Association of iron rim lesions with brain and cervical cord volume in relapsing multiple sclerosis.

OBJECTIVES: In multiple sclerosis (MS), iron rim lesions (IRLs) are indicators of chronic low-grade inflammation and ongoing tissue destruction. The aim of this study was to assess the relationship of IRLs with clinical measures and magnetic resonance imaging (MRI) markers, in particular brain and cervical cord volume. METHODS: Clinical and MRI parameters from 102 relapsing MS patients (no relapses for at least 6 months, no contrast-enhancing lesions) were included; follow-up data obtained after 12 months was available in 49 patients. IRLs were identified on susceptibility-weighted images (SWIs). In addition to standard brain and spinal cord MRI parameters, normalised cross-sectional area (nCSA) of the upper cervical cord was calculated. RESULTS: Thirty-eight patients had at least one IRL on SWI MRI. At baseline, patients with IRLs had higher EDSS scores, higher lesion loads (brain and spinal cord), and lower cortical grey matter volumes and a lower nCSA. At follow-up, brain atrophy rates were higher in patients with IRLs. IRLs correlated spatially with T1-hypointense lesions. CONCLUSIONS: Relapsing MS patients with IRLs showed more aggressive MRI disease characteristics in both the cross-sectional and longitudinal analyses. KEY POINTS: • Multiple sclerosis patients with iron rim lesions had higher EDSS scores, higher brain and spinal cord lesion loads, lower cortical grey matter volumes, and a lower normalised cross-sectional area of the upper cervical spinal cord. • Iron rim lesions are a new lesion descriptor obtained from susceptibility-weighted MRI. Our data suggests that further exploration of this lesion characteristic in regard to a poorer prognosis in multiple sclerosis patients is warranted.

Different patterns of longitudinal brain and spinal cord changes and their associations with disability progression in NMO and MS.

OBJECTIVE: To investigate the longitudinal spinal cord and brain changes in neuromyelitis optica (NMO) and multiple sclerosis (MS) and their associations with disability progression. PATIENTS AND METHODS: We recruited 28 NMO, 22 MS, and 20 healthy controls (HC), who underwent both spinal cord and brain MRI at baseline. Twenty-five NMO and 20 MS completed 1-year follow-up. Baseline spinal cord and brain lesion loads, mean upper cervical cord area (MUCCA), brain, and thalamus volume and their changes during a 1-year follow-up were measured and compared between groups. All the measurements were also compared between progressive and non-progressive groups in NMO and MS. RESULTS: MUCCA decreased significantly during the 1-year follow-up in NMO not in MS. Percentage brain volume changes (PBVC) and thalamus volume changes in MS were significantly higher than NMO. MUCCA changes were significantly different between progressive and non-progressive groups in NMO, while baseline brain lesion volume and PBVC were associated with disability progression in MS. MUCCA changes during 1-year follow-up showed association with clinical disability in NMO. CONCLUSION: Spinal cord atrophy changes were associated with disability progression in NMO, while baseline brain lesion load and whole brain atrophy changes were related to disability progression in MS. KEY POINTS: • Spinal cord atrophy progression was observed in NMO. • Spinal cord atrophy changes were associated with disability progression in NMO. • Brain lesion and atrophy were related to disability progression in MS.

Multiple sclerosis risk loci correlate with cervical cord atrophy and may explain the course of disability.

Genome-wide association studies (GWAS) underscore the genetic basis of multiple sclerosis (MS); however, only few of the newly reported genetic variations relevant in MS have been replicated or correlated for clinical/paraclinical phenotypes such as spinal cord atrophy in independent patient cohorts. We genotyped 141 MS patients for 58 variations reported to reach significance in GWAS. Expanded disability status scale (EDSS) and disease duration (DD) are available from regular clinical examinations. MRI included sagittal high-resolution 3D T1-weighted magnetization-prepared rapid acquisition gradient echo of the cervical cord region used for volumetry. Due dependency of mean upper cervical cord area (MUCCA) with EDSS and/or DD, correction operations were performed compensating for EDSS/DD. We assessed each MS risk locus for possible MUCCA association. We identified twelve risk loci that significantly correlated with MUCCA. For nine loci-BATF, CYP27B1, IL12B, NFKB1, IL7, PLEK, EVI5, TAGAP and nrs669607-patients revealed significantly higher degree of atrophy; TYK2, RGS1 and CLEC16A revealed inverse effects. The weighted genetic risk score over the twelve loci showed significant correlation with MUCCA. Our data reveal a risk gene depending paraclinical/clinical phenotype. Since MUCCA clearly correlates with disability, the candidates identified here may serve as prognostic markers for disability progression.

