Cross-sectional area reference values for peripheral nerve ultrasound in adults

Background and purpose Measurement of the cross-sectional area (CSA) of peripheral nerves using ultrasound is useful in the evaluation of focal lesions like entrapment syndromes and inflammatory polyneuropathies. Here, a systematic review and meta-analysis of published CSA reference values for upper extremity nerves was performed. Methods Available to date nerve ultrasound studies on healthy adults were included and a meta-analysis for CSA was provided of the following nerves: median nerve at the wrist, forearm, upper arm; ulnar nerve at the Guyon's canal, forearm, elbow, upper arm; radial nerve at the upper arm. Regression and correlation analyses for age, gender, height, weight, geographic continents and publication year are reported. Results Seventy-four studies with 4186 healthy volunteers (mean age 42.7 years) and 18,226 examined nerve sites were included. The calculated mean pooled CSA of the median nerve at the wrist was 8.3 mm$^{2}$ (95% confidence interval [95% CI] 7.9–8.7, $\it n$ = 4071), at the forearm 6.4 mm$^{2}$ (95% CI 5.9–6.9, $\it n$ = 3021), at the upper arm 8.3 mm$^{2}$ (95% CI 7.5–9.0, $\it n$ = 1388), of the ulnar nerve at the Guyon's canal 4.1 mm$^{2}$ (95% CI 3.6–4.6, $\it n$ = 1688), at the forearm 5.2 mm$^{2}$ (95% CI 4.8–5.7, $\it n$ = 1983), at the elbow 5.9 mm$^{2}$ (95% CI 5.4–6.5, $\it n$ = 2551), at the upper arm 6.6 mm$^{2}$ (95% CI 5.1–6.1, n = 1737) and of the radial nerve 5.1 mm$^{2}$ (95% CI 4.0–6.2, $\it n$ = 1787). Substantial heterogeneity across studies ($\it I$$^{2}$ > 50%) was found only for the radial nerve. Subgroup analysis revealed a positive effect of age for the median nerve at the wrist and for height and weight for different sites of the ulnar nerve. Conclusion The first meta-analysis on CSA reference values for the upper extremities with no or only low heterogeneity of reported CSA values in most nerve sites is provided. Our data facilitate the goal of an international standardized evaluation protocol

Cross-sectional area reference values for peripheral nerve ultrasound in adults

$\textbf {Background and purpose}$ Measurement of the cross-sectional area (CSA) of peripheral nerves using ultrasound is useful in the evaluation of focal lesions such as entrapment syndromes and inflammatory polyneuropathies. We performed a systematic review and meta-analysis of published CSA reference values for lower extremity nerves. $\bf Methods$ We included available-to-date nerve ultrasound studies on healthy adults and provide meta-analysis for CSA of the following nerves: fibular nerve at fibular head, popliteal fossa; tibial nerve at popliteal fossa, malleolus; and sural nerve at the level of the two heads of gastrocnemius muscle. We report regression and correlation analyses for age, gender distribution, height, weight, and geographic continent. $\bf Results$ We included 16 studies with 1001 healthy volunteers (mean age = 47.9 years) and 4023 examined nerve sites. Calculated mean pooled CSA of fibular nerve at fibular head was 8.4 mm2 (95% confidence interval [CI] = 6.8–9.9 mm2, n = 1166), at popliteal fossa was 7.9 mm2 (95% CI = 6.6–9.2 mm2, n = 995), of tibial nerve at popliteal fossa was 25.9 mm2 (95% CI = 17.5–34.4 mm2, n = 771), at malleolus was 10.0 mm2 (95% CI = 7.7–12.4 mm2, n = 779), and of sural nerve was 2.4 mm2 (95% CI = 1.7–3.1 mm2, n = 312). Substantial heterogeneity across studies (I2 > 50%) was found only for tibial nerve at popliteal fossa. Subgroup analysis revealed a lower CSA of tibial nerve at popliteal fossa and sural nerve in studies conducted in Europe than in North America and New Zealand. $\bf Conclusions$ We provide the first meta-analysis on CSA reference values for the lower extremities with no or low heterogeneity of reported CSA values in all nerve sites except tibial nerve at popliteal fossa. Our data facilitate the goal of an international standardized evaluation protocol

