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.

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

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 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 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. 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. RESULTS: Most patients (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%, p = 0.02) and were more likely to receive second-line therapy (75% vs. 54%, p = 0.05). 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 (n = 40) as well as patients with chronic inflammatory demyelinating polyneuropathy (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 ± 5, age at evaluation 71 ± 9, Hoehn and Yahr score 2.8 ± 8) were diagnosed with autonomic dysfunction (orthostatic hypertension n = 11, chronotropic incompetence n = 31, postural orthostatic tachycardia syndrome 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.

Prevalence and Characteristics of Polyneuropathy in Atypical Parkinsonian Syndromes: An Explorative Study.

(1) Background: Peripheral nerve involvement is increasingly recognized in Parkinson's disease (PD). Although non-motor symptoms and postural instability are early features of atypical parkinsonian syndromes (APS), peripheral neuropathies in APS have not been addressed in detail thus far. Therefore, the aim of this study was to investigate the prevalence and characteristics of polyneuropathies (PNP) in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), as representative syndromes of APS. (2) Methods: In total, 8 MSA and 6 PSP patients were comprehensively analyzed regarding subjective, clinical (motor and non-motor) and paraclinical PNP features using nerve conduction studies and high resolution nerve ultrasounds (HRUS). (3) Results: A total of 87.5% of MSA and 66.7% of PSP patients complained of at least one neuropathic symptom, with electrophysiological confirmation of PNP in 50.0% of both, MSA and PSP patients. PNP symptom severity in PSP and motor nerve amplitude in MSA were associated with compromised motor function. Morphologic nerve examination by HRUS showed few alterations according to the axonal type of PNP. (4) Conclusions: The overall high PNP symptom burden may be partially credited to the significant prevalence of electrophysiologically diagnosed PNP, and impact motor aspects of APS. The findings of this exploratory study reinforce further investigations on a larger scale, in order to elucidate peripheral nerve involvement and the underlying pathophysiological mechanisms of APS.

Correlates of polyneuropathy in Parkinson's disease.

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. 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. 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. 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.