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Quantitative sudomotor test helps differentiate Transthyretin familial amyloid polyneuropathy from Chronic Inflammatory Demyelinating Polyneuropathy
Journal Pre-proofs Quantitative sudomotor test helps differentiate Transthyretin familial amyloid polyneuropathy from Chronic Inflammatory Demyelinating Polyneuropathy E. Fortanier, E. Delmont, A Verschueren, S. Attarian PII: DOI: Reference:
S1388-2457(20)30058-4 https://doi.org/10.1016/j.clinph.2020.01.022 CLINPH 2009130
To appear in:
Clinical Neurophysiology
Received Date: Revised Date: Accepted Date:
26 April 2019 24 December 2019 26 January 2020
Please cite this article as: Fortanier, E., Delmont, E., Verschueren, A., Attarian, S., Quantitative sudomotor test helps differentiate Transthyretin familial amyloid polyneuropathy from Chronic Inflammatory Demyelinating Polyneuropathy, Clinical Neurophysiology (2020), doi: https://doi.org/10.1016/j.clinph.2020.01.022
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier B.V. on behalf of International Federation of Clinical Neurophysiology.
Quantitative sudomotor test helps differentiate Transthyretin familial amyloid polyneuropathy from Chronic Inflammatory Demyelinating Polyneuropathy
E. Fortanier1, E. Delmont1, A Verschueren1, S. Attarian1
1
Neuromuscular Disease and ALS Reference Center, Timone University Hospital, Aix-Marseille
University, Marseille, France
Corresponding author: Shahram Attarian Centre de référence des maladies neuromusculaires et de la SLA CHU Timone - 264 rue Saint Pierre - 13385 Marseille Cedex 05 – France Tel: +33 4 91 38 65 79 Fax: +33 4 91 38 49 46 E-mail: [email protected]
1
Abstract Objective Transthyretin familial amyloid polyneuropathy (TTR-FAP) is an aggressive hereditary neuropathy characterized by sensory and autonomic dysfunction. There are numerous reports of TTR-FAP misdiagnosed and treated as chronic inflammatory demyelinating polyneuropathy (CIDP), leading to delayed diagnosis, risk of iatrogenic adverse events and increased socio-economic costs. Quantitative sudomotor function measured by electrochemical skin conductance (ESC) appears to be a sensitive test in TTR-FAP. We aimed to evaluate the performance of ESC in differentiating TTR-FAP from CIDP. Methods Thirty-eight patients with genetically confirmed hereditary TTR amyloidosis and 26 with definite CIDP according to the EFNS/PNS guidelines and negative TTR-FAP genetic testing were involved in this study. We compared the ESC for feet and hands measured by Sudoscan for each patient. Results ESC (µS) was significantly lower in TTR-FAP for both hands (72 vs 45, p< 0.0001) and feet (77 vs 35, p< 0.0001). Feet ESC < 64 µS had a 89% sensitivity and a 96% specificity to differentiate between CIDP and TTR-FAP. Conclusion Sudoscan is a fast, non-invasive and easy to perform test, able to distinguish CIDP and TTRFAP patients with good sensitivity and specificity.
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Significance Sudoscan can be helpful in distinguishing between CIDP and TTR-FAP.
Keywords: Transthyretin familial amyloid polyneuropathy; chronic inflammatory demyelinating polyneuropathy; amyloidosis; electrochemical skin conductance; sudoscan; diagnosis.
Highlights 1. The most common misdiagnosis of transthyretin familial amyloid polyneuropathy (TTRFAP) is CIDP. 2. Sudoscan is a rapid quantitative sudomotor test, assessing autonomic function. 3. Sudoscan has good sensitivity and specificity to distinguish CIDP from TTR-FAP.
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1 Introduction
Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, hereditary and highly penetrant autosomal dominant disease due to a point mutation of the transthyretin (TTR) gene. It is characterized by endoneurial amyloid deposits in unmyelinated and small myelinated fibers with later involvement of the large fibers. This disorder leads to motor disability within 5 years and is generally fatal within a decade without treatment (Adams et al., 2017). Usually, amyloid neuropathy presents as a slowly ascending, principally sensory, symmetrical polyneuropathy with distal sensory loss, pain in the extremities, and early autonomic disturbances. This historical description is mainly seen in endemic countries such as Portugal, but investigators have described in other parts of the world late-onset forms with milder autonomic dysfunction and important clinical heterogeneities making the diagnosis of TTR-FAP more complicated and often delayed (Mariani et al., 2015). The most common misdiagnosis for TTR-FAP is chronic inflammatory demyelinating polyneuropathy (CIDP) (Planté-Bordeneuve et al., 2007). There have been several reports of TTR-FAP misdiagnosed as CIDP especially among sporadic cases, with TTR-FAP patients presenting sensorimotor impairment or diffuse areflexia and nerve conduction test results fulfilling the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite criteria for CIDP (Cortese et al., 2017). As specific treatments are now available for TTR-FAP and CIDP and appear to be more efficient when administered early in both disorders, it seems important to rapidly differentiate between these two diseases using optimal diagnostic tests (Adams et al, 2018, Benson et al., 2018, Coehlo et al., 2012).
