of these ATTRwt patients [9]. Another study published in 2022, concerning 16 ATTRwt patients with systematic electrodiagnostic (EDX) testing, found abnormal electrochemical skin conductance in nine patients [10]. In a case of ATTRwt associated with lumbar spinal canal stenosis leading to compression of spinal nerve roots, TTR deposition was observed in the yellow ligament [11]. These results suggest that amyloidogenic TTR deposition may occur in a multiplicity of tissue types, with clinical repercussions exceeding merely cardiomyopathy and CTS.

Age seems to be a major risk factor for systemic wild-type TTR-derived amyloid deposition. For instance, a study using systematic Congo red staining on flexor tenosynovium, rotator cuff tendon, and yellow ligament specimens from 111 patients with orthopedic disorders found 42% amyloid-positive samples,

and the prevalence of amyloid deposition in those tissues increased with age [12]. Furthermore, TTR aggregation leading to wild-type TTR deposition is considered to occur even under physiological conditions [13].

In this study, we aimed to better characterize the neurological consequences of amyloidogenic wild-type TTR deposition. Our objective was to evaluate the prevalence and characteristics of peripheral neurological impairment in ATTRwt patients, as well as its progress over time.

# 2. Methods

## 2.1. Patient eligibility and diagnostic criteria

We conducted an observational, retrospective, single-center cohort study of all ATTRwt patients diagnosed at Lille University Hospital between November 2018 and December 2022. ATTR patients were diagnosed according to AHA cardiac tranthyretin amyloidosis guidelines [14]. All patients underwent TTR gene testing in order to exclude ATTRv. Patients diagnosed with ATTR were systematically addressed to the neurology department by the cardiologists of Lille's amyloidosis network. All patients diagnosed with ATTRwt in our network underwent systematic clinical and EDX evaluation. A diagnostic workup was performed to exclude other etiologies of neuropathy, including glycated hemoglobin (HbA1c) testing, and serum protein electrophoresis. Patients were excluded if they presented with diabetes, or showed any other confounding etiology for neuropathy. Each patient went through a standardized evaluation by clinicians from the neuromuscular disorders reference center. This evaluation included assessment of the neuropathy impairment score (NIS), which comprises upper and lower limb motor, sensory, and osteotendinous reflex subscores [15], and the small-fiber neuropathy-symptom inventory questionnaire (SFN-SIQ), which tests for symptoms suggestive of small-fiber neuropathy [16]. Additional biomarkers were recorded: body mass index, fasting glucose levels, gamma-GT levels, and MDRD clearance estimates. Patients systematically underwent an EDX study with nerve conduction studies, needle electromyography and a small fiber evaluation by either sympathetic skin response (SSR) or electrochemical skin conductance (ESC), or both. EDX could be controlled during the follow-up period based on clinical indication.

## 2.2. Electrodiagnostic studies

We used stimuli detection on fibular, median, and ulnar nerves for motor studies and antidromic stimuli detection on sural, median, and ulnar nerves for sensory studies. Surface temperature was controlled for feet and hands before testing, and temperature was corrected if under 30 degrees Celsius. Distal symmetric PN was diagnosed using at least sural sensory and peroneal motor nerve conduction studies, according to England et al. PN was considered absent if both of these studies were normal, whereas the diagnosis of PN was established if nerve conduction was abnormal (≥ 99th or ≤ 1st percentile) in two separate nerves, one of which being the sural nerve [17].

Entrapment syndromes were defined by focal conduction modifications or conduction blocks associated with the
combination of three needle electromyographic results: (i) needle electromyographic (EMG) abnormalities in at least two muscles related to the entrapped nerve; (ii) normal EMG detection in muscles related to other nerve trunks; (iii) normal EMG detection in muscles related to the same nerve root but to a different nerve trunk.

