健康皮肤标本表皮神经纤维密度研究

目的 探讨健康皮肤标本表皮神经纤维密度的参考值范围,并分析年龄、解剖部位以及种族对表皮神经分布的影响.方法 对70例皮肤标本进行皮肤神经活体组织检查.标本经10%福尔马林常规固定后切成10μm厚石蜡切片,以PGP9.5为特异性轴突标记物进行免疫组织化学染色.观察皮肤神经纤维的形态学特点,并测定表皮神经纤维密度,进行统计学分析.结果 不同年龄组小腿远端及腕部表皮神经纤维密度差异无统计学意义,但随年龄增加,各部位表皮神经分布有减少的趋势.上臂(91.8±21.1)、大腿近端(89.2±21.4)的表皮神经分布较腕部(64.5±22.5)、小腿远端(62.9±15.3)密集.健康人小腿远端的表皮神经纤维密度正常参考值范围>40.6纤维/m2.结论 通过皮肤活体组织检查技术可清晰显示神经纤维形态,便于对表皮神经纤维进行定量研究,为周围神经病的诊断和研究提供了一个可靠的平台.     

Skin biopsy in assessing meralgia paresthetica

Introduction: Meralgia paresthetica is a focal neuropathy caused by compression of the lateral femoral cutaneous nerve (LFCN). The disease can be difficult to assess by neurophysiological or imaging studies. Methods: We studied 5 patients who presented to our neuromuscular clinic from April 2012 to December 2014 with a clinical suspicion of meralgia paresthetica and had skin biopsies with intraepidermal nerve fiber density (IENFD) evaluation. Results: The mean age at onset was 37.2 (range 21–59) years. There were 4 women and 1 man. Two were obese, 2 wore tight jeans, and 1 had mild diabetes mellitus. IENFD was reduced in the symptomatic proximal thigh in all 5 patients and was also reduced in the asymptomatic thigh in 2 patients. It was normal in the distal leg in 4 patients. Conclusion: Meralgia paresthetica is associated with loss of small intraepidermal nerve fibers. Skin biopsy with IENFD evaluation may be a useful diagnostic tool for this disease. Muscle Nerve 53 : 641–643, 2016     

Quantification of sudomotor innervation: A comparison of three methods

Peripheral sudomotor dysfunction is present in many peripheral neuropathies, but structural assessments of sudomotor fibers rarely occur. We evaluated 36 diabetic and 72 healthy control subjects who underwent detailed neurologic examinations and punch skin biopsies. Physical exam findings were quantified by neuropathy impairment score in the lower limb. Skin biopsies quantified intraepidermal nerve fiber density (IENFD) and sweat gland nerve fiber density (SGNFD) by a manual, automated, and semiquantitative method. The automated and manual SGNFD correlated with the IENFD at the same site (r = 0.62, P < 0.05 automated method, r = 0.67, P < 0.05 manual method). As neuropathy worsened, the SGNFD at the distal leg declined (automated counting r = ?0.81, P < 0.001; manual counting r = ?0.88, P < 0.001). The semiquantitative method displayed poor inter‐ and intrareviewer reliability and correlated poorly with standard neuropathy evaluation scores. Our results suggest that sudomotor fibers can be rapidly and reproducibly quantified, and results correlate well with physical exam findings. Muscle Nerve, 2010     

Changes in intraepidermal nerve fiber and Langerhans cell densities in the plantar skin of rats after mercuric chloride exposure