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TTR-FAP is considered a length-dependent small fiber predominant neuropathy (PlantéBordeneuve and Said, 2011) making the measurement of autonomic cutaneous innervation of the extremities particularly relevant in this disease. Small unmyelinated C fibers function at the distal extremities can be evaluated by measuring the sudomotor function. A recent device, called Sudoscan (Impeto Medical, Paris, France), aims to assess sudomotor function through the measurement of electrochemical skin conductance (ESC) using reverse iontophoresis and chronoamperometry. Sweat gland function of the hands and feet can be evaluated through the electrochemical reaction between sweat chloride and large stainless steel electrodes. ESC is then expressed in microSiemens (μS), reflecting the sudomotor skin reactivity modulated by the small C fibers innervating the sweat glands of the subject (Novak et al., 2017). In amyloidosis, a first study showed the ability of ESC to discriminate symptomatic Val30Met TTR-FAP patients from asymptomatic TTR-FAP and control subjects (Castro et al., 2016). This study aimed to evaluate the performance of ESC in differentiating TTR-FAP from CIDP. Our objective is to know if the measurement of ESC performed by Sudoscan allows to distinguish TTR-FAP from CIDP patients.
2 Materials and methods 2.1 Patients Thirty-eight patients with genetically proven TTR-FAP and a polyneuropathy disability (mPND) score ≥ 1 were included in this cross-sectional study. The diagnosis of TTR-FAP was confirmed by molecular analysis and the type of mutation was documented. For all TTR-FAP patients, the clinical parameters assessed included: age, gender, body mass index (BMI), presence
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of clinical dysautonomia, and the modified Polyneuropathy Disability Score (mPND) (Steen and Ek, 1983). mPND is a score evaluating the walking capacity of the patients as follows: 0: normal; 1: sensory disturbances in the lower limbs without walking incapacity; 2: impaired walking but no need of an aid or stick; 3: walking with one or two sticks; 4: wheelchair or bed confinement. Autonomic dysfunction was defined clinically by the presence of nausea and vomiting, diarrhea or diarrhea/constipation, orthostatic hypotension, sphincter abnormalities, sexual dysfunction or excessively dry mouth/eyes. Patients with TTR-FAP were compared to 26 patients with CIDP regularly followed over a 5year period at our center from 2012 to 2017. CIDP patients had to be classified as “definite” according to the EFNS/PNS Guidelines (Electrodiagnostic criteria of the EFNS/PNS, 2010) and had to have undergone a Sudoscan test. In addition, CIDP patients had no TTR gene mutation. CIDP and TTR-FAP patients with diabetes or other causes of autonomic dysfunction were excluded from the study. Informed consent was obtained from all the subjects according to the Declaration of Helsinki.
2.2 Sudoscan ESC measurements were performed using the Sudoscan device (Impeto Medical, Paris, France). Subjects placed both palms and soles on stainless steel electrodes during the 3-minute scan while standing. A low direct current voltage (< 4V) was applied to the electrodes, generating a current proportional to the chloride ion flow extracted from the skin and resulting from the electrochemical reaction between chloride and the stainless steel plates. ESC expressed in microSiemens (μS) was calculated for each foot and hand by the device.
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Sudoscan testing was performed in both CIDP and TTR-FAP patients, in a quiet room dedicated to this test. Individual ESC scores for the left and right hands and feet were measured, but only the final mean scores for both hands (HESC) and both feet (FESC) were used for data analysis (Yajnik et al., 2012).
2.3 Statistics Statistical analyses, ROC (Receiver Operating characteristic) curves and graphs were performed using SAS 9.4 software (SAS Institute, Inc., Cary, NC, USA) and GraphPad Prism for Windows (GraphPad Software, La Jolla California USA). Quantitative data were expressed as means with standard deviation and qualitative data in percentages. Quantitative data were compared using the Mann-Whitney U and Kruskal-Wallis tests and qualitative data using Fisher’s exact test. For the ROC analysis, the optimal cut-off values were defined by maximization of Youden’s Index, which provides the optimal sensitivity and specificity (Youden, 1950). p-values < 0.05 were considered significant. The area under the curve (AUC) was calculated.
3 Results Demographic and neurophysiological data are provided in Table 1. Thirty-eight TTR-FAP patients were enrolled in this study. Among the TTR-FAP patients, 26 patients had Val30Met mutations, 2 Ser77Tyr, 2 Phe44Leu, 2 Ser77Phe, 1 Ala36Pro, 1 Ile68Leu, 1 Gly6Ser, 1 Cys10Arg, 1 Val122Ile and 1 Ile107Val. Mean age (standard deviation) was 61.3 (± 15.8) years. Mean disease duration at the time the Sudoscan was performed was 3.1 (± 3.8) years.
