Differentiating Axonal from Demyelinating Neuropathies using Multiparametric Quantitative MRI of Peripheral Nerves

Objectives: To develop a multiparametric quantitative MRI (qMRI) method to track pathological changes in the peripheral neuropathies. Background: Irrespective of the causes or types of polyneuropathies, peripheral nerves are mainly afflicted by two kinds of pathologies – axonal loss and demyelination. It is critical to differentiate between the two as treatments are different for the two conditions. While nerve conduction studies (NCS) have been used to differentiate the two pathologies in the distal nerves, there are no tools to probe the pathologies in the proximal peripheral nerves. This is particularly needed when distal nerves become non-responsive in NCS. Methods: We have developed a qMRI method that quantifies the sciatic and tibial nerves with 10 parameters that are sensitive to different aspects of myelin and axonal pathologies: magnetization transfer ratio (MTR), magnetization transfer saturation index (MTsat), longitudinal relaxation time (T1), proton density (PD), effective transverse relaxation time (T2*), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and nerve fascicular volume (fVol). In this pilot study, we studied 4 patients with Charcot-Marie-Tooth type-1A (CMT1A), 2 patients with CMT type-2S (CMT2S), and 17 healthy controls. Results: Compared with the healthy controls, patients with CMT2S (axonal type) had a comparable MTR, MTsat, T1, PD and fVol, but a reduced T2*. While patients with CMT1A (demyelinating type) had a reduced MTR and MTsat, increased fVol, T1 and PD, and comparable T2*. All 6 patients with CMT shared a change in reduced FA, which was driven by a reduced AD and an increased RD. Conclusions: The data show different qMRI patterns between axonal and demyelinating neuropathies. The differential changes will be further verified in a larger cohort of patients with peripheral neuropathies

Mechanisms of Resistance to Decitabine in the Myelodysplastic Syndrome

Purpose: The DNA methylation inhibitor 5-aza-29-deoxycytidine (DAC) is approved for the treatment of myelodysplastic syndromes (MDS), but resistance to DAC develops during treatment and mechanisms of resistance remain unknown. Therefore, we investigated mechanisms of primary and secondary resistance to DAC in MDS. Patients and Methods: We performed Quantitative Real-Time PCR to examine expression of genes related to DAC metabolism prior to therapy in 32 responders and non-responders with MDS as well as 14 patients who achieved a complete remission and subsequently relapsed while on therapy (secondary resistance). We then performed quantitative methylation analyses by bisulfite pyrosequencing of 10 genes as well as Methylated CpG Island Amplification Microarray (MCAM) analysis of global methylation in secondary resistance. Results: Most genes showed no differences by response, but the CDA/DCK ratio was 3 fold higher in non-responders than responders (P,.05), suggesting that this could be a mechanism of primary resistance. There were no significant differences at relapse in DAC metabolism genes, and no DCK mutations were detected. Global methylation measured by the LINE1 assay was lower at relapse than at diagnosis (P,.05). On average, the methylation of 10 genes was lower at relapse (16.1%) compared to diagnosis (18.1%) (P,.05).MCAM analysis showed decreased methylation of an average of 4.5 % (range 0.6%– 9.7%) of the genes at relapse. By contrast, new cytogenetic changes were found in 20 % of patients

DNA Methylation Profiles of Primary Colorectal Carcinoma and Matched Liver Metastasis

BACKGROUND: The contribution of DNA methylation to the metastatic process in colorectal cancers (CRCs) is unclear. METHODS: We evaluated the methylation status of 13 genes (MINT1, MINT2, MINT31, MLH1, p16, p14, TIMP3, CDH1, CDH13, THBS1, MGMT, HPP1 and ERα) by bisulfite-pyrosequencing in 79 CRCs comprising 36 CRCs without liver metastasis and 43 CRCs with liver metastasis, including 16 paired primary CRCs and liver metastasis. We also performed methylated CpG island amplification microarrays (MCAM) in three paired primary and metastatic cancers. RESULTS: Methylation of p14, TIMP3 and HPP1 in primary CRCs progressively decreased from absence to presence of liver metastasis (13.1% vs. 4.3%; 14.8% vs. 3.7%; 43.9% vs. 35.8%, respectively) (P<.05). When paired primary and metastatic tumors were compared, only MGMT methylation was significantly higher in metastatic cancers (27.4% vs. 13.4%, P = .013), and this difference was due to an increase in methylation density rather than frequency in the majority of cases. MCAM showed an average 7.4% increase in DNA methylated genes in the metastatic samples. The numbers of differentially hypermethylated genes in the liver metastases increased with increasing time between resection of the primary and resection of the liver metastasis. Bisulfite-pyrosequencing validation in 12 paired samples showed that most of these increases were not conserved, and could be explained by differences in methylation density rather than frequency. CONCLUSIONS: Most DNA methylation differences between primary CRCs and matched liver metastasis are due to random variation and an increase in DNA methylation density rather than de-novo inactivation and silencing. Thus, DNA methylation changes occur for the most part before progression to liver metastasis