Cross-sectional area reference values for peripheral nerve ultrasound in adults

$\textbf {Background and purpose}$ Measurement of the cross-sectional area (CSA) of cervical nerve roots using ultrasound is useful in the evaluation of inflammatory polyneuropathies, and measurement of CSA of the vagal nerve might give information about involvement of the autonomic nervous system. We performed a systematic review and meta-analysis of published CSA reference values for cervical nerve roots and vagal nerve. $\bf Methods$ We included available-to-date nerve ultrasound studies on healthy adults and provide meta-analysis for CSA of the following nerves: cervical nerve roots C5, C6, and C7 as well as vagal nerve in the carotid sheath at the carotid bifurcation level. We report regression and correlation analyses for age, gender, height, weight, and geographic continent. $\bf Results$ We included 11 studies with 885 healthy volunteers (mean age = 42.7 years) and 3149 examined nerve sites. Calculated mean pooled CSA of C5 root was 5.6 mm$^{2}$ (95% confidence interval [CI] = 4.6–6.7 mm$^{2}$, $\it n$ = 911), of C6 root was 8.8 mm$^{2}$ (95% CI = 7.4–10.3 mm$^{2}$, $\it n$ = 909), of C7 root was 9.5 mm$^{2}$ (95% CI = 8.0–10.9 mm$^{2}$, $\it n$ = 909), and of vagal nerve was 2.2 mm$^{2}$ (95% CI = 1.5–2.9 mm$^{2}$, $\it n$ = 420). No heterogeneity was found across studies for any site. Subgroup analysis revealed no significant effects of age, gender, height, weight, and geographic continent on CSA for any of these nerve sites. $\bf Conclusions$ We provide the first meta-analysis on CSA reference values for the cervical nerve roots and the vagal nerve, with no heterogeneity of reported CSA values at all nerve sites. Our data facilitate the goal of an international standardized evaluation protocol

Increased muscle echointensity correlates with clinical disability and muscle strength in chronic inflammatory demyelinating polyneuropathy

$\textbf {Background and purpose}$ We evaluated muscle echointensity as a marker for secondary axonal damage in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) using ultrasonography. Findings were correlated with clinical disability and muscular strength. $\bf Methods$ Eighty patients with CIDP (40 with typical and 40 with atypical CIDP) were examined clinically, including assessment of Medical Research Council (MRC) sum score and Inflammatory Neuropathy Cause and Treatment Overall Disability Sum Score (INCAT-ODSS). Echointensity in eight proximal and distal muscles of the arms and legs was evaluated by muscle ultrasonography using the Heckmatt scale. $\bf Results$ Alterations of echointensity occurred most frequently in the distal leg muscles, with a median (range) Heckmatt score of 1.5 (1–4). There were no differences between typical and atypical CIDP patients with regard to Heckmatt score. Alterations of echointensity correlated to disability and muscle strength. The arm score of the INCAT-ODSS correlated to Heckmatt score for the distal arm muscles ($\it r$ = 0.23, ($\it p$ = 0.046) and the leg score of the INCAT-ODSS correlated to Heckmatt scores for the proximal (($\it r$ = 0.34, ($\it p$ = 0.002) and distal leg muscles (($\it r$ = 0.33, ($\it p$ = 0.004). MRC sum score, as well as individual MRC scores for arm and leg muscles, correlated to Heckmatt scores of the corresponding muscle groups (($\it r$ = −0.25, ($\it p$ = 0.02 for MRC sum score). $\bf Conclusion$ Increased muscle echointensity, reflecting fibrosis and fatty infiltration due to secondary axonal damage, correlated to muscular strength and disability in a large cohort of CIDP patients. Alterations of echointensity occur in both typical and atypical CIDP patients and are pronounced in the distal leg muscles