Small fiber impairment was defined as abnormal SSR and/or ESC testing. Sudomotor dysfunction on ESC evaluation was defined as > 60 µS indicating no dysfunction, 60-40 µS indicating moderate dysfunction, and < 40 µS indicating severe dysfunction [18].

Radicular impairment was defined on EDX, when (i) needle EMG abnormalities were observed in at least two muscles of same radicular innervation; and (ii) sensory stimuli detection values were normal on at least one nerve trunk corresponding to each muscle.

## 2.3. EDX sum scores

Sum scores were calculated using a previous methodology applied to Val30Met ATTRv [19]. Sensory neurophysiological scores (SNS) were derived from the sum of median and sural nerve sensory amplitudes, motor neurophysiological scores (MNS) were derived from the sum of the compound muscle action potential amplitudes of the median and peroneal nerves. Sympathetic skin response scores (SSRS) were derived from the sum of the palm and foot SSR amplitudes after electrical stimulation. ESC sum scores were derived from the sum of the conductances measured at the hands and feet.

## 2.4. Statistical analysis

Risk factors for neuropathy compared between patients with and without polyneuropathy are expressed as mean and standard deviation (according to the Mann-Whitney U test). Categorical variables are expressed as number and percentage. Paired samples t-tests were performed on clinical and neurophysiological data for comparison over the follow-up period. When appropriate, post-hoc analyses with a Bonferroni correction were performed. The significance threshold was set to 0.05 for all analyses. Statistical analysis was performed using JASP version 0.17.1.0.

## 2.5. Ethical approval

In line with French legislation on retrospective studies of routine clinical practice, the study protocol was approved by a hospital committee with competency for research not requiring approval by an institutional review board. A declaration to the Commission Nationale de l'Informatique et des Libertés (CNIL) was made under number 17022020.

# 3. Results

Fifty-eight patients were screened during the study period. Six patients were excluded because of evident confounding causes of neuropathy: one had toxic vincristine-related PN, the five others had diabetes. Amongst the patients with monoclonal gammopathy, none had diagnostic arguments for amyloid light-chain amyloidosis or inflammatory neuropathy. Of the 52 remaining

patients, 50 had complete NIS scores at baseline and 46 completed SFN-SIQ self-administered questionnaires. Demographical data, clinical complaints, prevalence of monoclonal gammopathy or metabolic risk factors, mean NIS and SFN-SIQ scores, and electrophysiological data are displayed in Table 1.

