Nerve cross-sectional area from childhood to old age: A high-resolution nerve ultrasound study.

BACKGROUND AND PURPOSE: Nerve cross-sectional area (CSA) is not constant over the human lifespan. The relationship between an increasing CSA and age has been described as a linear positive correlation, but few studies have found a linear decrease in nerve size with older age. The aim of the present study was to analyze the development of nerve CSA in a healthy population from early childhood to old age using high-resolution ultrasound. METHODS: The median, ulnar, radial and sural nerves were examined bilaterally at 18 nerve sites in 110 healthy children, adolescents and adults aged between 2 and 98 years. The CSA of every nerve site was evaluated separately and in different age groups. The correlation of CSA with age, height and weight was analyzed in a linear, logarithmic and quadratic model and correlation coefficients were compared in a goodness-of-fit analysis. Models were then adjusted for weight and height. RESULTS: Linear CSA-age correlations showed the lowest correlation coefficients for all nerve sites. An inverted parabolic curve suggesting a quadratic correlation of CSA and age was the best-fitting model. Weight and height had a higher predictive value than age in adjusted models. CONCLUSIONS: There is an increase in nerve size during childhood and adolescence and a trend towards a decrease in old age, suggesting an inverted parabolic curve partly explained by age-related changes in weight and height. Enlarged nerves in elderly individuals should not be attributed to age alone.

Nerve cross-sectional area in advanced uremic neuropathy: A nerve ultrasound pilot study.

BACKGROUND AND PURPOSE: Uremic neuropathy (UN) is a disabling neuropathy in end-stage kidney disease (ESKD) affecting the majority of patients receiving long-term hemodialysis (HD). One previous nerve ultrasound study reported an increased cross-sectional area (CSA) of the median nerve in moderate UN, while another study found enlarged sural nerves in small-fiber polyneuropathy associated with ESKD. The present cohort study aims to analyze bilateral CSA of multiple nerves in UN. METHODS: Ten nondiabetic ESKD patients with UN on HD for at least 2 years and 10 healthy age-matched controls underwent bilateral ultrasound examinations with CSA measurements in 13 arm and leg nerve sites. Nerve conduction studies (NCS) and the total neuropathy score (TNS) were recorded. Pearson's coefficient and the Mann-Whitney U-test were used to analyze correlations and compare groups. RESULTS: ESKD patients presented advanced neuropathic symptoms (mean TNS 15.9). NCS showed significantly reduced motor and sensory amplitudes in the UN group compared to the control group, and a slightly reduced nerve CSA was observed in 5 of 13 nerve sites (p < .05); the other nerve sites were not enlarged. Sural nerve CSA (p < .05) and sensory amplitude (p < .01) were negatively correlated with the TNS. CONCLUSIONS: Nerve enlargement was not observed in the present study in advanced UN. A reduced nerve CSA observed in the sural nerve suggests an axonal loss associated with long-term HD in ESKD. During clinical workup of an acute disease of the peripheral nervous system in ESKD patients, nerve enlargement might be attributable to other causes than chronic UN.

The multiple roles of nerve biopsy in the diagnosis and prognosis of suspected immune neuropathies.

INTRODUCTION: The value of a sural nerve biopsy for the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is controversial. Evidence-based recommendations for its implementation are lacking. We investigated factors leading to biopsy and analyzed biopsy outcomes and consequences, assessed the predictability of biopsy outcomes through clinical parameters to avoid unnecessary biopsies, and compared results with electrophysiological and clinical severity to determine their prognostic value. METHODS: 190 sural nerve biopsies were analyzed in two cohorts. One consisted of 163 biopsies and the second of 72 biopsies from the prospective Immune-mediated Neuropathies Biomaterial and Data registry (INHIBIT). Both have an intersection of 45 patients. 75 data sets from patients without biopsy were used. Analysis of nerve conduction studies, treatment, overall disability sum score (ODSS), biopsy outcomes, and diagnosis was performed. RESULTS: 51% of biopsied patients received the diagnosis CIDP (77% fulfilled EFNS/PNS criteria), 21% were not CIDP typical, and 27% were unspecific. Biopsied patients responded less frequently to immunotherapies at time of biopsy than non-biopsied patients (p = 0.003). Immunotherapy was initiated more frequently after biopsy (p < 0.001) and more often with intravenous immunoglobulins (p < 0.0001). 76% of all biopsied patients met the electrophysiological criteria for CIDP. Sensory nerve action potential amplitudes of 0 µV still provide 73% of histological diagnostic value. Histologic signs of degeneration predicted ODSS worsening after 1 year (p = 0.028) but disease severity did not correlate with histological damage severity. DISCUSSION: The main indication for nerve biopsy was the treatment of refractory cases of autoimmune neuropathies with the therapeutic consequence of treatment initiation or escalation. Sural biopsy also provided prognostic information. Even with extinguished sural SNAP, the biopsy can still have diagnostic value.

Morphological Differentiation of Corneal Inflammatory Cells: Proposal of Pragmatic Protocol.