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mPND score was 1 in 16 patients, 2 in 14 patients, and 3 in 8 patients. Among these patients, 30 TTR-FAP patients had clinical evidence of autonomic dysfunction. Twenty-six patients with CIDP followed in our center were enrolled in this study. Mean age was 59.4 (± 15.0) years. The mean disease duration at the time the Sudoscan was performed was 6.0 (± 6.5) years. Comparing TTR-FAP and CIDP patients, no significant differences were found for age (p = 0.46), gender (p = 0.09), or BMI (p = 0.27). Disease duration was significantly longer for CIDP patients compared to TTR-FAP patients (p=0.02). We analyzed the ESC measurements from a total of 64 subjects: 38 with TTR-FAP and 26 with definite CIDP (Table 1). The mean feet ESC (FESC) for TTR-FAP patients was 35.3μS (± 17.2), and the mean hands ESC (HESC) was 45.4μS (± 18.9). The mean FESC for CIDP patients was 76.6 μS (± 7.5) and the mean HESC was 72.0 μS (± 9.2) A significant difference was found for the mean feet (p < 0.0001) and hands (p < 0.0001) ESC between the two groups, with significantly lower values for TTR-FAP patients when compared with CIDP (Table 1 and Figure 1). The optimal cut-off for FESC measurements to differentiate all TTR-FAP patients from CIDP patients was 64 µS. (Table 2 and Figure 1). Feet ESC of 64μS had a sensitivity of 89% and a specificity of 96% for differentiating the two groups. The positive predictive value of FESC measurement was 97% and the negative predictive value 86%. The optimal cut-off for HESC measurements to differentiate all TTR-FAP patients from CIDP patients was 60µS (Table 2). Hands ESC of 60μS had a sensitivity of 65% and a specificity of 96% for differentiating the two groups. The positive predictive value was 84% and the negative predictive value 67%.
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Among the TTR-FAP patients, 16 had a PND score equal to 1. The mean FESC for the PND=1 subgroup was 42.4μS (± 25.0), and the mean HESC was 53.1μS (± 23.5). In this subgroup, 13 (81%) patients had a FESC value below 64µS. The difference between CIDP patients and the PND=1 subgroup was also significant for both FESC and HESC (p <0.0001). Eight TTR-FAP patients showed no signs of dysautonomia. The mean FESC for this subgroup was 61.4μS (± 18.0), and the mean HESC was 66.9μS (± 15.0). Interestingly, five out eight patients in this subgroup had a FESC value under 64 µS. There was no significant difference between CIDP patients and this subgroup for both FESC (p=0,08) and HESC (p=0,47).
4 Discussion Our study demonstrated that feet ESC can discriminate CIDP and TTR-FAP patients with a good sensitivity (89%) and specificity (96%). Sensitivity was lower for the hands ESC (65%). This is not surprising as TTR-FAP is a length-dependent neuropathy and ESC values are expected to be higher in the hands than in the feet making the difference with CIDP patients less obvious for the upper limbs. It is interesting to note that FESC and HESC differences were still significant between patients with an mPND score of 1 (representing patients at the beginning of the disease) and CIDP patients. These results are important to tease out the role that Sudoscan can play in differentiating TTR-FAP patients from CIDP and how this test may be helpful in clinical practice. Indeed, the most common misdiagnosis of TTR-FAP remains CIDP (Koike et al., 2011, Lozeron et al., 2018), and with the development of new efficient therapeutic options such as
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oligonucleotide drugs for TTR-FAP patients, it is now mandatory to differentiate these diseases to provide the best treatments (Adams et al., 2018). Causes of misdiagnosis between CIDP and TTR-FAP are numerous. From a clinical perspective, hereditary TTR amyloidosis shows broad genetic and phenotypic variability. Descriptions in the literature, for example, include a confusing ataxic variant of FAP due to Tyr77TTR mutation (Adams et al., 2012) or progressive multifocal upper limb demyelinating neuropathy leading to an initial diagnosis of Lewis-Sumner syndrome (Brienberg et al., 2014). Similarly, the clinical presentation of CIDP can also be confounding when characterized by a purely sensory deficit (Said et al., 2006) or mild autonomic dysfunction (Figueroa et al., 2012). Apart from clinical findings, the diagnosis of CIDP strongly relies on the evidence of demyelinating features on nerve conduction study (Electrodiagnostic criteria of the EFNS/PNS, 2010). Nerve conduction studies in TTR-FAP usually exhibit a decrease in sensory nerve action potential followed by an alteration of the compound muscle action potential (CMAP); but a primarily demyelinating pattern is not uncommon, with frequent slowing of motor nerve conduction velocities, increased distal latencies or even typical conduction blocks (Mathis et al., 2012). Ile107Val and LateMet30 mutations are associated with severe FAP and rapid onset of quadraparesis as a result of large fibers involvement. Up to 40% of Ile107Val patients can fulfill EFNS/PNS clinical and electrodiagnostic criteria for CIDP (Mariani et al., 2015). Recently, Lozeron and colleagues compared clinical and electrophysiological data of patients with transthyretin amyloid polyneuropathies mimicking a demyelinating polyneuropathy at their initial evaluation (TTR-FAP fulfilling the criteria for CIDP) with idiopathic CIDP (Lozeron et al., 2018). In this study, receiver operating characteristic analysis of an ulnar nerve CMAP amplitude < 5.4mV showed a sensitivity of 78.1%, specificity of 72.3% and an AUC of 0.77 to distinguish
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the two disorders, suggesting that the EFNS/PNS criteria have limitations. In comparison, the AUC of the ROC analysis for the FESC in our study was 0.93.
From a therapeutic perspective, there are several reports of patients with TTR-FAP treated unsuccessfully with intravenous immunoglobulins and corticosteroids, leading to a delayed correct diagnosis, risk of adverse events and increased healthcare costs. A poor response to first line treatment must be considered a red flag that CIDP may not be the correct diagnosis (Conceicao et al., 2016).