Evaluation of the EFNS/PNS diagnostic criteria in a cohort of CIDP patients

Objective To evaluate the European Federation of Neurological Societies (EFNS)/Peripheral Nerve Society (PNS) diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) in a cohort of patients diagnosed and treated for CIDP in a tertiary university hospital. Methods In a monocentric retrospective study of 203 CIDP patients, diagnosed according to expert opinion, we evaluated the EFNS/PNS diagnostic criteria. Clinical course and nerve conduction studies (NCS) over 1 year from first referral were studied. Secondarily, we compared the clinical and paraclinical characteristics, including nerve ultrasound, of patients who failed with those who fulfilled the criteria in order to identify clinically relevant differences. Results At 1 year, 182 (89.7%) patients fulfilled the criteria (156/76.9% definite, 22/10.8% probable, and 4/2% possible). Twenty-one (10.3%) patients did not because the electrodiagnostic criteria remained negative. These still showed signs of demyelination but did not reach the cut-off values. They also presented typical, albeit less pronounced, multifocal nerve enlargement in ultrasonography. Mean disability at presentation and 1 year after was significantly lower. Most importantly, a relevant proportion of these patients also responded to therapy (6/21 = 28.6% vs. 82/182 = 45.3% of those fulfilling the criteria). Interpretation CIDP diagnosis could be established for 89.7% of patients over the course of 1 year using EFNS/PNS criteria. The remaining patients (10.3%) presented with milder disability, less accentuated demyelination, but otherwise similar characteristics and still considerable probability of treatment response. Failure to fulfill diagnostic criteria should not automatically preclude treatment. Nerve ultrasound should be considered as a complementary diagnostic tool to detect signs of inflammation in CIDP

Correlates of polyneuropathy in Parkinson’s disease

$\bf Objective$ Previous studies in Parkinson’s disease (PD) patients have demonstrated a high prevalence of polyneuropathy (PNP) and pronounced alpha-Synuclein pathology in dermal nerve fibers already at early disease stages. The aim of this study was to analyze associations between the prevalence and severity of PNP with nonmotor and motor symptoms in PD patients. $\bf Methods$ Fifty PD patients were characterized comprehensively for the presence of clinical symptoms (nonmotor and motor), electrophysiologic alterations and – for the first time – using high-resolution ultrasound of peripheral nerves. $\bf Results$ Sixty-two percent of PD patients showed electrophysiological pathology of PNP. The prevalence of patient-reported PNP symptoms was 86% and was particularly present in patients with longer disease duration, compromised scores of nonmotor and motor symptoms as well as with a negative evaluation of quality of life. Seventy-five percent of patients showed morphologic alterations similar to axonal PNP in high-resolution ultrasound compared to healthy controls. $\bf Interpretation$ The study demonstrates the high burden of peripheral nervous system disease in Parkinson's disease. It advocates further studies to delineate the underlying pathophysiological mechanisms in order to optimize treatment approaches for PD, including the associated PNP

Small fibre integrity and axonal pathology in the rat model of experimental autoimmune neuritis

Experimental autoimmune neuritis is a common animal model for acute human immune-mediated polyneuropathies. Although already established in 1955, a number of pathophysiological mechanisms remain unknown. In this study, we extensively characterize experimental autoimmune neuritis progression in Lewis rats, including new insights into the integrity of small nerve fibres, neuropathic pain and macrophage activation. Acute experimental autoimmune neuritis was induced with $P2_{53–78}$ peptide and consequently investigated using the gait analysis system CatWalk XT, electrophysiological and histopathological analyses, quantitative polymerase chain reaction (PCR), dorsal root ganglia outgrowth studies, as well as the von Frey hair and Hargreaves tests. For the longitudinal setup, rats were sacrificed at Day (d) 10 (onset), d15 (peak), d26 (recovery) and d29 (late recovery). We confirmed the classical T-cell and macrophage-driven inflammation and the primarily demyelinating nature of the experimental autoimmune neuritis. The dual role of macrophages in experimental autoimmune neuritis is implicated by the high number of remaining macrophages throughout disease progression. Furthermore, different subpopulations of macrophages based on $\textit {Cx3-motif chemokine receptor 1 (Cx3cr1), platelet factor 4 (Pf4)}$ and $\textit {macrophage galactose-type lectin-1 (Mgl1)}$ expressions were identified. In addition, modulation of the sensory system in experimental autoimmune neuritis was detected. An outgrowth of small fibres in the plantar skin at the onset and peak of the experimental autoimmune neuritis was evident parallel to the development of acute hyperalgesia mediated through transient receptor potential vanilloid 1 modulation. Our data depict experimental autoimmune neuritis as a primary demyelinating disease with implicated axonal damage, a small unmyelinated fibre impairment throughout the disease progression course, and underline the pivotal role of macrophages in the effector and during the recovery stage