Mercury and its compounds possess strong neurotoxicity and patients with mercury poisoning often report pain and numbness in the distal extremities that conform to the “stocking–glove” pattern. However, no study has investigated whether damage to small nerve fibers is associated with mercury poisoning. The aims of the present study were to evaluate the effects of different doses of mercury chloride (HgCl₂) on intraepidermal nerve fibers density (IENFD) and Langerhans cells (LCs) in the plantar skin of rats and to assess the possible relationship between changes in IENFD and sensory testing. Male Sprague–Dawley rats were divided into three experimental groups and administered HgCl₂ solutions via gavage at three different doses (4.25, 8.5, and 17 mg/kg/day) for 21 days. Subsequently, behavioral tests and pathological changes in IENFD and LCs were assessed at three different time points (1, 2, and 3 weeks). Rats in all three HgCl₂ groups exhibited varying degrees of weight and hair loss. Thermal hypersensitivity was evident in all the HgCl₂ groups (for middle‐2w subgroup, p < 0.05). Mechanical sensitivity tests revealed hyposensitivity in all the HgCl₂ groups except the high‐1w subgroup. Significant decreases in IENFD (for the high‐1w, middle‐1w, low‐2w, and low‐3w subgroups, p < 0.05) and significant increases in the density of LCs (except for the low‐1w and high‐2w subgroups, all p < 0.05) were found in all groups after HgCl₂ exposure. An association analysis revealed a significant correlation between the decrease in IENFD and the increase in LCs densities (r = ?0.573, p < 0.01). The present study demonstrated a decrease in IENFD and an increase in LCs density in the plantar skin of rats after HgCl₂ poisoning, indicating that damage of the small nerve fibers occurs after mercury poisoning.     

帕金森病患者皮肤神经磷酸化α-突触核蛋白研究

目的探讨帕金森病患者磷酸化α-突触核蛋白(phosphorylated α synuclein,p-α-syn)在皮肤神经中的沉积特点,以及其作为帕金森病外周生物标志物的可能性。方法纳入2017年6月1日至2018年8月31日就诊于郑州大学第一附属医院神经内科的15例帕金森病患者及同期年龄匹配的健康志愿者31名,进行13项小纤维神经病和症状问卷(SFN-SIQ)评分。将帕金森病患者按照主要临床表现分为运动迟缓(n=7)和静止性震颤(n=8)2个亚组,并以Hoehn-Yahr分级评价病情的严重程度,其中0~2.5级为早期组(n=11),3.0~5.0级为中晚期(n=4)。采用环形钻孔器取帕金森病患者小腿和颈部皮肤,健康对照组只取小腿部位皮肤,进行免疫组织化学和免疫荧光染色,观察p-α-syn在皮肤神经中的沉积情况并计数穿过单位长度基底膜的神经纤维数量即表皮内神经纤维密度(intraepidermal nerve fiber density,IENFD)。结果12/15的帕金森病患者表皮下神经丛、真皮神经束、汗腺、立毛肌、血管或毛囊周围神经中可见点状或线状p-α-syn沉积,健康对照组皮肤中未见沉积。p-α-syn在单个部位沉积的阳性率分别为小腿6/15、颈部7/15,总阳性率为12/15。帕金森病组的IENFD为(6.85±1.94)根/mm,较对照组[(10.45±3.70)根/mm]明显下降(t=-3.303,P=0.002),与SFN-SIQ评分呈负相关(r=-0.561,P=0.046)。疾病早期与中晚期患者之间,以及以震颤和以运动迟缓为主要表现的患者之间比较,p-α-syn沉积阳性率和IENFD差异均无统计学意义。结论p-α-syn在帕金森病患者皮肤神经纤维中沉积,伴随IENFD明显下降。提示皮肤神经中p-α-syn沉积可能是帕金森病固有的外周病理改变,有作为帕金森病患者诊断外周生物标志物的可行性。     

Confirmation de l’intérêt de la biopsie cutanée dans la neuropathie des petites fibres. Résultats préliminaires

Introduction

In small-fiber neuropathy, skin biopsy reveals a reduction of intraepidermal nerve fiber density (IENFD), a feature often necessary for diagnosis. In France, this technique has not been widely used for this purpose.

Patient and method

To validate this method, we studied 13 patients with suspected small-fiber neuropathy, analyzed their nervous intra- and subepidermal network with a punch skin biopsy and compared our data with those of literature.