Another well-established red flag for CIDP is the presence of autonomic dysfunction (Cortese et al., 2017). Impairment of sudomotor function is one of the autonomic manifestations of TTR-FAP. It is due to reduced innervation of sweat glands and is correlated with a poorer prognosis (Chao et al., 2015). Several neurophysiological techniques are available to assess the impairment of sudomotor function. Among them, the quantitative sudomotor axon reflex test (QSART) is the most studied quantitative sudomotor function test and has a sensitivity of 75% for the detection of small-fiber neuropathy (SFN) (Tobin et al., 1999). More specifically, in a TTR-FAP cohort, this test managed to detect sudomotor dysfunction in 74% of patients (Kim et al., 2009). However, this test is complicated and time consuming. Determination of intraepidermal nerve fiber density using skin biopsy is one of the most sensitive tests available but remains invasive and thus not acceptable for follow-up purposes (Hoeijmakers et al., 2012). In this context, Sudoscan appears to be a compelling tool as it is a fast, non-invasive, reproducible and reliable test with good sensitivity. Two main studies have detailed the value of the Sudoscan in TTR-FAP patients (Castro et al., 2016; LeFaucheur et al., 2018). 11
A study in a large cohort of TTR-FAP patients with Val30Met mutation first showed the clinical application of the Sudoscan technique in the context of amyloidosis (Castro et al., 2016). Feet ESC was significantly reduced in symptomatic patients versus controls and asymptomatic subjects. In comparison with plantar sympathetic skin response and sural sensory nerve action potential (SNAP), it was the only test able to distinguish symptomatic patients from controls. ESC was also a predictive factor of autonomic dysfunction: a value under 66μS had 76% sensitivity and 85% specificity for confirming dysautonomia. ESC values measured with the Sudoscan test were then correlated with disease severity in a cohort of 126 TTR-FAP patients including TTR variant other than Val30Met mutation (LeFaucheur et al., 2018). ESC values were significantly lower in both groups compared to controls and were correlated with the Neuropathy impairment score (NIS), the Karnofsky performance status (KPS) and the modified Polyneuropathy Disability Score (mPND).
We demonstrated here that at steady-state, a significant difference in ESC values exists between CIDP and TTR-FAP patients which can be useful to distinguish these two diseases. The main limitation for our study was its cross-sectional aspect, which does not allow us to assess the value of Sudoscan in the early diagnostic phase. For more clinical relevance, our results need to be confirmed between patients with idiopathic CIDP and a cohort with TTR-FAP fulfilling the electrophysiological criteria for CIDP or during first evaluation as an early marker of the disease. Overall, the results of this simple neurophysiological test of sudomotor function show good diagnostic accuracy for autonomic involvement in TTR-FAP subjects and help differentiate between CIDP and TTR-FAP.
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Conflicts of interest None of the authors have potential conflicts of interest to be disclosed.
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Figure legends
Figure 1. This figure shows the FESC and HESC dot plots for CIDP and TTR-FAP groups and the ROC Curves for FESC and HESC between TTR-FAP and CIDP patients. ROC curve: Receiver Operating Characteristic TTR-FAP: Transthyretin Familial Amyloid Polyneuropathy CIDP: Chronic Inflammatory Demyelinating Polyneuropathy FESC: Feet Electrochemical Skin Conductance HESC: Hands Electrochemical Skin Conductance
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FESC (μS)
HESC (μS)
ROC Curve for FESC and HESC
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Table 1. Demographic data and neurophysiological results.
CIDP (n=26)
TTR-FAP (n=38)
P-value
Age (yrs)
59.4 ± 15
61.3 ± 15.8
NS
BMI
24.4 ± 3.5
23.6 ± 3.8
NS
Duration of illness [range] (yrs)
6.0 ± 6.5 [1- 32]
3.1 ± 3.8 [1-15]
0,02
Gender M/F, n (%)
18 (69)/ 8 (31)
33 (87) / 5 (13)
NS
FESC
76.6 ± 7.5
35.3 ± 17.2
<0.0001
HESC
72.0 ± 9.2
45.4 ± 18.9
<0,0001
FESC, n (%) **
<0.0001
>=64
25 (96)
4 (10.5)
<64
1 (4)
34 (89.5)
HESC, n (%) **
0.0005
>=60
24 (92)
10 (26)
<60
2 (8)
28 (74)
n (%) for categorical variables. Mean (Standard deviation) for continuous variables. CIDP Chronic Inflammatory Demyelinating Polyneuropathy TTR-FAP: Transthyretin Familial Amyloid Polyneuropathy BMI: Body Mass Index M: Male F: Female FESC: Feet Electrochemical Skin Conductance 20
HESC: Hands Electrochemical Skin Conductance ** Optimal Cutoff using Youden’s index
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Table 2. Performance of SUDOSCAN in differentiating TTR-FAP from CIDP.