Association of the neonatal Fc receptor promoter variable number of tandem repeat polymorphism with immunoglobulin response in patients with chronic inflammatory demyelinating polyneuropathy

$\textbf {Background and purpose:}$ Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease with humoral and cellular autoimmunity causing demyelination of peripheral nerves, commonly treated with intravenous immunoglobulins (IVIg). The neonatal Fc receptor (FcRn), encoded by the $\it FCGRT$ gene, prevents the degradation of immunoglobulin G (IgG) by recycling circulating IgG. A variable number of tandem repeat (VNTR) polymorphism in the promoter region of the $\it FCGRT$ gene is associated with different expression levels of mRNA and protein. Thus, patients with genotypes associated with relatively low FcRn expression may show a poorer treatment response to IVIg due to increased IVIg degradation. $\bf Methods:$ VNTR genotypes were analyzed in 144 patients with CIDP. Patients' clinical data, including neurological scores and treatment data, were collected as part of the Immune-Mediated Neuropathies Biobank registry. $\bf Results:$ Most patients ($\it n$ = 124, 86%) were VNTR 3/3 homozygotes, and 20 patients (14%) were VNTR 2/3 heterozygotes. Both VNTR 3/3 and VNTR 2/3 genotype groups showed no difference in clinical disability and immunoglobulin dosage. However, patients with a VNTR 2 allele were more likely to receive subcutaneous immunoglobulins (SCIg) than patients homozygous for the VNTR 3 allele (25% vs. 9.7%, $\it p$ = 0.02) and were more likely to receive second-line therapy (75% vs. 54%, $\it p$ = 0.05). $\bf Conclusions:$ The VNTR 2/3 genotype is associated with the administration of SCIg, possibly reflecting a greater benefit from SCIg due to more constant immunoglobulin levels without lower IVIg levels between the treatment circles. Also, the greater need for second-line treatment in VNTR 2/3 patients could be an indirect sign of a lower response to immunoglobulins

Vagal cross-sectional area correlates with parasympathetic dysfunction in Parkinson's disease

The aim of this prospective study was to investigate autonomic function in Parkinson’s disease with a multidimensional approach including clinical evaluation tools, head-up tilt test and morphological studies of the vagus nerve. Head-up tilt test parameters including high frequency power of the heart frequency interval, the ratio of low frequency power of the distance between two consecutive R waves in electrocardiogram (RR interval) to the high frequency and low frequency power of systolic blood pressure were used to evaluate parasympathetic, cardiac sympathetic and vasomotor sympathetic functions, respectively, in 80 patients with Parkinson's disease. We examined the cross-sectional area of the vagus nerves bilaterally using nerve ultrasound and compared mean values with a control group of healthy subjects ($\it n$ = 40) as well as patients with chronic inflammatory demyelinating polyneuropathy ($\it n$ = 76). The cross-sectional area of right/left vagus nerve of Parkinson's patients was significantly lower compared to the right/left vagus nerve of the control group and of chronic demyelinating polyneuropathy patients. Furthermore, the cross-sectional area of the right vagus nerve was significantly larger from the one of the left vagus nerve for all groups. Based on tilt test, 43 patients (disease duration 7 $\pm$ 5, age at evaluation 71 $\pm$ 9, Hoehn and Yahr score 2.8 $\pm$ 8) were diagnosed with autonomic dysfunction (orthostatic hypertension $\it n$ = 11, chronotropic incompetence $\it n$ = 31, postural orthostatic tachycardia syndrome $\it n$ = 1). Patients with orthostatic hypotension showed significantly higher Unified Parkinson’s Disease Rating Scale-III values than those with chronotropic incompetence. The cross-sectional area of the vagus nerve correlated inversely with heart rate in rest and supine position and positively with tilt test parameters representing parasympathetic modulation through vagal activity [high frequency power of the distance between two consecutive R waves in electrocardiogram (RR interval)] at rest. We demonstrate for the first time that morphological characteristics of the vagus nerve correlate with parameters of parasympathetic function from the spectral analysis of cardiovascular parameters in tilt test for Parkinson's patients. This correlation reveals the impact of the atrophy of vagal atrophy for autonomic function in Parkinson's disease. Nerve ultrasound of the vagus nerve could potentially be used as an adjunct to tilt table examination to diagnose autonomic dysfunction