<table><caption>Table 1 - Characteristics of patients at baseline (demographical data, symptoms, clinical neurological data, biological data and electrodiagnosis data).</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td>Baseline patient characteristics (n = 52)</td><td></td></tr><tr><td>Age at diagnosis (in years)</td><td>80.7 ± 7.8</td></tr><tr><td>Gender ratio F/M</td><td>12/40</td></tr><tr><td>Patient symptoms at baseline</td><td></td></tr><tr><td>Asymptomatic</td><td>4% (2)</td></tr><tr><td>Polyneuropathy-related symptoms (decreasing frequency)</td><td></td></tr><tr><td>Paresthesia/allodynia</td><td>35% (18)</td></tr><tr><td>Ataxia</td><td>31% (16)</td></tr><tr><td>Hands weakness and/or clumsiness</td><td>23% (12)</td></tr><tr><td>Gait disorder</td><td>23% (12)</td></tr><tr><td>Hypoesthesia/anesthesia</td><td>21% (11)</td></tr><tr><td>Neuropathic pain</td><td>21% (11)</td></tr><tr><td>Radicular claudication</td><td>6% (3)</td></tr><tr><td>Restless leg syndrome</td><td>2% (1)</td></tr><tr><td>Fasciculations</td><td>2% (1)</td></tr><tr><td>General symptoms (decreasing frequency)</td><td></td></tr><tr><td>Dysuria/urinary leakage</td><td>48% (25)</td></tr><tr><td>Dry eye syndrome</td><td>44% (23)</td></tr><tr><td>Hyperhidrosis</td><td>42% (22)</td></tr><tr><td>Orthostatic hypotension</td><td>42% (22)</td></tr><tr><td>Constipation</td><td>42% (22)</td></tr><tr><td>Palpitations</td><td>35% (18)</td></tr><tr><td>Dyspepsia</td><td>31% (16)</td></tr><tr><td>Visual accommodation disorders</td><td>21% (11)</td></tr><tr><td>Sexual disorders</td><td>15% (8)</td></tr><tr><td>Diarrhea</td><td>12% (6)</td></tr><tr><td>Facial flushing</td><td>10% (5)</td></tr><tr><td>Dry mouth syndrome</td><td>8% (4)</td></tr><tr><td>Excessive sweating</td><td>2% (1)</td></tr><tr><td>Neurological clinical data</td><td></td></tr><tr><td>Neuropathy impairment score (NIS)</td><td>23.3 ± 13.6</td></tr><tr><td>Upper limb motor NIS sub-score</td><td>6.3 ± 6.1</td></tr><tr><td>Lower limb motor NIS sub-score</td><td>1.7 ± 3.8</td></tr><tr><td>Sensory NIS sub-score</td><td>5.4 ± 4.3</td></tr><tr><td>Osteotendinous reflex NIS sub-score</td><td>9.9 ± 7.5</td></tr><tr><td>SFN-SIQ score</td><td>8.8 ± 6.4</td></tr><tr><td>Biological risk factors for neuropathy</td><td></td></tr><tr><td>Fasting glucose level (g/L)</td><td>1.05 ± 0.19</td></tr><tr><td>Glycated hemoglobin (%)</td><td>5.7 ± 0.55</td></tr><tr><td>Body mass index (kg/m²)</td><td>25.2 ± 4.0</td></tr><tr><td>Monoclonal gammopathy</td><td>11.5% (6)</td></tr><tr><td>GGT (IU/L)</td><td>98.9 ± 132.7</td></tr><tr><td>MDRD clearance estimate (mL/min)</td><td>63.0 ± 23.5</td></tr><tr><td>Electrodiagnostic data (n = 43)</td><td></td></tr><tr><td>Presence of polyneuropathy</td><td>66.7%</td></tr><tr><td>Carpal tunnel syndrome</td><td>88.4%</td></tr><tr><td>Ulnar tunnel syndrome</td><td>20.9%</td></tr><tr><td>Signs of radicular impairment</td><td>9.3%</td></tr><tr><td>Signs of small fiber impairment on SSR or ESC (n = 30)</td><td>23.3%</td></tr><tr><td>MNS (n = 37)</td><td>18.1 ± 8.9</td></tr><tr><td>SNS (n = 39)</td><td>34.3 ± 23</td></tr><tr><td>SSRS (n = 14)</td><td>3.55 ± 2.9</td></tr><tr><td>Upper limb mean ESC in µS (n = 21)</td><td>60.0 ± 15</td></tr><tr><td>Lower limb mean ESC in µS (n = 21)</td><td>67.5 ± 21</td></tr><tr><td>ESC sum score (n = 21)</td><td>253.0 ± 63</td></tr></tbody></table>

F: female; M: male. Variables are expressed as percentage or mean ± SD.
<figure><img src="image_4.png" /><figcaption>**Fig. 1** – Diagram representing the distribution of electrodiagnostic (EDX) findings amongst our ATTRwt population. EN: entrapment neuropathy (blue); PN: polyneuropathy (yellow); R: radicular impairment (red); N: normal EDX. “Green” was the most frequent pattern, associating length-dependent polyneuropathy and entrapment syndromes.</figcaption></figure>

Detailed clinical symptoms are presented in Supplemental Table 1. Concerning sensory complaints, 35% of the patients suffered from paresthesia or allodynia, 31% from ataxia, 21% from neuropathic pain. Concerning limitations, 23% of patients had significative lower limb involvement with gait disorders and 21% had upper limb impairment with hand weakness or clumsiness.