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Mortality and pulmonary complications in patients undergoing surgery with perioperative sars-cov-2 infection: An international cohort study

Background The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (740%) had emergency surgery and 280 (248%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (261%) patients. 30-day mortality was 238% (268 of 1128). Pulmonary complications occurred in 577 (512%) of 1128 patients; 30-day mortality in these patients was 380% (219 of 577), accounting for 817% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 175 [95% CI 128-240], p&lt;00001), age 70 years or older versus younger than 70 years (230 [165-322], p&lt;00001), American Society of Anesthesiologists grades 3-5 versus grades 1-2 (235 [157-353], p&lt;00001), malignant versus benign or obstetric diagnosis (155 [101-239], p=0046), emergency versus elective surgery (167 [106-263], p=0026), and major versus minor surgery (152 [101-231], p=0047). Interpretation Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

A Pilot Study on Hand Palmar and Digital Nerve Ultrasound in Peripheral Nerve Diseases

INTRODUCTION: Palmar and digital nerves of the hand can be imaged with high resolution using ultrasonography because of their superficial anatomic locations. However, no studies have systematically evaluated these nerves in polyneuropathies. OBJECTIVE: Measure the cross-sectional area (CSA) and echogenicity (represented as % black) of the palmar and digital nerves of the hand in chronic polyneuropathies. METHODS: We studied 52 individuals: 26 with electrodiagnostically confirmed chronic peripheral nerve diseases (16 demyelinating/10 axonal) compared with 26 age and gender matched controls. Ultrasonography was performed in the median and ulnar nerves at: digit 2/5 lateral common palmar nerves at the distal palmar crease(D2/5-LCP), digital nerve to digit 2/5 at the metacarpophalangeal joint (D2/5-MP), distal wrist crease (DWC) and forearm (FA) with a 22mHz transducer (GE Logiqe R8). CSA and % black were measured using ImageJ. RESULTS: In demyelinating polyneuropathies, regardless of underlying pathology D2-LCP was significantly enlarged in CSA compared to axonal polyneuropathies (3.23±0.399mm2 versus 1.17 ±0.582 mm2, p\u3c0.001) and healthy individuals (3.23±0.399mm2 versus 1.306±0.321, p\u3c0.001). The % black of the D2-LCP, D2-MP, and D5-MP was significantly reduced in axonal polyneuropathies compared to demyelinating polyneuropathies (35.4±7.72%, 41.9±6.97%, 46.6±6.54% versus 53.0±9.25%, 63.8±7.11%, 62.9±5.66% all p\u3e0.01) and healthy individuals (35.3±7.72%, 41.9±6.97%, 46.59±6.54% versus 51.36±6.29%, 60.08 ±8.71%, 59.4±7.11% all p\u3e0.05). No statistically significant difference in % black was seen in the DWC or FA. SUMMARY/CONCLUSION: In this pilot study we show digital and palmar nerves of the hand reproduces CSA enlargement of demyelinating polyneuropathies as reported in other nerves and may detect axonal loss in the form of increased intraneural echogenicity

Length-dependent MRI of hereditary neuropathy with liability to pressure palsies.

OBJECTIVE: Hereditary neuropathy with liability to pressure palsies (HNPP) is caused by heterozygous deletion of the peripheral myelin protein 22 (PMP22) gene. Patients with HNPP present multifocal, reversible sensory/motor deficits due to increased susceptibility to mechanical pressure. Additionally, age-dependent axonal degeneration is reported. We hypothesize that length-dependent axonal loss can be revealed by MRI, irrespective of the multifocal phenotype in HNPP. METHODS: Nerve and muscle MRI data were acquired in the proximal and distal leg of patients with HNPP (n = 10) and matched controls (n = 7). More specifically, nerve magnetization transfer ratios (MTR) were evaluated to assay proximal-to-distal gradients in nerve degeneration, while intramuscular fat percentages (F RESULTS: F INTERPRETATION: Despite the multifocal nature of the HNPP phenotype, muscle