PURPOSE: Corneal confocal microscopy is a noninvasive imaging technique to analyze corneal nerve fibers and corneal inflammatory cells (CICs). The amount of CICs is a potential biomarker of disease activity in chronic autoinflammatory diseases. To date, there are no standardized criteria for the morphological characterization of CICs. The aim was to establish a protocol for a standardized morphological classification of CICs based on a literature search and to test this protocol for applicability and reliability. METHODS: A systematic review of the literature about definitions of CICs was conducted. Existing morphological descriptions were translated into a structured algorithm and applied by raters. Subsequently, the protocol was optimized by reducing and defining the criteria of the cell types. The optimized algorithm was applied by 4 raters. The interrater reliability was calculated using Fleiss kappa (K). RESULTS: A systematic review of the literature revealed no uniform morphological criteria for the differentiation of the individual cell types in CICs. Our first protocol achieved only a low level of agreement between 3 raters (K = 0.09; 1062 rated cells). Our revised protocol was able to achieve a higher interrater reliability with 3 (K = 0.64; 471 rated cells) and 4 (K = 0.61; 628 rated cells) raters. CONCLUSIONS: The indirect use of criteria from the literature leads to a high error rate. By clearly defining the individual cell types and standardizing the protocol, reproducible results were obtained, allowing the introduction of this protocol for the future evaluation of CICs in the corneal confocal microscopy.

High-resolution nerve ultrasound and corneal confocal microscopy in taxane-induced polyneuropathy.

BACKGROUND AND PURPOSE: The role of high-resolution nerve ultrasound (HRUS) and corneal confocal microscopy (CCM) in the early detection of taxane-induced polyneuropathy (TIPN) is unclear. The present prospective longitudinal controlled observational pilot study estimates the role of HRUS and CCM in the early diagnosis of TIPN in breast cancer patients. METHODS: Fifteen breast cancer patients receiving paclitaxel and 15 healthy age matched controls were included. Visits before and 3 weeks, 8 weeks and 6 months after treatment included clinical examination, the total neuropathy score, nerve conduction studies (NCS), monocular CCM including corneal nerve fibre length, density and branching and HRUS of bilateral median, ulnar, radial, tibial, peroneal and sural nerves. Patients were compared between different visits and to healthy controls. RESULTS: Total neuropathy score increased from 2.2 at baseline to 5.8 (p < 0.001) at week 8. NCS showed a decreased sensory amplitude in the sural, radial, ulnar and median nerve after 6 months (p < 0.001). HRUS revealed a significant increase of cross-sectional area in the sural nerve (p = 0.004), the median nerve (p = 0.003) at the carpal tunnel and the ulnar nerve in the forearm (p = 0.006) after 6 months. CCM showed no changes at different visits. CONCLUSIONS: Corneal confocal microscopy and HRUS do not detect early signs of TIPN during the paclitaxel treatment period. HRUS and NCS might detect congruent signs of an axonal, predominantly sensory polyneuropathy after 6 months. The clinical examination remains the most sensitive tool in the early detection of TIPN in breast cancer patients.

Nerve ultrasound reference values in children and adolescents: Echogenicity and influence of anthropometric factors including hand volume.

Background: Nerve cross-sectional area (CSA) reference values in high-resolution ultrasound for children and adolescents are influenced by demographic and anthropometric factors such as age, height and weight. Objectives: The influence of hand volume as an additional morphometric factor was evaluated and nerve echogenicity was analyzed in a prospective cross-sectional study. Methods: CSA were measured in 30 healthy children and adolescents from 2 to 17 years in the median, ulnar, radial, tibial, peroneal and sural nerves. Height, weight, age, handedness and gender were recorded, the volume of the hands was measured using the water displacement method. The intra-nerve CSA variability (INV), left/right ratios and absolute differences were calculated. Age groups were compared by the Kruskal-Wallis test. The influence of demographic factors was analyzed using Spearman correlation and multiple linear regression. Echogenicity and fraction of black were determined for each nerve segment. Results: Nerve CSA values were consistently lower than those reported for adults and correlated in all measured nerve sites with age, height, weight and hand volume. Weight showed the highest correlation coefficient (R = .95) with the best fitting model predicting CSA. Correlation coefficients were higher in a linear than in a logarithmic model. Ratios were stable, the absolute differences increased with age and were significantly different between age groups. Most nerves showed a mixed or hypoechogenic pattern in echogenicity analysis, hyperechogenicity is less frequently observed. Conclusions: Nerve CSA in children and adolescents is lower than in adults and increases proportionally during growth with a constant INV and left/right ratio in different age groups. Weight and age are predominant anthropometric factors predicting nerve size. Hand volume is correlated with nerve size, but does not predict CSA independently. Echogenicity can provide additional information on nerve structure.

Vagus nerve cross-sectional area decreases in Parkinson's disease.

