- Email: [email protected]
Early diagnosis in patients with transthyretin familial amyloid polyneuropathy: A comparative study
Med Clin (Barc). 2017;148(2):63–66
www.elsevier.es/medicinaclinica
Brief report
Early diagnosis in patients with transthyretin familial amyloid polyneuropathy: A comparative study Manuel Raya-Cruz a,∗ , Juan Buades-Reines a , Cristina Gállego-Lezáun a , Tomás Ripoll-Vera b , Mercedes Usón-Martín c , Eugenia Cisneros-Barroso d a
Servicio de Medicina Interna, Hospital Son Llàtzer, Palma de Mallorca, Spain Servicio de Cardiología, Hospital Son Llàtzer, Palma de Mallorca, Spain c Servicio de Neurología, Hospital Son Llàtzer, Palma de Mallorca, Spain d Clinical Research Coordinator A-TTR Group, Hospital Son Llàtzer, Palma de Mallorca, Spain b
a r t i c l e
i n f o
Article history: Received 16 March 2016 Accepted 29 September 2016 Available online 21 February 2017 Keywords: Amyloidosis Nerve conduction study Peripheral neuropathy Quantitative sensory testing Transthyretin
a b s t r a c t Introduction and objective: Transthyretin-associated familial amyloid polyneuropathy (TTR-FAP) is a disease caused by the deposit of abnormal transthyretin on tissues, mainly nerves. Small nerve fibers are altered earlier during the course of the disease; hence, detection of their involvement may have serious consequences on the natural history of disease. Methods: A cross-sectional, observational study, was carried out on symptomatic patients, involving the conduct of several tests for small nerve fibers: Vibration, Touch Pressure (TP) and Heat Pain (HP). Results were compared with those obtained during a conventional neurological examination carried out on a group of healthy individuals. Results: Fifteen symptomatic patients were recruited at an early stage of the disease (60% stage 1), along with 13 healthy individuals, with both patient groups having similar epidemiological characteristics in terms of gender, age, weight, height or BMI. A comparison carried out between the neuropsychological tests performed revealed statistically significant differences: Vibration (P < .05), TP (P < .05) and HP (P < .05, except volar forearm). Conclusions: The neurophysiological tests performed revealed significant differences between both groups, allowing for an earlier detection of neurological injuries compared to conventional neurological examinations. ˜ S.L.U. All rights reserved. © 2016 Elsevier Espana,
Diagnóstico precoz en pacientes con polineuropatía amiloidótica familiar asociada a transtirretina. Estudio comparativo r e s u m e n Palabras clave: Amiloidosis Estudios de conducción nerviosa Neuropatía periférica Test cuantitativos sensitivos Transtirretina
Introducción y objetivo: La polineuropatía amiloidótica familiar causada por transtirretina) está carac˜ se alteran de manera más terizada por la afectación del sistema nervioso. Las fibras nerviosas pequenas precoz, por lo que la detección de su afectación tiene implicaciones serias en la historia natural de la enfermedad. Métodos: Estudio transversal, en el que se realizaron pruebas de detección de afectación de fibras ˜ en pacientes sintomáticos con TTR-PAF: Vibration, Touch Pressure (TP) y Heat Pain (HP). nerviosas pequenas Los resultados se compararon con la exploración neurológica convencional y con un grupo de individuos sanos.
∗ Corresponding author. E-mail address: [email protected] (M. Raya-Cruz). ˜ S.L.U. All rights reserved. 2387-0206/© 2016 Elsevier Espana,
64
M. Raya-Cruz et al. / Med Clin (Barc). 2017;148(2):63–66
Resultados: Se seleccionaron 15 pacientes con TTR-PAF en una fase precoz de la enfermedad (60% en estadio 1) y 13 individuos sanos. En la comparación entre ambos grupos no existían diferencias en cuanto a sexo, edad, peso, talla o IMC; sin embargo, en los test neurofisiológicos realizados se evidenciaron diferencias estadísticamente significativas: Vibration (p < 0,05), TP (p < 0,05) y HP (p < 0,05, excepto en la localización de antebrazo). Conclusiones: Los test neurofisiológicos realizados describen diferencias significativas entre ambos gru˜ neurológico de forma más precoz que cuando se realiza pos, lo que podría permitir la detección del dano una exploración neurológica convencional. ˜ S.L.U. Todos los derechos reservados. © 2016 Elsevier Espana,
Introduction
Cross-sectional single-center study in the TTR-FAP multidisciplinary unit of the Internal Medicine Service of Hospital Son Llàtzer during 2015.
