Reduced cortical thickness in patients with Sickle Cell Disease and a high pain burden: baseline results from the Prevention of Morbidity in Sickle Cell Anaemia (POMS2b) trial

Abstract

Background: Sickle cell anaemia (SCA) is associated with frequent episodes of vaso‐occlusive pain crises, but many patients also experience chronic daily pain1, which may be due to avascular necrosis of joints, bone infarction, osteomyelitis or due to intractable chronic pain without obvious pathology2 or neuropathic pain3. Not all patients experience a significant chronic pain burden4. The impact of chronic sickle cell pain on the brain is not yet clear; a recent resting‐state fMRI study showed a correlation between functional connectivity of the default‐mode network and number of hospitalizations for pain5. In other chronic pain conditions, reduced grey matter volume has been noted in various cortical regions involved in pain processing such as the anterior6 and posterior7‐9 cingulate cortex (ACC and PCC, respectively), primary motor cortex9 (M1), primary somatosensory cortex5,6 (S1) and insula cortex. The aim of this study is to investigate the relationship between daily pain and a priori selected grey matter regions. Methods: As part of the baseline assessments for the Prevention of Morbidity in Sickle Cell Anaemia (POMS2b) phase‐II trial, 52 children and adults recorded baseline daily pain and underwent neuropsychological testing and MRI in the 14 days prior to randomisation. Daily pain was recorded on a numerical scale 0‐10 for 14 days. Patients were split into “Low‐Pain” group (<50% recorded days in pain) or “High‐Pain” group (>50% of recorded days in pain). Neuropsychological assessment was carried out using: Wechsler full‐scale IQ (FSIQ), working memory index (WMI) and processing speed index (PSI), Delis‐Kaplan Executive Function System Tower and Sorting subtests. Patients underwent MRI on a 3T Siemens Prisma that included T2‐weighted sequences to diagnose silent cerebral infarction and a 3D T1‐weighted MPRAGE. Cortical parcellation was carried out using Freesurfer. A model was fitted to the imaging data variables to investigate differences between low‐pain and highpain groups, controlling for age, gender and presence of SCI and socioeconomic status10 (Index of Multiple Deprivation decile by UK postcode). Results: Five children were excluded from analysis (poor quality data or braces artefact). The final sample was 47 children and adults with SCA. There was a significant correlation with percentage of days in pain and age (r = 0.53, p = 0.0001). In the low‐pain group, 11 patients reported no pain during the recorded days. High‐pain patients had significantly lower WMI and a trend for lower FSIQ, PSI, Sorting‐correct sorts and Sorting‐free sorting description. High‐pain patients had significantly reduced cortical thickness in the mean cortex of the left and right hemispheres, and significantly thinner cortex in the bilateral precuenus, bilateral PCC, left M1 and right caudal ACC. There was a trend for positive correlation between average pain and right‐hemisphere rostral ACC thickness. Conclusion: This study is the first to describe structural brain abnormalities in patients with high burden of sickle cell pain. These patients are part of a 6‐month randomised controlled trial of overnight respiratory support with cognitive and pain endpoints as well as repeat MRI; this study may provide structural biomarkers that may parallel amelioration of chronic daily pain.