Optimal cut-off (Youden’s Index)
Sensitivity
Specificity
PPV
NPV
FESC
FESC < 64 µS
0.89
0.96
0.97
0.86
HESC
HESC < 60 µS
0.65
0.96
0.84
0.67
The optimal cut-off values for FESC and HESC were obtained using Youden’s Index applied to a ROC curve (Receiver Operating Characteristic). TTR-FAP: Transthyretin Familial Amyloid Polyneuropathy FESC: Feet Electrochemical Skin Conductance HESC: Hands Electrochemical Skin Conductance PPV: Positive Predictive Value PNV: Negative Predictive Value
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S1388-2457(20)30058-4 https://doi.org/10.1016/j.clinph.2020.01.022 CLINPH 2009130
To appear in:
Clinical Neurophysiology
Received Date: Revised Date: Accepted Date:
26 April 2019 24 December 2019 26 January 2020
Please cite this article as: Fortanier, E., Delmont, E., Verschueren, A., Attarian, S., Quantitative sudomotor test helps differentiate Transthyretin familial amyloid polyneuropathy from Chronic Inflammatory Demyelinating Polyneuropathy, Clinical Neurophysiology (2020), doi: https://doi.org/10.1016/j.clinph.2020.01.022
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier B.V. on behalf of International Federation of Clinical Neurophysiology.
Quantitative sudomotor test helps differentiate Transthyretin familial amyloid polyneuropathy from Chronic Inflammatory Demyelinating Polyneuropathy
E. Fortanier1, E. Delmont1, A Verschueren1, S. Attarian1
1
Neuromuscular Disease and ALS Reference Center, Timone University Hospital, Aix-Marseille
University, Marseille, France
Corresponding author: Shahram Attarian Centre de référence des maladies neuromusculaires et de la SLA CHU Timone - 264 rue Saint Pierre - 13385 Marseille Cedex 05 – France Tel: +33 4 91 38 65 79 Fax: +33 4 91 38 49 46 E-mail: [email protected]
1
Abstract Objective Transthyretin familial amyloid polyneuropathy (TTR-FAP) is an aggressive hereditary neuropathy characterized by sensory and autonomic dysfunction. There are numerous reports of TTR-FAP misdiagnosed and treated as chronic inflammatory demyelinating polyneuropathy (CIDP), leading to delayed diagnosis, risk of iatrogenic adverse events and increased socio-economic costs. Quantitative sudomotor function measured by electrochemical skin conductance (ESC) appears to be a sensitive test in TTR-FAP. We aimed to evaluate the performance of ESC in differentiating TTR-FAP from CIDP. Methods Thirty-eight patients with genetically confirmed hereditary TTR amyloidosis and 26 with definite CIDP according to the EFNS/PNS guidelines and negative TTR-FAP genetic testing were involved in this study. We compared the ESC for feet and hands measured by Sudoscan for each patient. Results ESC (µS) was significantly lower in TTR-FAP for both hands (72 vs 45, p< 0.0001) and feet (77 vs 35, p< 0.0001). Feet ESC < 64 µS had a 89% sensitivity and a 96% specificity to differentiate between CIDP and TTR-FAP. Conclusion Sudoscan is a fast, non-invasive and easy to perform test, able to distinguish CIDP and TTRFAP patients with good sensitivity and specificity.
2
Significance Sudoscan can be helpful in distinguishing between CIDP and TTR-FAP.
Keywords: Transthyretin familial amyloid polyneuropathy; chronic inflammatory demyelinating polyneuropathy; amyloidosis; electrochemical skin conductance; sudoscan; diagnosis.
Highlights 1. The most common misdiagnosis of transthyretin familial amyloid polyneuropathy (TTRFAP) is CIDP. 2. Sudoscan is a rapid quantitative sudomotor test, assessing autonomic function. 3. Sudoscan has good sensitivity and specificity to distinguish CIDP from TTR-FAP.
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1 Introduction
Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, hereditary and highly penetrant autosomal dominant disease due to a point mutation of the transthyretin (TTR) gene. It is characterized by endoneurial amyloid deposits in unmyelinated and small myelinated fibers with later involvement of the large fibers. This disorder leads to motor disability within 5 years and is generally fatal within a decade without treatment (Adams et al., 2017). Usually, amyloid neuropathy presents as a slowly ascending, principally sensory, symmetrical polyneuropathy with distal sensory loss, pain in the extremities, and early autonomic disturbances. This historical description is mainly seen in endemic countries such as Portugal, but investigators have described in other parts of the world late-onset forms with milder autonomic dysfunction and important clinical heterogeneities making the diagnosis of TTR-FAP more complicated and often delayed (Mariani et al., 2015). The most common misdiagnosis for TTR-FAP is chronic inflammatory demyelinating polyneuropathy (CIDP) (Planté-Bordeneuve et al., 2007). There have been several reports of TTR-FAP misdiagnosed as CIDP especially among sporadic cases, with TTR-FAP patients presenting sensorimotor impairment or diffuse areflexia and nerve conduction test results fulfilling the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite criteria for CIDP (Cortese et al., 2017). As specific treatments are now available for TTR-FAP and CIDP and appear to be more efficient when administered early in both disorders, it seems important to rapidly differentiate between these two diseases using optimal diagnostic tests (Adams et al, 2018, Benson et al., 2018, Coehlo et al., 2012).