Mean SFN-SIQ score was 8.8 ± 6.4. Ninety-six percent of patients described symptoms suggestive of neurological impairment due to ATTR. The most common symptoms were dysuria or urinary leakage, dry eye syndrome, hyperhidrosis, orthostatic hypotension, constipation paresthesia or allodynia, and palpitations.

Forty-three patients underwent EXD testing and 30 had small fiber evaluation. Thirty-four of the 38 cases (89%) of CTS were bilateral. A summary of the EDX study results of all our patients is shown in Fig. 1. EDX data were compared between patients with and without PN, as illustrated in Supplementary Figure 1.

We compared the values of biomarkers considered as risk factors for PN, and therefore at risk of being confounding factors, between ATTRwt patients with and without PN. These values did not differ significantly between the two groups (Table 2).

Concerning follow-up, 29 patients underwent clinical re-evaluation and 13 patients had a control EDX study during the follow-up period. The mean follow-up period was 16.7 months. During this period, 49 (94%) patients were receiving tafamidis 61 mg per day. No other anti-amyloid therapy was used in our cohort, as prescribed by the cardiologist. No statistically significant variation of clinical and EDX scales was observed during the follow-up period (P > 0.05 for all scales, Table 3).

An anatomopathological assessment was performed for 36 patients (69%) per the attending neurologist's decision. Among these patients, amyloid testing was positive in 12/36 (33%) on accessory salivary gland biopsies (n = 5), periumbilical fat

<table><caption>**Table 2** – Risk factors for polyneuropathy compared between patients with and without polyneuropathy.</caption><thead><tr><th>Risk factor</th><th>Mean ± SD</th><th>P</th></tr></thead><tbody><tr><td><strong>Clinical scales</strong></td><td></td><td></td></tr><tr><td>Body mass index (kg/m²)</td><td></td><td></td></tr><tr><td>PN +</td><td>24.8 ± 4.3</td><td rowspan="2">0.28</td></tr><tr><td>PN –</td><td>26.2 ± 3.1</td></tr><tr><td>Fasting glucose (g/L)</td><td></td><td></td></tr><tr><td>PN +</td><td>1.03 ± 0.17</td><td rowspan="2">0.96</td></tr><tr><td>PN –</td><td>1.07 ± 0.22</td></tr><tr><td>Glycated hemoglobin (%)</td><td></td><td></td></tr><tr><td>PN +</td><td>5.6 ± 0.45</td><td rowspan="2">0.57</td></tr><tr><td>PN –</td><td>5.9 ± 0.78</td></tr><tr><td>Gamma-GT (U/L)</td><td></td><td></td></tr><tr><td>PN +</td><td>91.5 ± 125</td><td rowspan="2">0.42</td></tr><tr><td>PN –</td><td>79.9 ± 116</td></tr><tr><td>MDRD clearance (mL/min/1.73 m²)</td><td></td><td></td></tr><tr><td>PN +</td><td>57.6 ± 21</td><td rowspan="2">0.16</td></tr><tr><td>PN –</td><td>69.3 ± 24</td></tr></tbody></table>

These variables are expressed as mean and standard deviation (SD). Mann-Whitney U tests were used for these analyses. EDX: electrodiagnostic; PN: polyneuropathy on EDX. Results were considered statistically significant for P ≤ 0.05.