and characterize sensory thresholds of the nerve fibers expressed according to age, sex and BMI. The tests performed were: Vibration: vibratory stimulation in the first toe, which is increased exponentially. It has 25 levels of intensity, according to the just noticeable difference by means of the 4,2,1 rule described by PJ Dyck. The software determines the percentile of the patient, considered normal when it is less than or equal to the 95th percentile.4 TP: modified Semmes–Weinstein monofilament test, in which 19 touch-pressure magnitudes are evaluated with a 2:1 algorithm. When the individual did not perceive the correct stimulus on 3 out of 5 occasions, it was considered as suppressed sensitivity (2 points), decreased (1 point) when ≤2 stimuli were not perceived, and normal when all stimuli (0 points) were perceived. Heat pain (HP): exponential heating (according to PJ Dyck) from 34 to 49 ◦ C with a duration of 10 s. The following variables are obtained; HP 5.0: painless heat detection threshold and HP 0.5: intermediate painless heat response. Normal values in healthy subjects5 of HP 5.0 are between 21 and 23, and the HP 0.5, between 18 and 21. A descriptive study was performed by means of calculating the frequencies for qualitative variables, as well as mean and standard deviation, or median and interquartile range for quantitative variables. In addition, a comparative analysis between the two groups was conducted; the chi-square test was used for qualitative variables and the Student’s t test for quantitative variables. The level ® of statistical significance was set at 0.05. SPSS 15.0 for Windows was used.
Patients
Results
Cases: fifteen symptomatic patients with positive Val30Met mutation obtained by TTR/DNA genetic testing, which also had peripheral neuropathy confirmed by electroneurography. Controls: healthy individuals in whom any neurological diseases or other conditions such as diabetes mellitus, hypothyroidism, neoplasia, thrombocytosis, HIV infection or hypoproteinaemia had been ruled out, including being under the influence of alcohol or other drugs. Collected variables: age, sex, weight, height, body mass index (BMI), clinical manifestations, PND classification and FAP stage.
The clinical characteristics of both groups are described in Table 1.
Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a hereditary disease characterized by the involvement of the sensory nervous system, motor and autonomic.1 In our country, the largest endemic focus is on the Balearic Islands, which has published a series of 107 cases.2 The diagnosis may be obtained by the presence of mutated TTR, identification of amyloid deposits in tissues (adipose tissue, salivary glands, nerve or intestine) and the existence of polyneuropathic involvement confirmed by neurological test.1 Conventional neurophysiological studies (electroneurography) are limited to determining the effect of large myelinated fibers, showing motor impairment and impaired pain sensitivity; however, the use of other tools to quantify the involvement of the smaller nerve fibers and determine early damage on the thermalpain and postganglionic sympathetic nerve endings is necessary.3 The aim of this study was to compare a group of symptomatic patients with a group of healthy individuals using a diagnostic tool to assess the involvement of the small nerve fibers. Furthermore, a comparison between conventional neurological examination and the Touch Pressure (TP) test was performed. Methods
Neurological studies A neurological examination aimed to explore the sensitivity and motor system of the middle third of the volar forearm, central dorsal part of the hand, anterior middle third of the tibia and dorsum of the foot was performed. It was considered unchanged (0 points) when the force/sensitivity was greater than 75% of that expected in a healthy individual, decreased (1 point) when there was a reduction of 50%, and suppressed (2 points) when less than 25% of expected was obtained. Neurophysiological studies were performed in these locations using Computer Aided Sensory Evaluator IV, which allows to detect
Comparison between the two groups as per the neurological studies conducted In the Vibration test, the case group had an average percentile of 98.47 (0.85), while the control group had 48.6 (38.2). Statistically significant differences were found (p < 0.05; 29.47–70.14). Only 2 (13.3%) cases had a normal test (percentile 88 and 94). In the TP test, all controls were found to have a normal examination (0 points); however, in the case group, all examined areas were compromised, with statistically significant differences, as described in Table 2. The HP test showed that for the HP 5.0, no case was normal in the tibial area, only one (6.7%) was normal in the foot, 3 (20%) were normal in the forearm and one (6.7%) in the hand. Regarding the HP 0.5 test, 3 (20%) cases had normal results in the tibial area, one (6.7%) in the foot, 10 (66.7%) in the forearm and 4 (26.7%) in the hand. Statistically significant differences were found in the comparison between the two groups, described in Table 2.