Results

Ten patients had pure small-fiber neuropathy and three an axonal polyneuropathy involving large-caliber nerve fibers. In the group of patients with pure small-fiber neuropathy, we found medium IENFD (11.6 ± 4.46 fibers per millimeter in the proximal thigh and 7.15 ± 3.59 fibers per millimeter in distal leg), well correlated with the electron microscopy quantitative and qualitative analysis of the unmyelinated subepidermal fibers.

Conclusion

This work demonstrated the good reproducibility of skin biopsy for analyzing the small-fibers in our cohort. These results require further confirmation in a larger cohort and validation in comparison with controls analyzed on a local level. Nevertheless, these techniques seem to be useful to assess the difficult diagnosis of small-fiber neuropathy.     

Contribution of QSART to the diagnosis of small fiber neuropathy

Introduction: We evaluated incorporation of the quantitative sudomotor axon reflex test (QSART) into the diagnostic criteria for small fiber neuropathy (SFN) as an addition to quantitative sensory testing (QST) and intraepidermal nerve fiber density (IENFD) testing. Methods: One hundred one patients with clinically suspected SFN underwent QSART, QST, and skin biopsy. The diagnostic yield of existing SFN criteria in these patients was compared with criteria incorporating QSART. The new combined diagnostic criteria were evaluated. Results: SFN was diagnosed in 38 of the 101 patients (38%) using current criteria. Addition of QSART existing SFN criteria resulted in an increased diagnostic yield to 67 patients (66%). Applying new SFN criteria requiring abnormality in at least 2 assessments among QSART, QST, and IENFD resulted in a diagnosis of SFN in 57 patients (56%). Conclusion: Assessment of both somatic and peripheral autonomic small nerve fibers enhances diagnostic criteria for SFN. Muscle Nerve 48 : 883–888, 2013     

Atrophy/hypertrophy cell signaling in muscles of young athletes trained with vibrational-proprioceptive stimulation

Abstract

Objective: To compare the effects of isokinetic (ISO-K) and vibrational-proprioceptive (VIB) trainings on muscle mass and strength.

Methods: In 29 ISO-K- or VIB-trained young athletes we evaluated: force, muscle fiber morphometry, and gene expression of muscle atrophy/hypertrophy cell signaling.

Results: VIB training increased the maximal isometric unilateral leg extension force by 48·1%. ISO-K training improved the force by 24·8%. Both improvements were statistically significant (P0·01). The more functional effectiveness of the VIB training in comparison with the ISO-K training was shown by the statistical significance changes only in VIB group in: rate of force development in time segment 0-50 ms (P<0·001), squat jump (P<0·05) and 30-m acceleration running test (P<0·05). VIB training induced a highly significant increase of mean diameter of fast fiber (+9%, P<0·001), but not of slow muscle fibers (?3%, not significant). No neural cell adhesion molecule-positive (N-CAM⁺) and embryonic myosin heavy chain-positive (MHC-emb⁺) myofibers were detected. VIB induced a significant twofold increase (P<0·05) of the skeletal muscle isoform insulin-like growth factor-1 (IGF-1) Ec mRNA. Atrogin-1 and muscle ring finger-1 (MuRF-1) did not change, but myostatin was strongly downregulated after VIB training (P<0·001). Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression increased in post-training groups, but only in VIB reached statistical significance (+228%, P<0·05).

Discussion: We demonstrated that both trainings are effective and do not induce muscle damage. Only VIB-trained group showed statistical significance increase of hypertrophy cell signaling pathways (IGF-1Ec and PGC-1α upregulation, and myostatin downregulation) leading to hypertrophy of fast twitch muscle fibers.     

