Continuum of sensory profiles in diabetes mellitus patients with and without neuropathy and pain.

BACKGROUND: Quantitative sensory testing (QST) assesses the functional integrity of small and large nerve fibre afferents and central somatosensory pathways; QST was assumed to provide insight into the mechanisms of neuropathy. We analysed QST profiles and phenotypes in patients with diabetes mellitus to study whether these could differentiate patients with and without pain and neuropathy. METHODS: A standardized QST protocol was performed and 'loss and gain of function' abnormalities were analysed in four groups of subjects: diabetic patients with painful (pDSPN; n = 220) and non-painful distal symmetric polyneuropathy (nDSPN; n = 219), diabetic patients without neuropathy (DM; n = 23) and healthy non-diabetic subjects (n = 37). Based on the QST findings, diabetic subjects were further stratified into four predefined prototypic phenotypes: sensory loss (SL), thermal hyperalgesia (TH), mechanical hyperalgesia (MH) and healthy individuals. RESULTS: Patients in the pDSPN group showed the greatest hyposensitivity ('loss of function'), and DM patients showed the lowest, with statistically significant increases in thermal, thermal pain, mechanical and mechanical pain sensory thresholds. Accordingly, the frequency of the SL phenotype was significantly higher in the pDSPN subgroup (41.8%), than expected (p < 0.0042). The proportion of 'gain of function' abnormalities was low in both pDSPN and nDSPN patients without significant differences. CONCLUSIONS: There is a continuum in the sensory profiles of diabetic patients, with a more pronounced sensory loss in pDSPN group probably reflecting somatosensory nerve fibre degeneration. An analysis of 'gain of function' abnormalities (allodynia, hyperalgesia) did not offer a key to understanding the pathophysiology of spontaneous diabetic peripheral neuropathic pain. SIGNIFICANCE: This article, using quantitative sensory testing profiles in large cohorts of diabetic patients with and without polyneuropathy and pain, presents a continuum in the sensory profiles of diabetic patients, with more pronounced 'loss of function' abnormalities in painful polyneuropathy patients. Painful diabetic polyneuropathy probably represents a 'more progressed' type of neuropathy with more pronounced somatosensory nerve fibre degeneration. The proportion of 'gain of function' sensory abnormalities was low, and these offer limited understanding of pathophysiological mechanisms of spontaneous neuropathic pain.

Relapsing MRI-negative myelitis associated with myelin-oligodendrocyte glycoprotein autoantibodies: a case report.

BACKGROUND: Serum antibodies to myelin-oligodendrocyte glycoprotein (MOG) are biomarkers of MOG-IgG-associated disorder (MOGAD), a demyelinating disease distinct from both multiple sclerosis and aquaporin-4-IgG neuromyelitis optica spectrum disorder. The phenotype of MOGAD is broad and includes optic neuritis, transverse myelitis, and acute demyelinating encephalomyelitis. Myelitis is common with MOGAD and typically results in acute and severe disability, although prospects for recovery are often favorable with prompt immunotherapy. CASE PRESENTATION: This contribution presents a unique case report of a young male patient exhibiting relapsing myelitis with normal spinal cord and brain magnetic resonance imaging. Comprehensive diagnostic assessment revealed myelin-oligodendrocyte glycoprotein-IgG-associated disorder. CONCLUSION: MOGAD is one of the conditions which should be considered in MRI-negative myelitis. The diagnosis, however, may prove difficult, especially if the patient is not exhibiting other neurological symptoms of MOGAD. Conus or epiconus involvement is common in MOGAD; the patient reported herein exhibited incomplete rostral epiconus symptoms which, together with somatosensory evoked potential abnormalities, led to the diagnosis.

Risk factors for depression and anxiety in painful and painless diabetic polyneuropathy: A multicentre observational cross-sectional study.