M. Raya-Cruz et al. / Med Clin (Barc). 2017;148(2):63–66
65
Table 1 Clinical and demographic characteristics of both groups.
Sex (M/F) Age in years, median (range) Years from diagnosis, median (range) FAP classification PND score, n (%)
Weight (kg), mean (SD) Height (m), mean (SD) BMI, mean (SD) Stretch reflex, n (%)
Cases
Controls
p
12/3 68 (44–79) 2 (1–6) Stage 1: 9 (60%) Stage 2: 6 (40%) Stage I: 8 (53.3) Stage II: 2 (13.3) Stage IIIA: 2 (13.3) Stage IIIB: 2 (13.3) 74 (10.74) 1.68 (0.089) 26.02 (3.5) Achillean Normal: 9 (60) Decreased: 3 (20) Suppressed: 3 (20) Patellar Normal: 10 (66.6) Decreased: 5 (33.3)
6/7 44.5 (31–57) – –
NS NS NS NS
–
NS
72.38 (8.2) 1.69 (0.089) 25.1 (2.06) Achilleian Normal: 13 (100)
NS NS NS NS
Patellar Normal: 13 (100)
45 42 40 35 30
30
29
25
30
23 20
20
17 15 10
10 7 5 1 0 Normal lower limbs
Normal upper limbs
Decreased lower limbs
Examination
0 Decreased upper limbs
1 Suppressed lower limbs
Suppressed upper limbs
Touch pressure
Fig. 1. Sensitivity determination according to conventional examination versus Touch Pressure test.
Table 2 Touch Pressure test and Heat Pain test comparison between cases and controls. Site HP test Tibia 5.0 Tibia 0.5 Foot 5.0 Foot 0.5 Forearm 5.0 Forearm 0.5 Hand 5.0 Hand 0.5 TP test Tibia Foot Forearm Hand
Cases, mean (SD) 26.28 (2.9) 22.43 (1.9) 26.81 (2.9) 22.83 (2.4) 23.73 (3.0) 19.65 (2.7) 26.67 (4.2) 22.37 (4.0) 1.27 (0.9) 1.33 (0.9) 0.4 (0.8) 0.93 (1.0)
Controls, mean (SD) 22.56 (1.5) 20.87 (1.0) 21.45 (2.9) 17.9 (4.4) 20.96 (3.6) 18.19 (3.7) 20.77 (3.6) 18.75 (2.9) 0 0 0 0
p 0.001 0.02 0.001 0.007 0.03 NS 0.001 0.02 0.001 0.001 0.09 0.003
was normal in 12 (80%) and decreased in 3 (20%); and in the hand, it was normal in 8 (53.4%) and decreased in 7 (46.7%). On sensitivity examination: the tibial area was normal in 10 (66.7%) and decreased in 5 (33.3%); in the foot, 7 (46.7%) were normal, 7 (46.7%) decreased (6.7%) and one suppressed; in the forearm, 14 (93.3%) normal and one (6.7%) decreased; and in hand, 9 (60%) normal and 6 (40%) decreased. TP test results were: in the tibial area, 5 (33.3%) normal, one (6.7%) decreased and 9 (60%) suppressed; in the foot, 5 (33.3%) normal and 10 (66.7%) suppressed, in the forearm, 12 (80%) normal and 3 (20%) suppressed; and in the hand, 8 (53.4%) normal and 7 (46.7%) suppressed. The comparison between the two examinations is reflected in Fig. 1.