Intraepidermal nerve fiber density as a marker of early diabetic neuropathy

The purpose of the study was to reliably identify an early stage of diabetic polyneuropathy (DPN) by measuring injury to epidermal nerve fibers. We compared intraepidermal nerve fiber density (IENFD) at the ankle and thigh of 29 diabetic subjects who had no clinical or electrophysiological evidence of small- or large-fiber neuropathy to that of 84 healthy controls. The mean ankle IENFD of diabetic subjects was 9.1+/-5.0 mm and that of controls, 13.0+/-4.8 mm (P<0.001). The thigh IENFD did not differ significantly. The IENFD ratio (thigh IENFD divided by ankle IENFD) was 2.39+/-1.30 in diabetic subjects and 1.77+/-0.58 in controls (P<0.001), indicating a length-dependent reduction of IENFD in diabetics. Ankle IENFD remained significantly lower and the IENFD ratio higher in diabetic subjects after adjusting for age. Two subjects had parasympathetic dysfunction, two had retinopathy, and two early nephropathy. Age, height, weight, duration of diabetes, and average HbA1c did not influence IENFD among diabetic subjects. We used receiver operating characteristic (ROC) curves to describe and compare the utility of various threshold values of ankle IENFD and IENFD ratio for the diagnosis of early DPN. The sensitivity and specificity of diagnosing DPN using ankle IENFD of less than 10 mm were 72.4% and 76.2%, respectively. Thus, asymptomatic diabetics have a measurable, length-dependent reduction of distal epidermal nerves. Analogous to microalbuminuria in diabetic nephropathy, reliable identification and quantitation of nascent diabetic neuropathy may have potential therapeutic implications.     

Small‐nerve‐fiber pathology in critical illness documented by serial skin biopsies

Introduction: Small‐fiber pathology can develop in the acute phase of critical illness and may explain chronic sensory impairment and pain in critical care survivors. Methods: Eleven adult ischemic stroke patients in a neurocritical care unit were enrolled in an observational cohort study. Intraepidermal nerve fiber density (IENFD) in the distal leg was assessed on admission to the intensive care unit and 10–14 days later, together with electrophysiological testing. Results: Of the 11 patients recruited, 9 (82%) had sepsis or multiple‐organ failure. Median IENFD on admission (5.05 fibers/mm) decreased significantly to 2.18 fibers/mm (P < 0.001), and abnormal IENFD was found in 6 patients (54.5%). Electrodiagnostic signs of large‐fiber neuropathy and/or myopathy were found in 6 patients (54.5%), and autonomic dysfunction was found in 2 patients (18.2%). Conclusion: Serial IENFD measurements confirmed the development of small‐fiber sensory involvement in the acute phase of critical illness. Muscle Nerve 52 : 28–33, 2015     

Normal values of median nerve cross‐sectional area obtained by ultrasound along its course in the arm with electrophysiological correlations,in 100 Asian subjects

Introduction: The objective of this study is to obtain normative cross‐sectional area (CSA) values for median nerve by ultrasound at predetermined sites and correlate them with electrophysiological variables in healthy Asian subjects. Methods: The median nerve was examined ultrasonographically in 100 healthy volunteers, mean age 39 years (range, 18–75 years). CSA of the median nerve was measured at wrist, mid‐forearm, mid‐arm, and axilla. All subjects underwent simultaneous standardized nerve conduction studies. Results: The mean median nerve CSAs ± SD at the distal wrist crease was 7.2 ± 1 mm²; mid‐forearm 4.8 ± 0.9 mm²; mid‐arm 6.1 ± 1 mm²; axilla 5.9 ± 0.9 mm². The CSA at the wrist was the largest compared with other levels (P < 0.001), and it increased with advancing age (P < 0.002). Conclusions: These normative data show that median nerve CSA is not uniform along its length. There are differences between gender, and values increase with advancing age. Muscle Nerve 49 : 284–286, 2014     

The histopathological evaluation of small fiber neuropathy in patients with vitamin B12 deficiency

Small fiber neuropathy (SFN), due to loss of A-delta and unmyelinated C fibers, is a cause of neuropathic pain. Although the patients with vitamin B12 deficiency are included in SFN studies in the literature, there is no histopathological study investigating the small fiber loss solely in patients with vitamin B12 deficiency. In this pilot study, we aim to demonstrate the intraepidermal nerve fiber density (IENFD) in skin punch biopsy of patients with vitamin B12 deficiency. Ten patients with vitamin B12 deficiency suffering from neuropathic pain and as control group ten patients with vitamin B12 deficiency without neuropathic pain were included. Neurological examination, electrophysiological evaluation, and DN4 questionnaire were performed. Subsequently, skin punch biopsy 10 cm above the lateral malleolus was done. The biopsy samples were stained with PGP9.5 antibody, and IENFD was determined. IENFD was low in two groups compared to their age normative values. The median of IENFD was 3.345 (1.12–5.32) in patients with neuropathic pain and 6. 20 (4.6–9.8) in controls (p < 0.001). Our pilot study showed that vitamin B12 deficiency causes symptomatic as well as asymptomatic small fiber loss like diabetes mellitus.     