BACKGROUND: Despite the high prevalence of depression and anxiety in chronic pain conditions, current knowledge concerning emotional distress among painful diabetic polyneuropathy (pDSPN) and other diabetes mellitus (DM) sufferers is limited. METHODS: This observational multicentre cohort study employed the Hospital Anxiety and Depression Scale, the Beck Depression Inventory II and the State-Trait Anxiety Inventory to assess symptoms of depression and anxiety in several groups with diabetes, as well as in a control group. The study cohort included 347 pDSPN patients aged 63.4 years (median), 55.9% males; 311 pain-free diabetic polyneuropathy (nDSPN) patients aged 63.7 years, 57.9% males; 50 diabetes mellitus (DM) patients without polyneuropathy aged 61.5 years, 44.0% males; and 71 healthy controls (HC) aged 63.0 years, 42.3% males. The roles played in emotional distress were explored in terms of the biological, the clinical (diabetes-, neuropathy- and pain-related), the socio-economic and the cognitive factors (catastrophizing). RESULTS: The study disclosed a significantly higher prevalence of the symptoms of depression and anxiety not only in pDSPN (46.7% and 60.7%, respectively), but also in patients with nDSPN (24.4% and 44.4%) and DM without polyneuropathy (22.0% and 30.0%) compared with HCs (7.0% and 14.1%, p < 0.001). Multiple regression analysis demonstrated the severity of pain and neuropathy, catastrophic thinking, type 2 DM, lower age and female sex as independent contributors to depression and anxiety. CONCLUSIONS: In addition to the severity of neuropathic pain and its cognitive processing, the severity of diabetic polyneuropathy and demographic factors are key independent contributors to emotional distress in diabetic individuals. SIGNIFICANCE: In large cohorts of well-defined painless and painful diabetic polyneuropathy patients and diabetic subjects without polyneuropathy, we found a high prevalence of the symptoms of depression and anxiety, mainly in painful individuals. We have confirmed neuropathic pain, its severity and cognitive processing (pain catastrophizing) as dominant risk factors for depression and anxiety. Furthermore, some demographic factors (lower age, female sex), type 2 diabetes mellitus and severity of diabetic polyneuropathy were newly identified as important contributors to emotional distress independent of pain.

Detailed Phenotype of GLA Variants Identified by the Nationwide Neurological Screening of Stroke Patients in the Czech Republic.

Fabry disease (FD) is a rare X-linked disorder of glycosphingolipid metabolism caused by pathogenic variants within the alpha-galactosidase A (GLA) gene, often leading to neurological manifestations including stroke. Multiple screening programs seeking GLA variants among stroke survivors lacked detailed phenotype description, making the interpretation of the detected variant's pathogenicity difficult. Here, we describe detailed clinical characteristics of GLA variant carriers identified by a nationwide stroke screening program in the Czech Republic. A total of 23 individuals with 8 different GLA variants were included in the study. A comprehensive diagnostic workup was performed by a team of FD specialists. The investigation led to the suggestion of phenotype reclassification for the G325S mutation from late-onset to classical. A novel variant R30K was found and was classified as a variant of unknown significance (VUS). The typical manifestation in our FD patients was a stroke occurring in the posterior circulation with an accompanying pathological finding in the cerebrospinal fluid. Moreover, we confirmed that cornea verticillata is typically associated with classical variants. Our findings underline the importance of detailed phenotype description and data sharing in the correct identification of pathogenicity of gene variants detected by high-risk-population screening programs.

Sensory profiles and immune-related expression patterns of patients with and without neuropathic pain after peripheral nerve lesion.