Discussion Comparison between conventional physical examination and Touch Pressure test in the case group In the conventional neurological examination, the motor system examination revealed a normal tibial area in 10 (66.7%) cases and decreased in 5 (33.3%); normal in the foot in 9 cases (60%), decreased in 3 (20%) and suppressed in 3 (20%); in the forearm, it
Nowadays, early diagnosis when polyneuropathy symptoms are emerging is crucial, as it has several therapeutic options to prevent disease progression.6 The most common method for nerve involvement detection is the nerve conduction study; however, these tests are not very useful for the detection of small nerve fibers. In a previous study by
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M. Raya-Cruz et al. / Med Clin (Barc). 2017;148(2):63–66
electroneurography no differences were documented between a group of asymptomatic cases, a group of symptomatic patients and another of healthy individuals.7 Our study shows that neurophysiological tests targeting small fiber diagnosis demonstrate involvement in symptomatic patients compared to healthy individuals, reaching statistical significance in all tests except the HP test in BUL, possibly due to the fact that in TTR-FAP, proximal involvement of BUL appears in advanced stages of the disease, and, in our cohort, approximately 60% of patients were at an early stage. These findings are similar to those of previous studies where early stage symptomatic patients were compared with healthy individuals; the studies conducted to determine involvement of small nerve fibers found abnormalities in symptomatic cases 8 . Possibly, in order to confirm diagnosis and initiate treatment, the best option would be to perform a combination of conventional physical examination, nerve conduction study for small fibers and perhaps, in the near future, magnetic resonance imaging,9 ion® tophoresis studies10 (Sudoscan ) or skin biopsies for pathological studies. As limitations, stands out the small number of patients and, possibly, multicenter studies are needed to provide greater sample sizes; however, the number of cases presented in this study is similar to previous single-center studies. Perhaps, future studies could include a comparison between asymptomatic mutation carriers and symptomatic patients, but the low prevalence of the disease makes patient selection complicated. Authorship Those related to the authorship of the manuscript have collaborated in the conception and design of the same, the collection,
analysis and interpretation of data, its writing and review, as well as its approval. Conflict of interests The authors declare no conflict of interest. References 1. Munar-Qués M. [Familial amyloid polyneuropathy 2003] Spanish. Med Clin (Barc). 2003;121:100–1. 2. Buades Reinés J, Ripoll Vera T, Uson Martín M, Andréu Serra H, Company Campins MM, Diéguez Millán JM, et al. Epidemiology of transthyretin-associated familial amyloid polyneuropathy in the Majorcan area: Son Llàtzer Hospital descriptive study. Orphanet J Rare Dis. 2014;9:29. 3. Ando Y, Ueda M. Diagnosis and therapeutic approaches to transthyretin amyloidosis. Curr Med Chem. 2012;19:2312–23. 4. O’Brien PC, Dyck PJ. Procedures for setting normal values. Neurology. 1995;45:17–23. 5. Dyck PJ, Zimmerman IR, Johnson DM, Gillen D, Hokanson JL, Karnes JL, et al. A standard test of heat-pain responses using CASE IV. J Neurol Sci. 1996;136:54–63. 6. Ueda M, Ando Y. Recent advances in transthyretin amyloidosis therapy. Transl Neurodegener. 2014;3:19. 7. Walk D, Wendelschafer-Crabb G, Davey C, Kennedy WR. Concordance between epidermal nerve fiber density and sensory examination in patients with symptoms of idiopathic small fiber neuropathy. J Neurol Sci. 2007;255:23–6. 8. Conceic¸ão I, Costa J, Castro J, de Carvalho M. Neurophysiological techniques to detect early small-fiber dysfunction in transthyretin amyloid polyneuropathy. Muscle Nerve. 2014;49:181–6. 9. Kollmer J, Hund E, Hornung B, Hegenbart U, Schönland SO, Kimmich C, et al. In vivo detection of nerve injury in familial amyloid polyneuropathy by magnetic resonance neurography. Brain. 2015;138:549–62. 10. Casellini CM, Parson HK, Richardson MS, Nevoret ML, Vinik AI. Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction. Diabetes Technol Ther. 2013;15:948–53.