<table><caption>**Table 3** – Clinical and EDX scales compared over the follow-up period.</caption><thead><tr><th>Scale</th><th>t1</th><th>t2</th><th>t3</th><th>P</th></tr></thead><tbody><tr><td>NIS</td><td>23.3 ± 14</td><td>24.7 ± 16</td><td>27.8 ± 17.0</td><td>0.104 (t1/t2)<br>0.400 (t1/t3)</td></tr><tr><td>SFN-SIQ</td><td>8.80 ± 6.4</td><td>8.73 ± 5.9</td><td>9.25 ± 5.8</td><td>0.542 (t1/t2)<br>0.222 (t1/t2)</td></tr><tr><td>MNS</td><td>18.1 ± 8.9</td><td>20.0 ± 8.5</td><td></td><td>0.970</td></tr><tr><td>SNS</td><td>34.3 ± 23</td><td>37.0 ± 21</td><td></td><td>0.791</td></tr><tr><td>SSRS</td><td>3.5 ± 2.9</td><td>4.2 ± 2.7</td><td></td><td>0.813</td></tr><tr><td>ESC sum score</td><td>253.0 ± 63</td><td>268.1 ± 52</td><td></td><td>0.181</td></tr></tbody></table>

t1, t2 and t3 refer to the first, second and third evaluations, respectively, over time. No patient had a third EDX evaluation during the follow-up period. Comparisons were made using a Wilcoxon signed-rank test. Values are expressed as mean ± SD. These analyses were accomplished according to Student tests. EDX: electrodiagnostic; MNS: motor neurophysiological score; SNS: sensory neurophysiological score; SSRS: sympathetic skin response score.

biopsies (n = 2), fundic or duodenal biopsies (n = 2), carpal tunnel biopsies (n = 1) and a thigh skin biopsy (n = 1).

## 4. Discussion

This retrospective systematic study concerning 56 ATTRwt patients provides evidence that PN can be observed in patients suffering from ATTRwt not better explained by another coexisting affection. After excluding six patients that had comorbidities, we found that about one-third of patients had sensory symptomatic impairments characterized by ataxia or paresthesia, and about one-quarter had functional complaints such as gait impairment or hand weakness/clumsiness. Furthermore, in this population, 65% of ATTRwt patients showed signs of PN on systematic EDX studies, which is higher
than the prevalence expected for elderly patients, i.e. 39% [20,21]. However, this overrepresentation of idiopathic PN was not associated with more frequent vascular risk factors. Generally, the frequency of vascular risk factors is low in the ATTRwt population compared to the general population, probably explained by a selection bias linked to advanced age: patients with more vascular risk factors die prematurely from other causes, before reaching the age to develop senile ATTRwt.

Mean age was 81 years, which is consistent with previous findings. However, our cohort was composed of only 77% male patients, which is lower than the 90-95% male predominance described in other publications [22]. Mean SFN-SIQ score was 8.8, which is above the recommended cutoff for small-fiber neuropathy at 6.5 [16]. A large majority of our patients suffered from CTS (88%), which concords with the results of precedent publications. Other types of peripheral nerve system involvement were well represented in our cohort: 24% of patients had signs of small fiber impairment, 22% had ulnar tunnel syndromes, 9% had signs of radicular impairment. Thus, we suggest that mixed neurological damage associating length-dependent sensory and/or motor peripheral neuropathy, entrapment syndromes (CTS and/or ulnar entrapments) and radicular impairment may be a neurological profile evocative of ATTRwt.

Sensory-motor complaints and functional impairment, such as dysautonomia, can interfere with quality of life but can also lead to falls and morbidity. They should be addressed in patients with ATTRwt who display signs of neuropathy, through a global approach to care. Further studies are necessary to explore the progression of these neurological manifestations under treatment, and ideally pathology studies would be necessary to confirm the link between neurological symptoms and systemic TTR deposition.

Regarding neurophysiological studies, we must point out that amongst the 46 patients who had an EDX study, only 33 were tested for small fiber impairment. Patients with more pronounced clinical signs of small fiber dysfunction may have had more chances of being tested by SSR and/or ESC, and this may have induced bias by overestimating the proportion of small fiber impairment in our cohort.