In this multicenter cross-sectional study, we determined sensory profiles of patients with (NL-1) and without neuropathic pain (NL-0) after nerve lesion and assessed immune-related systemic gene expression. Patients and matched healthy controls filled in questionnaires and underwent neurological examination, neurophysiological studies, quantitative sensory testing, and blood withdrawal. Neuropathic pain was present in 67/95 (71%) patients (NL-1). Tactile hyperalgesia was the most prominent clinical sign in NL-1 patients (P < 0.05). Questionnaires showed an association between neuropathic pain and the presence of depression, anxiety, and catastrophizing (P < 0.05 to P < 0.01). Neuropathic pain was frequently accompanied by other chronic pain (P < 0.05). Quantitative sensory testing showed ipsilateral signs of small and large fiber impairment compared to the respective contralateral side, with elevated thermal and mechanical detection thresholds (P < 0.001 to P < 0.05) and lowered pressure pain threshold (P < 0.05). Also, more loss of function was found in patients with NL-1 compared to NL-0. Pain intensity was associated with mechanical hyperalgesia (P < 0.05 to P < 0.01). However, quantitative sensory testing did not detect or predict neuropathic pain. Gene expression of peptidylglycine α-amidating monooxygenase was higher in NL patients compared with healthy controls (NL-1, P < 0.01; NL-0, P < 0.001). Also, gene expression of tumor necrosis factor-α was higher in NL-1 patients compared with NL-0 (P < 0.05), and interleukin-1ß was higher, but IL-10 was lower in NL-1 patients compared with healthy controls (P < 0.05 each). Our study reveals that nerve lesion presents with small and large nerve fiber dysfunction, which may contribute to the presence and intensity of neuropathic pain and which is associated with a systemic proinflammatory pattern.

Soluble Epoxide Hydrolase as a Potential Key Factor for Human Prenatal Development.

Soluble epoxide hydrolase (sEH) converts highly active epoxyeicosatrienoic acids (EETs) generated by cytochrome P450 (CYP) epoxygenases from arachidonic acid to less active dihydroxyeicosatrienoic acids. Because of the role of EETs in processes potentially relevant to the development of organisms, EETs could be suggested as potential morphogens. Unfortunately, only little is known about sEH expression during human intrauterine development (IUD). We investigated the spatio-temporal expression pattern of sEH in human embryonic/foetal intestines, liver and kidney from the 6th to the 20th week of IUD by two-step immunohistochemistry. sEH was expressed during the whole tested period of prenatal development and its level of expression remained more or less the same during the estimated period of IUD. Distribution of CYP epoxygenases and sEH in the intestinal epithelium and the nephrogenic zone of the kidney suggests an influence of EETs on cell proliferation and differentiation and, consequently, on the development of intestines and kidney. Thus, alterations in the strict spatio-temporal pattern of expression of CYP epoxygenases and/or sEH during human prenatal development by xenobiotics could have a harmful impact for developing organisms.

Spatio-temporal expression of peroxisome proliferator-activated receptor α during human prenatal development.

Peroxisome proliferator-activated receptor α (PPARα) is a ligand-dependent transcription factor which is activated by various endogenous as well as exogenous compounds. It is involved in the regulation of a variety of biological processes, such as nutrient metabolism, energy homoeostasis, immunological response and xenobiotic metabolism. Little is known about its expression during human prenatal development. We examined the spatio-temporal expression pattern of PPARα in human embryonic/foetal intestines, liver and kidney from the 5th to 20th week of prenatal life by indirect two-step immunohistochemistry. PPARα expression can already be detected in the early stages of prenatal development; as early as the 7th week of intrauterine development (IUD) in the intestines, 5th week of IUD in the liver and 6th week of IUD in the kidney. We found age-dependent changes in the PPARα expression pattern in the intestines and kidney. These events occur approximately at the commencement of function of these organs. In the intestines, we detected an obvious change of the PPARα expression pattern along the crypt-villous axis in the 11th week of IUD. In the kidney, the most apparent change was increased expression of PPARα in glomeruli in the 12th week of IUD. Moreover, in the liver, we detected a strong positivity in part of the developing blood elements. Information about the spatio-temporal expression pattern of PPARα could be the first step in evaluating the potential harmful impact of a wide range of environmental or pharmaceutical compounds which serve as PPARα ligands on the developing human organism.