www.elsevier.es/medicinaclinica
Brief report
Early diagnosis in patients with transthyretin familial amyloid polyneuropathy: A comparative study Manuel Raya-Cruz a,∗ , Juan Buades-Reines a , Cristina Gállego-Lezáun a , Tomás Ripoll-Vera b , Mercedes Usón-Martín c , Eugenia Cisneros-Barroso d a
Servicio de Medicina Interna, Hospital Son Llàtzer, Palma de Mallorca, Spain Servicio de Cardiología, Hospital Son Llàtzer, Palma de Mallorca, Spain c Servicio de Neurología, Hospital Son Llàtzer, Palma de Mallorca, Spain d Clinical Research Coordinator A-TTR Group, Hospital Son Llàtzer, Palma de Mallorca, Spain b
a r t i c l e
i n f o
Article history: Received 16 March 2016 Accepted 29 September 2016 Available online 21 February 2017 Keywords: Amyloidosis Nerve conduction study Peripheral neuropathy Quantitative sensory testing Transthyretin
a b s t r a c t Introduction and objective: Transthyretin-associated familial amyloid polyneuropathy (TTR-FAP) is a disease caused by the deposit of abnormal transthyretin on tissues, mainly nerves. Small nerve fibers are altered earlier during the course of the disease; hence, detection of their involvement may have serious consequences on the natural history of disease. Methods: A cross-sectional, observational study, was carried out on symptomatic patients, involving the conduct of several tests for small nerve fibers: Vibration, Touch Pressure (TP) and Heat Pain (HP). Results were compared with those obtained during a conventional neurological examination carried out on a group of healthy individuals. Results: Fifteen symptomatic patients were recruited at an early stage of the disease (60% stage 1), along with 13 healthy individuals, with both patient groups having similar epidemiological characteristics in terms of gender, age, weight, height or BMI. A comparison carried out between the neuropsychological tests performed revealed statistically significant differences: Vibration (P < .05), TP (P < .05) and HP (P < .05, except volar forearm). Conclusions: The neurophysiological tests performed revealed significant differences between both groups, allowing for an earlier detection of neurological injuries compared to conventional neurological examinations. ˜ S.L.U. All rights reserved. © 2016 Elsevier Espana,
Diagnóstico precoz en pacientes con polineuropatía amiloidótica familiar asociada a transtirretina. Estudio comparativo r e s u m e n Palabras clave: Amiloidosis Estudios de conducción nerviosa Neuropatía periférica Test cuantitativos sensitivos Transtirretina
Introducción y objetivo: La polineuropatía amiloidótica familiar causada por transtirretina) está carac˜ se alteran de manera más terizada por la afectación del sistema nervioso. Las fibras nerviosas pequenas precoz, por lo que la detección de su afectación tiene implicaciones serias en la historia natural de la enfermedad. Métodos: Estudio transversal, en el que se realizaron pruebas de detección de afectación de fibras ˜ en pacientes sintomáticos con TTR-PAF: Vibration, Touch Pressure (TP) y Heat Pain (HP). nerviosas pequenas Los resultados se compararon con la exploración neurológica convencional y con un grupo de individuos sanos.
∗ Corresponding author. E-mail address: [email protected] (M. Raya-Cruz). ˜ S.L.U. All rights reserved. 2387-0206/© 2016 Elsevier Espana,
64
M. Raya-Cruz et al. / Med Clin (Barc). 2017;148(2):63–66
Resultados: Se seleccionaron 15 pacientes con TTR-PAF en una fase precoz de la enfermedad (60% en estadio 1) y 13 individuos sanos. En la comparación entre ambos grupos no existían diferencias en cuanto a sexo, edad, peso, talla o IMC; sin embargo, en los test neurofisiológicos realizados se evidenciaron diferencias estadísticamente significativas: Vibration (p < 0,05), TP (p < 0,05) y HP (p < 0,05, excepto en la localización de antebrazo). Conclusiones: Los test neurofisiológicos realizados describen diferencias significativas entre ambos gru˜ neurológico de forma más precoz que cuando se realiza pos, lo que podría permitir la detección del dano una exploración neurológica convencional. ˜ S.L.U. Todos los derechos reservados. © 2016 Elsevier Espana,
Introduction
Cross-sectional single-center study in the TTR-FAP multidisciplinary unit of the Internal Medicine Service of Hospital Son Llàtzer during 2015.
and characterize sensory thresholds of the nerve fibers expressed according to age, sex and BMI. The tests performed were: Vibration: vibratory stimulation in the first toe, which is increased exponentially. It has 25 levels of intensity, according to the just noticeable difference by means of the 4,2,1 rule described by PJ Dyck. The software determines the percentile of the patient, considered normal when it is less than or equal to the 95th percentile.4 TP: modified Semmes–Weinstein monofilament test, in which 19 touch-pressure magnitudes are evaluated with a 2:1 algorithm. When the individual did not perceive the correct stimulus on 3 out of 5 occasions, it was considered as suppressed sensitivity (2 points), decreased (1 point) when ≤2 stimuli were not perceived, and normal when all stimuli (0 points) were perceived. Heat pain (HP): exponential heating (according to PJ Dyck) from 34 to 49 ◦ C with a duration of 10 s. The following variables are obtained; HP 5.0: painless heat detection threshold and HP 0.5: intermediate painless heat response. Normal values in healthy subjects5 of HP 5.0 are between 21 and 23, and the HP 0.5, between 18 and 21. A descriptive study was performed by means of calculating the frequencies for qualitative variables, as well as mean and standard deviation, or median and interquartile range for quantitative variables. In addition, a comparative analysis between the two groups was conducted; the chi-square test was used for qualitative variables and the Student’s t test for quantitative variables. The level ® of statistical significance was set at 0.05. SPSS 15.0 for Windows was used.