Mean upper cervical cord area (MUCCA) measurement in long-standing multiple sclerosis: relation to brain findings and clinical disability.

BACKGROUND: The majority of patients with multiple sclerosis (MS) present with spinal cord pathology. Spinal cord atrophy is thought to be a marker of disease severity, but in long-disease duration its relation to brain pathology and clinical disability is largely unknown. OBJECTIVE: Our aim was to investigate mean upper cervical cord area (MUCCA) in patients with long-standing MS and assess its relation to brain magnetic resonance imaging (MRI) measures and clinical disability. METHODS: MUCCA was measured in 196 MS patients and 55 healthy controls using 3DT1-weighted cervical images obtained at 3T MRI. Clinical disability was measured using the Expanded Disability Status Scale (EDSS), Nine-Hole-Peg test (9-HPT), and 25 feet Timed Walk Test (TWT). Stepwise linear regression was performed to assess the association between MUCCA and MRI measures, and between MUCCA and clinical disability. RESULTS: MUCCA was smaller (mean 11.7%) in MS patients compared with healthy controls (72.56±9.82 and 82.24±7.80 mm2 respectively; p<0.001), most prominently in male patients. MUCCA was associated with normalized brain volume, and number of cervical cord lesions. MUCCA was independently associated with EDSS, TWT, and 9-HPT. CONCLUSION: MUCCA was reduced in MS patients compared with healthy controls. It provides a relevant marker for clinical disability in long-standing disease, independent of other MRI measures.

Adaptation and Health: Are Countries with More Climate-sensitive Health Sectors More Likely to Receive Adaptation Aid?

Climate change poses a severe challenge for many developing countries, and the need to adapt has been widely recognized. Public health is one of the sectors where adaptation is necessary, as a warming climate likely affects general health conditions, the spread of various diseases, etc. Some countries are more affected by such climatic challenges, as their climate sensitivity-both to health-related issues and to climate change in general-is higher. This study examines whether more climate-sensitive countries are more likely to receive support from donors through the relatively new channel of adaptation aid, with a particular focus on the health sector. To investigate this relationship, this study proposes and operationalizes a new indicator to capture climate sensitivity of countries' health sectors. The results, however, indicate that climate sensitivity does not matter for adaptation aid allocation. Instead, adaptation aid to a large degree follows development aid. In light of the promises repeatedly made by donors in the climate negotiations that adaptation aid should go to the most vulnerable, developing countries should push for a different allocation mechanism of adaptation aid in future negotiation rounds.

Homogeneous application of imaging criteria in a multicenter trial supported by investigator training: A report from the WAKE-UP study.

BACKGROUND AND PURPOSE: WAKE-UP is a randomized, placebo-controlled trial of thrombolysis in stroke with unknown time of symptom onset using magnetic resonance imaging criteria to determine patients' eligibility. As it is a multicenter trial, homogeneous interpretation of criteria is an important contributor to the trial's success. We describe the investigator image training as well as results of the quality control done by the central image reading board (CIRB). METHODS: Investigators at local centers were given an imaging manual and passed a software-based image training prior to being allowed to judge images in the trial. Throughout the trial, the CIRB gave feedback to recruiting centers in cases of disagreement regarding a patient's randomization. We evaluated the investigators performance in the image training and analyzed results of this quality control from the first 1069 screened patients. Additionally, we obtained feedback from investigators regarding their experiences with the trial. RESULTS: Four-hundred-and-sixty physicians from eight European countries took part in the image training, of whom 436 (95%) successfully completed it. In the trial, agreement rates between the local investigators and members of the CIRB were high for the presence of an acute ischemic lesion (94%, κ = 0.87) as well as for the judgment of infarct extent (93%, κ = 0.87). Agreement for the criterion of DWI-FLAIR mismatch was 74%, κ = 0.60. The majority of investigators reported that the DWI-FLAIR mismatch was the hardest imaging criterion to evaluate. Ninety-one percent of investigators who responded to our survey stated that the image training specifically increased their confidence when assessing the DWI-FLAIR mismatch. CONCLUSIONS: Despite its multicenter design, the WAKE-UP study has demonstrated a high level of homogeneity amongst raters in interpreting the various imaging criteria for patient randomization, including the novel criterion of DWI-FLAIR mismatch. Systematic image training increased the confidence of investigators in applying imaging criteria.