Cramps and small‐fiber neuropathy

Introduction: Muscle cramps are a common complaint and are thought to arise from spontaneous discharges of the motor nerve terminal. Polyneuropathy is often causative, but small‐fiber neuropathy (SFN) has not been assessed. Methods: We performed skin biopsies on consecutive patients with cramps but without neuropathic complaints. Twelve patients were biopsied, 8 with normal small‐fiber sensation. Results: Seven patients had decreased intraepidermal nerve fiber density (IENFD), 2 with non–length‐dependent loss. A cause for neuropathy was found in 1 patient with cramp–fasciculation syndrome. Creatine kinase was elevated in 8 patients, 4 with decreased IENFD. Muscle biopsy, performed in 8 patients, but was diagnostic in only 1, with McArdle disease. Conclusions: Our data show that 60% of patients with muscle cramps who lack neuropathic complaints have SFN, as documented by decreased IENFD. Cramps may originate as local mediators of inflammation released by damaged small nerve that excite intramuscular nerves. Muscle Nerve, 48: 252–255, 2013     

皮肤神经活体组织检查在周围神经病诊断中的应用

目的 探讨皮肤神经活体组织检查在周围神经病诊断中的作用,建立正常参考值范围,并比较临床表现、神经电生理检查与表皮神经纤维病变的一致性.方法 对51例有周围神经病症状和(或)体征的患者进行皮肤神经活体组织检查,计算表皮神经纤维密度(IENFD);同时收集10名健康志愿者作为对照.51例患者中,41例行常规肌电图及神经传导速度(NCV)检查.21例行皮肤交感反射(SSR),比较IENFD与NCV及SSR的一致性.结果 对照组与病例组相比,大腿IENFD(根/mm)分别为21.4±2.7及15.0±6.3(t=2.976,P=0.004);小腿IENFD分别为15.4±2.2及8.1±5.9(t=3.191,P=0.002).病例组与对照组相比大、小腿IENFD均有减少,差异有统计学意义.51例患者中,皮肤神经活体组织检查异常48例(94.1%),其中33例表现为长度依赖性周围神经病变;41例行常规肌电图检查,21例异常(51.2%);21例行SSR检查,异常17例(81.0%).仅表现为小纤维病变症状和(或)体征的29例患者中,27例(93.1%)皮肤神经活体组织检查异常;其中20例行NCV,异常6例(30.0%);14例行SSR,11例异常.结论 皮肤神经活体组织检查操作简单安全,对于以小神经纤维受累为主的周围神经病皮肤神经活体组织检查有较高的灵敏度.     

Comparative study of 3D reconstruction of rat sciatic nerve microvessels using Evans blue and lead oxide

Abstract

Background:

The blood supply of peripheral nerve grafts is one of the important factors that affect nerve regeneration. Many investigators have studied how intraneural microvessels are distributed and ways to promote the angiogenesis of grafts. However, there still does not exist an ideal intraneural microvascular model. The purpose of this study was to compare the three-dimensional (3D) reconstruction of microvessels of the sciatic nerve in Sprague-Dawley (SD) rats after systemic perfusion with Evans blue (EB) or lead oxide.

Methods:

Ten adult SD rats were randomized to a fluorography group (EB) or radiography group (lead oxide). After administration of the perfusion agents, imaging information was obtained by fluorescence microscopy and micro-computed tomography (μCT). Three-dimensional reconstruction was performed, and the diameter of microvessels at a constant distance (a cross-section was taken every 1 mm), the vascular index, and volume were measured. Two-dimensional (2D) images were obtained by serial sectioning and μCT scanning using the two methods described.