Patients
Results
Cases: fifteen symptomatic patients with positive Val30Met mutation obtained by TTR/DNA genetic testing, which also had peripheral neuropathy confirmed by electroneurography. Controls: healthy individuals in whom any neurological diseases or other conditions such as diabetes mellitus, hypothyroidism, neoplasia, thrombocytosis, HIV infection or hypoproteinaemia had been ruled out, including being under the influence of alcohol or other drugs. Collected variables: age, sex, weight, height, body mass index (BMI), clinical manifestations, PND classification and FAP stage.
The clinical characteristics of both groups are described in Table 1.
Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a hereditary disease characterized by the involvement of the sensory nervous system, motor and autonomic.1 In our country, the largest endemic focus is on the Balearic Islands, which has published a series of 107 cases.2 The diagnosis may be obtained by the presence of mutated TTR, identification of amyloid deposits in tissues (adipose tissue, salivary glands, nerve or intestine) and the existence of polyneuropathic involvement confirmed by neurological test.1 Conventional neurophysiological studies (electroneurography) are limited to determining the effect of large myelinated fibers, showing motor impairment and impaired pain sensitivity; however, the use of other tools to quantify the involvement of the smaller nerve fibers and determine early damage on the thermalpain and postganglionic sympathetic nerve endings is necessary.3 The aim of this study was to compare a group of symptomatic patients with a group of healthy individuals using a diagnostic tool to assess the involvement of the small nerve fibers. Furthermore, a comparison between conventional neurological examination and the Touch Pressure (TP) test was performed. Methods
Neurological studies A neurological examination aimed to explore the sensitivity and motor system of the middle third of the volar forearm, central dorsal part of the hand, anterior middle third of the tibia and dorsum of the foot was performed. It was considered unchanged (0 points) when the force/sensitivity was greater than 75% of that expected in a healthy individual, decreased (1 point) when there was a reduction of 50%, and suppressed (2 points) when less than 25% of expected was obtained. Neurophysiological studies were performed in these locations using Computer Aided Sensory Evaluator IV, which allows to detect
Comparison between the two groups as per the neurological studies conducted In the Vibration test, the case group had an average percentile of 98.47 (0.85), while the control group had 48.6 (38.2). Statistically significant differences were found (p < 0.05; 29.47–70.14). Only 2 (13.3%) cases had a normal test (percentile 88 and 94). In the TP test, all controls were found to have a normal examination (0 points); however, in the case group, all examined areas were compromised, with statistically significant differences, as described in Table 2. The HP test showed that for the HP 5.0, no case was normal in the tibial area, only one (6.7%) was normal in the foot, 3 (20%) were normal in the forearm and one (6.7%) in the hand. Regarding the HP 0.5 test, 3 (20%) cases had normal results in the tibial area, one (6.7%) in the foot, 10 (66.7%) in the forearm and 4 (26.7%) in the hand. Statistically significant differences were found in the comparison between the two groups, described in Table 2.
M. Raya-Cruz et al. / Med Clin (Barc). 2017;148(2):63–66
65
Table 1 Clinical and demographic characteristics of both groups.
Sex (M/F) Age in years, median (range) Years from diagnosis, median (range) FAP classification PND score, n (%)
Weight (kg), mean (SD) Height (m), mean (SD) BMI, mean (SD) Stretch reflex, n (%)
Cases
Controls
p
12/3 68 (44–79) 2 (1–6) Stage 1: 9 (60%) Stage 2: 6 (40%) Stage I: 8 (53.3) Stage II: 2 (13.3) Stage IIIA: 2 (13.3) Stage IIIB: 2 (13.3) 74 (10.74) 1.68 (0.089) 26.02 (3.5) Achillean Normal: 9 (60) Decreased: 3 (20) Suppressed: 3 (20) Patellar Normal: 10 (66.6) Decreased: 5 (33.3)
6/7 44.5 (31–57) – –
NS NS NS NS
–
NS
72.38 (8.2) 1.69 (0.089) 25.1 (2.06) Achilleian Normal: 13 (100)
NS NS NS NS
Patellar Normal: 13 (100)
45 42 40 35 30
30
29
25
30
23 20
20
17 15 10
10 7 5 1 0 Normal lower limbs
Normal upper limbs
Decreased lower limbs
Examination
0 Decreased upper limbs
1 Suppressed lower limbs
Suppressed upper limbs
Touch pressure
Fig. 1. Sensitivity determination according to conventional examination versus Touch Pressure test.
