Index of Pain Experience in Sickle Cell Anaemia (<scp>IPESCA</scp>): development from daily pain diaries and initial findings from use with children and adults with sickle cell anaemia

Kawadler, Jamie M.; Slee, April; Stotesbury, Hanne; Kölbel, Melanie; Balfour, Philippa; Saunders, Dawn; Rees, David C.; Howard, Jo; Inusa, Baba; Pelidis, Maria; Kesse‐Adu, Rachel; Chakravorty, Subarna; Awogbade, Moji; Clark, Chris A.; Kirkham, Fenella J.; Liossi, Christina

doi:10.1111/bjh.15841

Cited by 3 publications

(4 citation statements)

References 5 publications

(6 reference statements)

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“… 68 , 69 Altered functional connectivity has been observed in regions associated with pain processing, 18 , 70 consistent with central sensitization to chronic daily pain and/or acute pain crises. 71 , 72 However, we only had pain diary data for the POMS patients, 71 , 72 so we did not investigate associations with pain.…”

Section: Discussionmentioning

confidence: 99%

Structural connectivity mediates the relationship between blood oxygenation and cognitive function in sickle cell anemia

Clayden¹,

Stotesbury²,

Kawadler³

et al. 2023

Blood Advances

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In sickle cell disease (SCD), the relative importance of reduced hemoglobin and peripheral oxygen saturation (SpO2) on brain structure remains uncertain. We applied graph-theoretical analysis to diffusion MRI data to investigate the effect of structural brain connectivity on cognitive function, alongside presence/absence, number and volume of silent cerebral infarction (SCI). In patients, we investigated the relationships between network properties, blood oxygenation and cognition (working memory, WMI, and processing speed, PSI, indices). Based on streamline counts and fractional anisotropy (FA), we identified a subnetwork with weakened connectivity in 92 SCA patients (49 males; 8.0-38.8 years), compared to 54 non-SCA controls (22 males; 6.7-30.6 years). Multiple regression analyses showed a significant effect of hemoglobin on full-network edge density (p<0.05), and of peripheral SpO2 on streamline-weighted subnetwork efficiency (p<0.01). There were effects of FA-weighted full-network and subnetwork efficiency on WMI (both p<0.05), and of streamline-weighted subnetwork efficiency on PSI (p=0.05) but no effects on SCI. Streamline-weighted efficiency was progressively lower with lower SpO2, with a downstream effect on PSI. In path analysis, indirect relationships between blood oxygenation and cognition, mediated by network properties, were better supported than direct alternatives, with an indirect relationship between low SpO2 and PSI in patients, mediated by structural connectivity efficiency in a subnetwork of the brain differing from controls. Our findings are consistent with the notion that cognitive impairment is primarily mediated by hypoxic-ischemic effects on normal-appearing white matter, and highlight the utility of network-based methods in providing biomarkers of cognitive dysfunction in SCA patients.

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Section: Discussionmentioning

confidence: 99%

Structural connectivity mediates the relationship between blood oxygenation and cognitive function in sickle cell anemia

Clayden¹,

Stotesbury²,

Kawadler³

et al. 2023

Blood Advances

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“…Coordinating cognitive testing only when patients are not experiencing pain can be a goal. However, this may generally not be achievable given that many patients with SCD experience persistent pain ( 127 , 128 ). One potential option is to use pain-related PROs to determine potential pain interference and intensity and their relation to cognitive endpoints.…”

Section: Other Considerationsmentioning

confidence: 99%

Considerations for Selecting Cognitive Endpoints and Psychological Patient-Reported Outcomes for Clinical Trials in Pediatric Patients With Sickle Cell Disease