Results:

In the EB group, the diameter, vascular area, and vascular index of microvessels were 11·79 ± 7·23 μm, 0.14 ± 0.05 mm², and 24·19 ± 5·03%, respectively, and in the lead oxide group 26·45 ± 11·81 μm, 0.06 ± 0.02 mm², and 10·73 ± 2·06%, respectively. Microvessels with diameters <20 μm were visualized better in the EB group than in the lead oxide group (P < 0·01). However, there was no significant difference between the groups in the visualization of microvessels with diameters 20–49 μm (P > 0·05).

Conclusions:

Both EB and lead oxide can be used for 2D study of intraneural microvessels and 3D observation after reconstruction. Lead oxide is easy to use, and though its resolution is lower than that of EB for smaller microvessels with diameters <20 μm, it is more suitable for studying a large sample volume.     

Quantitative pathology of cutaneous nerve terminal degeneration in the human skin

Pathological diagnosis of neuropathy has traditionally depended on ultrastructural examinations of nerve biopsy specimens, particularly for sensory neuropathies affecting unmyelinated and small-myelinated nociceptive nerves. These sensory nerves terminate in the epidermis of the skin, and the pathology of neuropathy usually begins from nerve terminals. We investigated the feasibility of diagnosing small-fiber sensory neuropathy by evaluating cutaneous innervation. Skin biopsy specimens of 3-mm in diameter were obtained from the distal leg and the distal forearm of 55 healthy controls and 35 patients with sensory neuropathy. In the healthy controls, conventional intraepidermal nerve fiber densities (IENF densities) as measured using the image analysis system in the distal forearm and in the distal leg were correlated (r=0.55, P<0.0001), with significantly higher values in the distal forearm than in the distal leg (17.07+/-6.51 vs 12.92+/-5.33 fibers/mm, P<0.001). Compared to IENF densities of healthy controls, these values of neuropathic patients were significantly reduced in the distal forearm (5.82+/-6.50 fibers/mm, P<0.01) and in the distal leg (2.40+/-2.30, P<0.001). We further explored the possibility of quantifying skin innervation by counting "ocular intraepidermal nerve fiber density" (ocular nerve fiber density) with no aid of an image analysis system. This was based on the fact that the epidermal length on specifically defined sections was very close to the predicted epidermal length of 3 mm, the diameter of skin punches (P=0.14). Ocular nerve fiber densities were significantly correlated with IENF densities as measured by the image analysis system (r=0.99, P<0.0001). Dermal nerve fibers of neuropathic patients either disappeared or became degenerated. These findings were consistent with the notion of early terminal degeneration in neuropathy, and will facilitate quantitative interpretation of epidermal innervation in human neuropathy.     

Signs of sympathetic and endothelial cell activation in the skin of patients with restless legs syndrome

ObjectivesTo evaluate skin biopsies of patients with early- and late onset restless legs syndrome (RLS) for concomitant small fiber neuropathy (SFN) and to determine cutaneous sympathetic innervation and microvascularization in comparison to healthy individuals.MethodsDensity of intraepidermal nerve fibers (IENFD), adrenergic nerve fibers and dermal capillaries was analyzed by immunofluorescence for PGP9.5, tyrosine hydroxylase and endothelial markers CD31 and CD105 in skin biopsies of 11 individuals with RLS and 8 age- and sex-matched controls.ResultsIENFD did not differ between RLS and controls, but two RLS patients with comorbid impaired glucose metabolism fulfilled morphometric criteria of SFN according to published normative values. In contrast, dermal nerve bundles of RLS patients showed an increased density of tyrosine hydroxylase⁺ adrenergic nerve fibers (p < 0.005). Moreover, an increased ratio between immature CD105⁺ and mature CD31⁺ endothelial cells within dermal capillaries was observed in RLS (p < 0.02).ConclusionsSFN, as a potential contributing factor for RLS, should be considered in patients with predisposing comorbidities presenting with burning or shooting pain, dysesthesias and impaired sensory and temperature perception. Evidence of an increased adrenergic innervation of the skin in RLS patients is in accordance with sympathetic hyperactivity while signs of endothelial cell activation may reflect an adaptive response to tissue hypoxia.     