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TTR-FAP is considered a length-dependent small fiber predominant neuropathy (PlantéBordeneuve and Said, 2011) making the measurement of autonomic cutaneous innervation of the extremities particularly relevant in this disease. Small unmyelinated C fibers function at the distal extremities can be evaluated by measuring the sudomotor function. A recent device, called Sudoscan (Impeto Medical, Paris, France), aims to assess sudomotor function through the measurement of electrochemical skin conductance (ESC) using reverse iontophoresis and chronoamperometry. Sweat gland function of the hands and feet can be evaluated through the electrochemical reaction between sweat chloride and large stainless steel electrodes. ESC is then expressed in microSiemens (μS), reflecting the sudomotor skin reactivity modulated by the small C fibers innervating the sweat glands of the subject (Novak et al., 2017). In amyloidosis, a first study showed the ability of ESC to discriminate symptomatic Val30Met TTR-FAP patients from asymptomatic TTR-FAP and control subjects (Castro et al., 2016). This study aimed to evaluate the performance of ESC in differentiating TTR-FAP from CIDP. Our objective is to know if the measurement of ESC performed by Sudoscan allows to distinguish TTR-FAP from CIDP patients.
2 Materials and methods 2.1 Patients Thirty-eight patients with genetically proven TTR-FAP and a polyneuropathy disability (mPND) score ≥ 1 were included in this cross-sectional study. The diagnosis of TTR-FAP was confirmed by molecular analysis and the type of mutation was documented. For all TTR-FAP patients, the clinical parameters assessed included: age, gender, body mass index (BMI), presence
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of clinical dysautonomia, and the modified Polyneuropathy Disability Score (mPND) (Steen and Ek, 1983). mPND is a score evaluating the walking capacity of the patients as follows: 0: normal; 1: sensory disturbances in the lower limbs without walking incapacity; 2: impaired walking but no need of an aid or stick; 3: walking with one or two sticks; 4: wheelchair or bed confinement. Autonomic dysfunction was defined clinically by the presence of nausea and vomiting, diarrhea or diarrhea/constipation, orthostatic hypotension, sphincter abnormalities, sexual dysfunction or excessively dry mouth/eyes. Patients with TTR-FAP were compared to 26 patients with CIDP regularly followed over a 5year period at our center from 2012 to 2017. CIDP patients had to be classified as “definite” according to the EFNS/PNS Guidelines (Electrodiagnostic criteria of the EFNS/PNS, 2010) and had to have undergone a Sudoscan test. In addition, CIDP patients had no TTR gene mutation. CIDP and TTR-FAP patients with diabetes or other causes of autonomic dysfunction were excluded from the study. Informed consent was obtained from all the subjects according to the Declaration of Helsinki.
2.2 Sudoscan ESC measurements were performed using the Sudoscan device (Impeto Medical, Paris, France). Subjects placed both palms and soles on stainless steel electrodes during the 3-minute scan while standing. A low direct current voltage (< 4V) was applied to the electrodes, generating a current proportional to the chloride ion flow extracted from the skin and resulting from the electrochemical reaction between chloride and the stainless steel plates. ESC expressed in microSiemens (μS) was calculated for each foot and hand by the device.
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Sudoscan testing was performed in both CIDP and TTR-FAP patients, in a quiet room dedicated to this test. Individual ESC scores for the left and right hands and feet were measured, but only the final mean scores for both hands (HESC) and both feet (FESC) were used for data analysis (Yajnik et al., 2012).
2.3 Statistics Statistical analyses, ROC (Receiver Operating characteristic) curves and graphs were performed using SAS 9.4 software (SAS Institute, Inc., Cary, NC, USA) and GraphPad Prism for Windows (GraphPad Software, La Jolla California USA). Quantitative data were expressed as means with standard deviation and qualitative data in percentages. Quantitative data were compared using the Mann-Whitney U and Kruskal-Wallis tests and qualitative data using Fisher’s exact test. For the ROC analysis, the optimal cut-off values were defined by maximization of Youden’s Index, which provides the optimal sensitivity and specificity (Youden, 1950). p-values < 0.05 were considered significant. The area under the curve (AUC) was calculated.
3 Results Demographic and neurophysiological data are provided in Table 1. Thirty-eight TTR-FAP patients were enrolled in this study. Among the TTR-FAP patients, 26 patients had Val30Met mutations, 2 Ser77Tyr, 2 Phe44Leu, 2 Ser77Phe, 1 Ala36Pro, 1 Ile68Leu, 1 Gly6Ser, 1 Cys10Arg, 1 Val122Ile and 1 Ile107Val. Mean age (standard deviation) was 61.3 (± 15.8) years. Mean disease duration at the time the Sudoscan was performed was 3.1 (± 3.8) years.