et al. 2022

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Pediatric patients with sickle cell disease (SCD) experience a range of medical complications that result in significant morbidity and mortality. Recent advances in prophylactic and curative treatment approaches have highlighted the need for sensitive and clinically-meaningful trial endpoints. The detrimental effects of cognitive and psychological difficulties on social and economic mobility are well described. Although numerous reviews have assessed cognitive outcomes in other rare genetic disorders, SCD has not received the same focus. This review describes the cognitive (i.e., executive function and processing speed) and psychological domains (i.e., depression and anxiety) that are consistently associated with SCD pathology and, therefore, may be of particular interest as clinical trial endpoints. We then discuss corresponding well-validated and reliable cognitive tests and patient-reported outcomes (PROs) that may be appropriate for clinical trials given their robust psychometric properties, ease of administration, and previous use in the SCD population. Further, we provide a discussion of potential pitfalls and considerations to guide endpoint selection. In line with the move toward patient-centered medicine, we identify specific tests (e.g., NIH Toolbox Cognition Module, Wechsler Cancellation Test) and psychological PROs (e.g., PROMIS depression and anxiety scales) that are sensitive to SCD morbidity and have the potential to capture changes that are clinically meaningful in the context of patients' day to day lives. In particularly vulnerable cognitive domains, such as executive function, we highlight the advantages of composite over single-test scores within the context of trials. We also identify general (i.e., practice effects, disease heterogeneity) and SCD-specific considerations (i.e., genotype, treatment course, and disease course, including degree of neurologic, pain, and sleep morbidity) for trial measures. Executive function composites hold particular promise as trial endpoints that are clinically meaningful, amenable to change, relatively easy to collect, and can be incorporated into the routine care of patients with SCD in various settings and countries.

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“…Observational studies, to date, have mainly looked at differences in functional connectivity from resting-state functional MRI data (rsfMRI), e.g. amplitude of low-frequency fluctuations (ALFF) [79] or independent component analysis [103] between patients with SCD and controls and associations with hemoglobin, hemoglobin F, oxygen saturation, cognition and pain [79,[103][104][105][106][107][108][109][110][111].…”

Section: Structural and Functional Connectivitymentioning

confidence: 99%

“…Acute pain secondary to vaso-occlusion is the cardinal symptom of SCD, but daily questionnaire data suggest that chronic neuropathic pain is increasingly important from childhood onwards [111][112][113]. This may be related to central sensitizing mechanisms which in turn may lead to alteration in the connectivity of networks measurable using fMRI.…”

Section: Structural and Functional Connectivitymentioning

confidence: 99%

MRI detection of brain abnormality in sickle cell disease

Stotesbury

Kawadler

Saunders

et al. 2021

Expert Review of Hematology

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Introduction: Over the past decades, neuroimaging studies have clarified that a significant proportion of patients with sickle cell disease (SCD) have functionally significant brain abnormalities. Clinically, structural magnetic resonance imaging (MRI) sequences (T2, FLAIR, diffusion-weighted imaging) have been used by radiologists to diagnose chronic and acute cerebral infarction (both overt and clinically silent), while magnetic resonance angiography and venography have been used to diagnose arteriopathy and venous thrombosis. In research settings, imaging scientists are increasingly applying quantitative techniques to shine further light on underlying mechanisms. Areas covered: From a June 2020 PubMed search of 'magnetic' or 'MRI' and 'sickle' over the previous 5 years, we selected manuscripts on T1-based morphometric analysis, diffusion tensor imaging, arterial spin labeling, T2-oximetry, quantitative susceptibility, and connectivity. Expert Opinion: Quantitative MRI techniques are identifying structural and hemodynamic biomarkers associated with risk of neurological and neurocognitive complications. A growing body of evidence suggests that these biomarkers are sensitive to change with treatments, such as blood transfusion and hydroxyurea, indicating that they may hold promise as endpoints in future randomized clinical trials of novel approaches including hemoglobin F upregulation, reduction of polymerization, and gene therapy. With further validation, such techniques may eventually also improve neurological and neurocognitive risk stratification in this vulnerable population.

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Index of Pain Experience in Sickle Cell Anaemia (IPESCA): development from daily pain diaries and initial findings from use with children and adults with sickle cell anaemia

Cited by 3 publications

References 5 publications

Structural connectivity mediates the relationship between blood oxygenation and cognitive function in sickle cell anemia

Structural connectivity mediates the relationship between blood oxygenation and cognitive function in sickle cell anemia

Considerations for Selecting Cognitive Endpoints and Psychological Patient-Reported Outcomes for Clinical Trials in Pediatric Patients With Sickle Cell Disease

MRI detection of brain abnormality in sickle cell disease

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