Table 2 Touch Pressure test and Heat Pain test comparison between cases and controls. Site HP test Tibia 5.0 Tibia 0.5 Foot 5.0 Foot 0.5 Forearm 5.0 Forearm 0.5 Hand 5.0 Hand 0.5 TP test Tibia Foot Forearm Hand
Cases, mean (SD) 26.28 (2.9) 22.43 (1.9) 26.81 (2.9) 22.83 (2.4) 23.73 (3.0) 19.65 (2.7) 26.67 (4.2) 22.37 (4.0) 1.27 (0.9) 1.33 (0.9) 0.4 (0.8) 0.93 (1.0)
Controls, mean (SD) 22.56 (1.5) 20.87 (1.0) 21.45 (2.9) 17.9 (4.4) 20.96 (3.6) 18.19 (3.7) 20.77 (3.6) 18.75 (2.9) 0 0 0 0
p 0.001 0.02 0.001 0.007 0.03 NS 0.001 0.02 0.001 0.001 0.09 0.003
was normal in 12 (80%) and decreased in 3 (20%); and in the hand, it was normal in 8 (53.4%) and decreased in 7 (46.7%). On sensitivity examination: the tibial area was normal in 10 (66.7%) and decreased in 5 (33.3%); in the foot, 7 (46.7%) were normal, 7 (46.7%) decreased (6.7%) and one suppressed; in the forearm, 14 (93.3%) normal and one (6.7%) decreased; and in hand, 9 (60%) normal and 6 (40%) decreased. TP test results were: in the tibial area, 5 (33.3%) normal, one (6.7%) decreased and 9 (60%) suppressed; in the foot, 5 (33.3%) normal and 10 (66.7%) suppressed, in the forearm, 12 (80%) normal and 3 (20%) suppressed; and in the hand, 8 (53.4%) normal and 7 (46.7%) suppressed. The comparison between the two examinations is reflected in Fig. 1.
Discussion Comparison between conventional physical examination and Touch Pressure test in the case group In the conventional neurological examination, the motor system examination revealed a normal tibial area in 10 (66.7%) cases and decreased in 5 (33.3%); normal in the foot in 9 cases (60%), decreased in 3 (20%) and suppressed in 3 (20%); in the forearm, it
Nowadays, early diagnosis when polyneuropathy symptoms are emerging is crucial, as it has several therapeutic options to prevent disease progression.6 The most common method for nerve involvement detection is the nerve conduction study; however, these tests are not very useful for the detection of small nerve fibers. In a previous study by
66
M. Raya-Cruz et al. / Med Clin (Barc). 2017;148(2):63–66
electroneurography no differences were documented between a group of asymptomatic cases, a group of symptomatic patients and another of healthy individuals.7 Our study shows that neurophysiological tests targeting small fiber diagnosis demonstrate involvement in symptomatic patients compared to healthy individuals, reaching statistical significance in all tests except the HP test in BUL, possibly due to the fact that in TTR-FAP, proximal involvement of BUL appears in advanced stages of the disease, and, in our cohort, approximately 60% of patients were at an early stage. These findings are similar to those of previous studies where early stage symptomatic patients were compared with healthy individuals; the studies conducted to determine involvement of small nerve fibers found abnormalities in symptomatic cases 8 . Possibly, in order to confirm diagnosis and initiate treatment, the best option would be to perform a combination of conventional physical examination, nerve conduction study for small fibers and perhaps, in the near future, magnetic resonance imaging,9 ion® tophoresis studies10 (Sudoscan ) or skin biopsies for pathological studies. As limitations, stands out the small number of patients and, possibly, multicenter studies are needed to provide greater sample sizes; however, the number of cases presented in this study is similar to previous single-center studies. Perhaps, future studies could include a comparison between asymptomatic mutation carriers and symptomatic patients, but the low prevalence of the disease makes patient selection complicated. Authorship Those related to the authorship of the manuscript have collaborated in the conception and design of the same, the collection,
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