Factors predisposing to small lacunar versus large non-lacunar cerebral infarcts: is left ventricular mass involved?

Abstract

Objectives:

To find some specific determinants of lacunar strokes (LS), this study compared LS and non-LS patients using the size and location of cerebral lesions as discriminant between the two groups.

Methods:

The main cardiovascular risk factors and some echocardiographic parameters were assessed in 225 ischemic stroke patients aged 75·1±11·4 (SD) years, including 101 patients with symptoms and lesions of lacunar type (deep hypodensities with diameter ≤ 1·5 cm) and 124 patients with non-lacunar lesions.

Results:

LS patients tended to be younger and had a higher prevalence of smokers than non-LS patients. In a subgroup undergoing echocardiogram, those with LS had a higher left ventricular mass index (LVMI) than non-LS patients (141·6±44·9 vs. 115·1±31·8 g/m², P = 0·005). The prevalence of hypertension, diabetes, and carotid stenoses > 50% was similar in the two groups. In multivariable analysis the ever-smoker status (OR = 1·9, P = 0·02), atrial fibrillation (inverse association, OR = 0·5, P = 0·03), LVMI ≧ 130 g/m² (OR = 6·6, P = 0·001), and age ≤ 72 years (OR = 5·9, P = 0·003) remained independently associated with LS.

Conclusions:

The patients with lacunar cerebral lesions had a greater left ventricular mass than those with non-lacunar lesions, while blood pressure values did not differ. Lacunar lesions were also associated with smoking and a younger age.     

Quantitative sensory testing and skin biopsy findings in late-onset ATTRv presymptomatic carriers: Relationships with predicted time of disease onset (PADO)

Introduction

Hereditary transthyretin amyloidosis polyneuropathy (ATTRv-PN) presymptomatic carriers often show preclinical abnormalities at small fiber-related diagnostic tests. However, no validated biomarker is currently available to use for presymptomatic carriers' follow-up, thus helping therapeutic decision making. Our study aimed at assessing nerve conduction study (NCS), quantitative sensory testing (QST), and skin biopsy parameters in a large cohort of late-onset ATTRv presymptomatic carriers and to evaluate whether they correlated with predicted age of disease onset (PADO).

Methods

Late-onset ATTRv presymptomatic carriers were consecutively enrolled and underwent NCS, QST, and skin biopsy with intraepidermal nerve fiber density (IENFD) evaluation from a distal and a proximal site. Douleur Neuropathique-4 (DN4) and Small Fiber Neuropathy-Symptoms Inventory (SFN-SIQ) were used to assess painful and small fiber neuropathy-related symptoms. PADO and time-to-PADO (delta-PADO) were estimated for each carrier, and correlations with diagnostic test measures were analyzed.

Results

Forty presymptomatic ATTRv subjects were enrolled. Twenty carriers (50%) had distal IENFD reduction, with a non-length-dependent distribution in 73% of cases. Eleven subjects (27.5%) had cold and/or warm detection threshold (CDT and/or WDT) abnormalities at QST. Delta-PADO positively correlated with sural sensory nerve action potential (SNAP) amplitude (r = .416, p = .004), and z-values of QST parameters like CDT (r = .314, p = .028), WDT (r = −.294, p = .034), and mechanical detection threshold (MDT; r = −.382, p = .012). Simple linear regression models showed a linear relation between delta-PADO and sural SAP, CDT, and MDT.

Conclusions

Our findings confirm that IENFD reduction and QST abnormalities may occur early in ATTRv presymptomatic carriers, often with a non-length-dependent pattern. However, only sural SAP amplitude and QST parameters correlated with delta-PADO, suggesting that serial combined QST and NCS evaluation could be useful in ATTRv presymptomatic carriers' follow-up.