Central Atrophy Early in Multiple Sclerosis: Third Ventricle Volumetry versus Planimetry.

BACKGROUND AND PURPOSE: Cerebral atrophy has been suggested to be a reliable magnetic resonance imaging (MRI) predictor of subsequent disability in all stages of multiple sclerosis (MS). However, no accepted methodology for routine clinical use exists to date. We sought an easy to apply and fast technique to evaluate cerebral ventricular volume in patients with MS with similar accuracy as a semiautomatic volumetric method. METHODS: The study included 104 patients, 61 diagnosed with MS and 43 with clinically isolated syndrome. In addition, 30 healthy controls were enrolled. Physical disability was assessed with the expanded disability status scale and cognitive disability with the Multiple Sclerosis Inventory Cognition (MUSIC) test. All subjects received standardized 3-dimensional (3D) MR-imaging on a 3 T scanner. Third ventricle volume (3VV) was obtained from 3D T1-weighted images using a semiautomated technique, and compared against planimetric assessment of the width of the third ventricle aligned (a3VW) and unaligned (u3VW) to anatomical landmarks. RESULTS: a3VW was obtained within seconds with excellent intra- and interrater agreement, and outperformed volumetric measurements regarding the differentiation of MS patients from healthy controls. a3VW had the strongest correlations with 3VV (r = .78, P < .001) and showed moderate inverse correlation with MUSIC cognition score (r = -.310, P < .005). CONCLUSIONS: a3VW is a time-effective and robust biomarker that has strong correlations with volumetric measurements and can be established as standard in the MRI quantification of central brain atrophy in patients with early MS.

Relevance of early cervical cord volume loss in the disease evolution of clinically isolated syndrome and early multiple sclerosis: a 2-year follow-up study.

Upper cervical cord area (UCCA) atrophy is a prognostic marker for clinical progression in longstanding multiple sclerosis (MS). The objectives of the study were to quantify UCCA atrophy and evaluate its impact in clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS); to compare converting CIS patients with stable CIS, and to study changes of UCCA and brain white matter (WM) and grey matter (GM) at 2-year follow-up. 110 therapy-naive patients including 53 CIS [6 ± 6 months after symptom onset (SO)] and 57 early RRMS (SO: 12 ± 9 months) underwent sagittal 3D-T1w brain MR (3T). Mean UCCA (C1-C3 level), WM and GM, disability status (EDSS), pyramidal and sensory functional scores, motoric fatigue were assessed at baseline (BL), 12 and 24 months. Volumes were compared with 34 age- and gender-matched healthy controls to assess atrophy. RRMS (78.1 ± 8.7 mm2, p = 0.011) and converting CIS (77.3 ± 8.0 mm2, p = 0.046) presented with baseline UCCA atrophy, when compared with controls (82.7 ± 5.2 mm2), but not stable CIS (82.6 ± 7.4 mm2, p = 0.998). Baseline WM was reduced in RRMS (509.3 ± 25.7 ml vs. CONTROLS: 528.4 ± 24.1 ml, p = 0.032). Baseline UCCA correlated negative with muscular weakness and fatigability in all patients and RRMS. EDSS exceeding 3 was associated with lower baseline UCCA. Longitudinal atrophy rates were higher in UCCA than in brain volumes. Early cervical cord atrophy in CIS and RRMS was confirmed and may represent a potential new risk marker for conversion from CIS to MS. Baseline atrophy and atrophy change rates were higher in UCCA compared to WM and GM, suggesting that cervical cord volumetry might become an additional MRI marker relevant in future clinical studies in CIS and early MS.

Multi-criterial patient positioning based on dose recalculation on scatter-corrected CBCT images.