NIS scores and the EXD sum scores did not vary significantly during follow-up. Ninety-four percent of patients studied were under treatment with tafamidis 61 mg per day, due to ATTR-related cardiomyopathy. This result suggests that PN in ATTRwt was relatively stable during the follow-up period. This observed stability could be explained by multiple reasons, which could be independent or interlinked: the slow evolution of PN in ATTRwt patients, this study's relatively short mean follow-up period of 17 months, the lack of power of this study to detect PN aggravation or regression, and/or a clinical effect of tafamidis on PN progression in ATTRwt patients.

Clinical assessment of PN in ATTRwt patients may be challenging, in part because some clinical findings typical of PN, such as altered vibrotactile sensitivity, diminished osteotendinous reflexes or atrophy of extensor digitorum brevis muscles, may be interpreted as physiological in relation to age [20]. In addition, in concordance with recent literature, we observed that a majority of patients have

multiple types of peripheral nervous system impairment, which may make PN harder to evaluate as it is combined with other neurological affections. Indeed, in our study, at least 64% of patients had two or more types of neurological involvement on EDX. For comparison, a cohort study published in 2022 in which ATTRwt patients underwent systematic EDX, 44% showed neuropathy (large and/or small fiber) without evidence of another underlying cause, and over 50% showed pathological autonomic testing [9]. More recently, a study published in 2024 assessing gait parameters in ATTR cardiac amyloidosis showed significantly slower, narrower and shorter strides compared to healthy older male controls [23]. These observations underline the potential role of EDX to demonstrate PN in ATTRwt patients with significant neurological complaints.

This study found a high prevalence of peripheral nervous system involvement in ATTRwt; however, the pathophysiological link between these two entities remains to be proven. This would require studies including histological nerve examination of ATTRwt patients, which is problematic since nerve biopsies seem inappropriate considering the slow progression and epidemiological profile of the ATTRwt population. Post-mortem histological studies may be a solution to this dilemma. Nevertheless, in our cohort the presence of systemic amyloid depositions on histological fragments of various locations in 12 out of 36 anatomopathological analyses (33.3%) would support this hypothesis.

In clinical practice, the combined presence of such neurological impairments (radicular syndrome, entrapment syndromes and PN) should lead to investigate for ATTRwt. Further studies are necessary to prove the pathophysiological link between these neurological lesions and TTR deposition. However, it seems important to screen for neurological manifestations in ATTRwt patients who report significant symptoms suggesting neurological impairment through a global and multidisciplinary evaluation. This may help improve patient management, for example via symptomatic treatments such as nerve compression prevention, rehabilitative care, and neuropathic pain relief. Some symptoms relative to dysautonomia, such as dysuria, dry eye syndrome, hyperhidrosis, palpitations, and orthostatic hypotension were frequent in our population (prevalence was between 35 and 48% for each of these symptoms), and were not better explained by another age-related disease. It may be of interest to specifically track these symptoms in elderly patients as part of the diagnostic process or initial evaluation of ATTRwt.

In summary, neurological involvement seems to be largely prevalent in ATTRwt, and not restricted to CTS. Our study found sensorimotor and small-fiber PN to be prevalent in 67% of ATTRwt patients, as well as ulnar compression and radicular impairment. We could hypothesize that chronic idiopathic axonal PN, more frequent in the elderly population, could sometimes in fact be caused by undiagnosed wild-type TTR deposits.

Therapeutic approaches have been developed in ATTR amyloidosis, resulting in the reduction of amyloidogenic TTR or stabilization of circulating TTR [24,25]. A randomized controlled trial has demonstrated the efficacy of tafamidis on cardiac involvement for both ATTRv and ATTRwt patients [26]. To this day, no treatment has been studied on neuropa-
thic dysfunction in ATTRwt, because it is insufficiently documented [27]. Further neurophysiological and histological investigation of these patients may therefore help pave the way towards future controlled trials testing modern disease-modifying therapeutics for efficacy on peripheral neuropathy in ATTRwt.

## Disclosure of interest

The authors declare that they have no competing interest.

## Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.neurol.2025.06.007.

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