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mPND score was 1 in 16 patients, 2 in 14 patients, and 3 in 8 patients. Among these patients, 30 TTR-FAP patients had clinical evidence of autonomic dysfunction. Twenty-six patients with CIDP followed in our center were enrolled in this study. Mean age was 59.4 (± 15.0) years. The mean disease duration at the time the Sudoscan was performed was 6.0 (± 6.5) years. Comparing TTR-FAP and CIDP patients, no significant differences were found for age (p = 0.46), gender (p = 0.09), or BMI (p = 0.27). Disease duration was significantly longer for CIDP patients compared to TTR-FAP patients (p=0.02). We analyzed the ESC measurements from a total of 64 subjects: 38 with TTR-FAP and 26 with definite CIDP (Table 1). The mean feet ESC (FESC) for TTR-FAP patients was 35.3μS (± 17.2), and the mean hands ESC (HESC) was 45.4μS (± 18.9). The mean FESC for CIDP patients was 76.6 μS (± 7.5) and the mean HESC was 72.0 μS (± 9.2) A significant difference was found for the mean feet (p < 0.0001) and hands (p < 0.0001) ESC between the two groups, with significantly lower values for TTR-FAP patients when compared with CIDP (Table 1 and Figure 1). The optimal cut-off for FESC measurements to differentiate all TTR-FAP patients from CIDP patients was 64 µS. (Table 2 and Figure 1). Feet ESC of 64μS had a sensitivity of 89% and a specificity of 96% for differentiating the two groups. The positive predictive value of FESC measurement was 97% and the negative predictive value 86%. The optimal cut-off for HESC measurements to differentiate all TTR-FAP patients from CIDP patients was 60µS (Table 2). Hands ESC of 60μS had a sensitivity of 65% and a specificity of 96% for differentiating the two groups. The positive predictive value was 84% and the negative predictive value 67%.
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Among the TTR-FAP patients, 16 had a PND score equal to 1. The mean FESC for the PND=1 subgroup was 42.4μS (± 25.0), and the mean HESC was 53.1μS (± 23.5). In this subgroup, 13 (81%) patients had a FESC value below 64µS. The difference between CIDP patients and the PND=1 subgroup was also significant for both FESC and HESC (p <0.0001). Eight TTR-FAP patients showed no signs of dysautonomia. The mean FESC for this subgroup was 61.4μS (± 18.0), and the mean HESC was 66.9μS (± 15.0). Interestingly, five out eight patients in this subgroup had a FESC value under 64 µS. There was no significant difference between CIDP patients and this subgroup for both FESC (p=0,08) and HESC (p=0,47).
4 Discussion Our study demonstrated that feet ESC can discriminate CIDP and TTR-FAP patients with a good sensitivity (89%) and specificity (96%). Sensitivity was lower for the hands ESC (65%). This is not surprising as TTR-FAP is a length-dependent neuropathy and ESC values are expected to be higher in the hands than in the feet making the difference with CIDP patients less obvious for the upper limbs. It is interesting to note that FESC and HESC differences were still significant between patients with an mPND score of 1 (representing patients at the beginning of the disease) and CIDP patients. These results are important to tease out the role that Sudoscan can play in differentiating TTR-FAP patients from CIDP and how this test may be helpful in clinical practice. Indeed, the most common misdiagnosis of TTR-FAP remains CIDP (Koike et al., 2011, Lozeron et al., 2018), and with the development of new efficient therapeutic options such as
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oligonucleotide drugs for TTR-FAP patients, it is now mandatory to differentiate these diseases to provide the best treatments (Adams et al., 2018). Causes of misdiagnosis between CIDP and TTR-FAP are numerous. From a clinical perspective, hereditary TTR amyloidosis shows broad genetic and phenotypic variability. Descriptions in the literature, for example, include a confusing ataxic variant of FAP due to Tyr77TTR mutation (Adams et al., 2012) or progressive multifocal upper limb demyelinating neuropathy leading to an initial diagnosis of Lewis-Sumner syndrome (Brienberg et al., 2014). Similarly, the clinical presentation of CIDP can also be confounding when characterized by a purely sensory deficit (Said et al., 2006) or mild autonomic dysfunction (Figueroa et al., 2012). Apart from clinical findings, the diagnosis of CIDP strongly relies on the evidence of demyelinating features on nerve conduction study (Electrodiagnostic criteria of the EFNS/PNS, 2010). Nerve conduction studies in TTR-FAP usually exhibit a decrease in sensory nerve action potential followed by an alteration of the compound muscle action potential (CMAP); but a primarily demyelinating pattern is not uncommon, with frequent slowing of motor nerve conduction velocities, increased distal latencies or even typical conduction blocks (Mathis et al., 2012). Ile107Val and LateMet30 mutations are associated with severe FAP and rapid onset of quadraparesis as a result of large fibers involvement. Up to 40% of Ile107Val patients can fulfill EFNS/PNS clinical and electrodiagnostic criteria for CIDP (Mariani et al., 2015). Recently, Lozeron and colleagues compared clinical and electrophysiological data of patients with transthyretin amyloid polyneuropathies mimicking a demyelinating polyneuropathy at their initial evaluation (TTR-FAP fulfilling the criteria for CIDP) with idiopathic CIDP (Lozeron et al., 2018). In this study, receiver operating characteristic analysis of an ulnar nerve CMAP amplitude < 5.4mV showed a sensitivity of 78.1%, specificity of 72.3% and an AUC of 0.77 to distinguish
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the two disorders, suggesting that the EFNS/PNS criteria have limitations. In comparison, the AUC of the ROC analysis for the FESC in our study was 0.93.
From a therapeutic perspective, there are several reports of patients with TTR-FAP treated unsuccessfully with intravenous immunoglobulins and corticosteroids, leading to a delayed correct diagnosis, risk of adverse events and increased healthcare costs. A poor response to first line treatment must be considered a red flag that CIDP may not be the correct diagnosis (Conceicao et al., 2016).