INTRODUCTION: Morphological alterations of the vagus nerve (VN) in Parkinson's disease (PD) are discussed controversially. Several studies reported no difference in VN cross-sectional area (CSA) in PD patients in nerve ultrasound, others found a reduced CSA interpreted as atrophy of the VN and involvement of the dorsal nucleus of VN. METHODS: In a prospective comparative cross-sectional study, CSA of the VN bilaterally and the right ulnar nerve, clinical PD scales, non-motor symptoms and autonomic tests were compared between 49 PD patients and 24 healthy controls. Nerve ultrasound was performed by two independent investigators, patients and controls were compared at Bonferroni corrected p < 0.025 using results of both investigators and averaged results. Blinding included CSA measurements and PD scores, but not PD diagnosis. RESULTS: Bilateral averaged VN CSA was significantly lower in PD patients than in controls (Right VN PD mean 2.70 mm2 SD 0.69, controls 3.30 mm2 SD 0.49, p < 0.001. Left VN PD mean 2.45 mm2 SD 0.57, controls 2.77 mm2 SD 0.46, p = 0.012). No difference was found in the ulnar nerve. There was a weak negative correlation between the right VN CSA and the Unified Parkinson Disease Rating Scale (-0.08 mm2 per 10 points). The area under the receiver operating characteristic curve for the right VN was 0.78 (p < 0.001). CONCLUSION: The present results support the hypothesis of atrophy of the VN in PD. Reduction of VN CSA is a weak marker of disease progression. Nerve ultrasound of the VN might represent a supplementary method in diagnosis of PD.

Assessment of Operator Reliability in Ultrasound of the Median and Ulnar Nerve Using Bland-Altman Analysis.

Currently, there is no standardized method to evaluate operator reliability in nerve ultrasound. A short prospective protocol using Bland-Altman analysis was developed to assess the level of agreement between operators with different expertise levels. A control rater without experience in nerve ultrasound, three novices after two months of training, an experienced rater with two years of experience, and a reference rater performed blinded ultrasound examinations of the left median and ulnar nerve in 42 nerve sites in healthy volunteers. The precision of Bland-Altman agreement analysis was tested using the Preiss-Fisher procedure. Intraclass correlation coefficients (ICC), coefficients of variation, and Bland-Altman limits of agreement were calculated. The sample size calculation and Preiss-Fisher procedure showed a sufficient precision of Bland-Altman agreement analysis. Limits of agreement of all trained novices ranged from 2.0 to 2.9 mm2 and were within the test's maximum tolerated difference. Ninety-five percent confidence intervals of limits of agreement revealed a higher precision in the experienced rater's measurements. Operator reliability in nerve ultrasound of the median and ulnar nerve arm nerves can be evaluated with a short prospective controlled protocol using Bland-Altman statistics, allowing a clear distinction between an untrained rater, trained novices after two months of training, and an experienced rater.

Cross-sectional area in median and ulnar nerve ultrasound correlates with hand volume.

BACKGROUND: The influence of demographic and anthropometric factors on nerve cross-sectional area (CSA) reference values in high-resolution ultrasound was evaluated in a prospective observational study. METHODS: We measured CSA of median, ulnar, radial, and sural nerves in 80 healthy adults from 18 to 98 years of age. Pearson's correlation and multiple linear regression with age, gender, body mass index, and hand volume were calculated. RESULTS: Ulnar and median nerve CSA showed a significant positive correlation with ipsilateral hand volume. Median nerve CSA in the left forearm (mean, 6.2 mm2 ; SD, 1.2) increased by 0.006 mm2 (SE = 0.002; P < .001) per cm3 of hand volume, resulting in a difference of 1.9 mm2 predictable by hand volume (mean, 326 cm3 ; SD, 81; range, 180-500). CONCLUSIONS: The observed correlation of CSA and hand volume may influence the interpretation of CSA values in patients with very large or small hands.

Treatment of progressive stroke with tirofiban--experience in 35 patients.

BACKGROUND: In an open pilot study, we studied the safety and efficacy of treatment with the nonpeptide glycoprotein IIb/IIIa antagonist tirofiban in patients with progressive ischemic stroke. The rationale for the use of tirofiban in progressive stroke is the effect on vessel patency and microcircu lation. METHODS: Patients with acute ischemic stroke and progression of > or =2 points on the National Institute of Health Stroke Scale (NIHSS) in the first 96 h after stroke onset were treated with intravenous tirofiban. Serial NIHSS measurements and intra- and extracerebral bleeding complications were recorded. RESULTS: Progressive stroke was observed in 35 patients with a mean progression of 5.4 (SD 4.1) points on the NIHSS. No severe bleeding complications occurred during tirofiban treatment. Analysis of variance revealed a significant interaction between stroke etiology (small-vessel vs. large-vessel occlusion) and NIHSS during treatment with tirofiban: patients with small-vessel occlusion showed significant improvement, while patients with large-vessel occlusion did not. The mean NIHSS improvement after tirofiban infusion was 3.4 (SD 3.4) for small-vessel occlusion versus 0.8 (SD 4.2) for large-vessel occlusion (p = 0.048). CONCLUSION: Treatment with tirofiban was well tolerated in patients with progressive stroke. However, only patients with small-vessel occlusion recovered significantly during infusion of tirofiban. The effect of tirofiban in progressive stroke and different subgroups of stroke deserves to be studied in a randomized controlled trial.