Another well-established red flag for CIDP is the presence of autonomic dysfunction (Cortese et al., 2017). Impairment of sudomotor function is one of the autonomic manifestations of TTR-FAP. It is due to reduced innervation of sweat glands and is correlated with a poorer prognosis (Chao et al., 2015). Several neurophysiological techniques are available to assess the impairment of sudomotor function. Among them, the quantitative sudomotor axon reflex test (QSART) is the most studied quantitative sudomotor function test and has a sensitivity of 75% for the detection of small-fiber neuropathy (SFN) (Tobin et al., 1999). More specifically, in a TTR-FAP cohort, this test managed to detect sudomotor dysfunction in 74% of patients (Kim et al., 2009). However, this test is complicated and time consuming. Determination of intraepidermal nerve fiber density using skin biopsy is one of the most sensitive tests available but remains invasive and thus not acceptable for follow-up purposes (Hoeijmakers et al., 2012). In this context, Sudoscan appears to be a compelling tool as it is a fast, non-invasive, reproducible and reliable test with good sensitivity. Two main studies have detailed the value of the Sudoscan in TTR-FAP patients (Castro et al., 2016; LeFaucheur et al., 2018). 11
A study in a large cohort of TTR-FAP patients with Val30Met mutation first showed the clinical application of the Sudoscan technique in the context of amyloidosis (Castro et al., 2016). Feet ESC was significantly reduced in symptomatic patients versus controls and asymptomatic subjects. In comparison with plantar sympathetic skin response and sural sensory nerve action potential (SNAP), it was the only test able to distinguish symptomatic patients from controls. ESC was also a predictive factor of autonomic dysfunction: a value under 66μS had 76% sensitivity and 85% specificity for confirming dysautonomia. ESC values measured with the Sudoscan test were then correlated with disease severity in a cohort of 126 TTR-FAP patients including TTR variant other than Val30Met mutation (LeFaucheur et al., 2018). ESC values were significantly lower in both groups compared to controls and were correlated with the Neuropathy impairment score (NIS), the Karnofsky performance status (KPS) and the modified Polyneuropathy Disability Score (mPND).
We demonstrated here that at steady-state, a significant difference in ESC values exists between CIDP and TTR-FAP patients which can be useful to distinguish these two diseases. The main limitation for our study was its cross-sectional aspect, which does not allow us to assess the value of Sudoscan in the early diagnostic phase. For more clinical relevance, our results need to be confirmed between patients with idiopathic CIDP and a cohort with TTR-FAP fulfilling the electrophysiological criteria for CIDP or during first evaluation as an early marker of the disease. Overall, the results of this simple neurophysiological test of sudomotor function show good diagnostic accuracy for autonomic involvement in TTR-FAP subjects and help differentiate between CIDP and TTR-FAP.
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Conflicts of interest None of the authors have potential conflicts of interest to be disclosed.
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Figure legends
Figure 1. This figure shows the FESC and HESC dot plots for CIDP and TTR-FAP groups and the ROC Curves for FESC and HESC between TTR-FAP and CIDP patients. ROC curve: Receiver Operating Characteristic TTR-FAP: Transthyretin Familial Amyloid Polyneuropathy CIDP: Chronic Inflammatory Demyelinating Polyneuropathy FESC: Feet Electrochemical Skin Conductance HESC: Hands Electrochemical Skin Conductance
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FESC (μS)
HESC (μS)
ROC Curve for FESC and HESC
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Table 1. Demographic data and neurophysiological results.
CIDP (n=26)
TTR-FAP (n=38)
P-value
Age (yrs)
59.4 ± 15
61.3 ± 15.8
NS
BMI
24.4 ± 3.5
23.6 ± 3.8
NS
Duration of illness [range] (yrs)
6.0 ± 6.5 [1- 32]
3.1 ± 3.8 [1-15]
0,02
Gender M/F, n (%)
18 (69)/ 8 (31)
33 (87) / 5 (13)
NS
FESC
76.6 ± 7.5
35.3 ± 17.2
<0.0001
HESC
72.0 ± 9.2
45.4 ± 18.9
<0,0001
FESC, n (%) **
<0.0001
>=64
25 (96)
4 (10.5)
<64
1 (4)
34 (89.5)
HESC, n (%) **
0.0005
>=60
24 (92)
10 (26)
<60
2 (8)
28 (74)
n (%) for categorical variables. Mean (Standard deviation) for continuous variables. CIDP Chronic Inflammatory Demyelinating Polyneuropathy TTR-FAP: Transthyretin Familial Amyloid Polyneuropathy BMI: Body Mass Index M: Male F: Female FESC: Feet Electrochemical Skin Conductance 20
HESC: Hands Electrochemical Skin Conductance ** Optimal Cutoff using Youden’s index
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Table 2. Performance of SUDOSCAN in differentiating TTR-FAP from CIDP.
Optimal cut-off (Youden’s Index)
Sensitivity
Specificity
PPV
NPV
FESC
FESC < 64 µS
0.89
0.96
0.97
0.86
HESC
HESC < 60 µS
0.65
0.96
0.84
0.67
The optimal cut-off values for FESC and HESC were obtained using Youden’s Index applied to a ROC curve (Receiver Operating Characteristic). TTR-FAP: Transthyretin Familial Amyloid Polyneuropathy FESC: Feet Electrochemical Skin Conductance HESC: Hands Electrochemical Skin Conductance PPV: Positive Predictive Value PNV: Negative Predictive Value
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