BACKGROUND AND PURPOSE: Our aim was to evaluate the feasibility and potential advantages of dose guided patient positioning based on dose recalculation on scatter corrected cone beam computed tomography (CBCT) image data. MATERIAL AND METHODS: A scatter correction approach has been employed to enable dose calculations on CBCT images. A recently proposed tool for interactive multicriterial dose-guided patient positioning which uses interpolation between pre-calculated sample doses has been utilized. The workflow was retrospectively evaluated for two head and neck patients with a total of 39 CBCTs. Dose-volume histogram (DVH) parameters were compared to rigid image registration based isocenter corrections (clinical scenario). RESULTS: The accuracy of the dose interpolation was found sufficient, facilitating the implementation of dose guided patient positioning. Compared to the clinical scenario, the mean dose to the parotid glands could be improved for 2 out of 5 fractions for the first patient while other parameters were preserved. For the second patient, the mean coverage over all fractions of the high dose PTV could be improved by 4%. For this patient, coverage improvements had to be traded against organ at risk (OAR) doses within their clinical tolerance limits. CONCLUSIONS: Dose guided patient positioning using in-room CBCT data is feasible and offers increased control over target coverage and doses to OARs.

Ultrahigh-field MPRAGE Magnetic Resonance Angiography at 7.0 T in patients with cerebrovascular disease.

OBJECTIVES: Time-of-flight (TOF) magnetic-resonance-angiography (MRA) identifies vessel pathology in cerebrovascular disease. At 7.0 T, the clinical performance of TOF-MRA is constrained owing to radio frequency power deposition. We studied the diagnostic value of whole-brain MPRAGE-based MRA as an alternative imaging technique in comparison to the clinical standard 3.0 T TOF-MRA. METHODS: Patients with stroke and/or moya-moya disease were included. TOF-MRA was performed at 3.0 T and MPRAGE-MRA at 7.0 T. Two radiologists rated the MRAs independently for overall quality and local arterial segment visualization. The identification of steno-occlusive pathology was reported for each protocol. RESULTS: In 18 patients (9 females; 6 patients with moya-moya) 7.0 T MPRAGE-MRA provided better overall image quality and better distinction of small structures compared to 3.0 T TOF-MRA. These findings were pronounced in the proximal segments of the anterior cerebral artery (A1), middle cerebral artery (M1, M2), posterior cerebral artery (P1) and the posterior communicating artery. Seven steno-occlusive findings were identified by both imaging protocols. CONCLUSIONS: For clinical studies using ultrahigh field MRI, 7.0 T MPRAGE-MRA provides a suitable alternative to TOF-MRA imaging to identify brain vessel pathology and yields simultaneous structural brain imaging within clinically feasible acquisition times.

Differential patterns of spinal cord and brain atrophy in NMO and MS.

OBJECTIVE: To investigate spinal cord and brain atrophy in neuromyelitis optica (NMO), and its relationship with other MRI measurements and clinical disability, compared with patients with multiple sclerosis (MS) and healthy controls (HC). METHODS: We recruited 35 patients with NMO, 35 patients with MS, and 35 HC, who underwent both spinal cord and brain MRI. Mean upper cervical cord area (MUCCA), brain parenchymal fraction (BPF), gray matter fraction (GMF), white matter fraction (WMF), and spinal cord and brain lesion loads were measured and compared among groups. Multivariate associations between MUCCA and brain volume measurement and clinical variables were assessed by partial correlations and multiple linear regression. RESULTS: Patients with NMO showed smaller MUCCA than HC (p = 0.004), and patients with MS had a trend of smaller MUCCA compared to HC (p = 0.07), with no significant difference between the patient groups. Patients with NMO showed lower BPF than HC, and patients with MS had lower BPF and GMF than patients with NMO. In NMO, MUCCA was correlated with Expanded Disability Status Scale score (EDSS), number of relapses, and total spinal cord lesion length, while in MS, MUCCA was correlated with WMF and EDSS. MUCCA was the only independent variable for predicting clinical disability measured by EDSS in NMO (R(2) = 0.55, p < 0.001) and MS (R(2) = 0.17, p = 0.013). CONCLUSION: NMO showed predominately spinal cord atrophy with mild brain atrophy, while MS demonstrated more brain atrophy, especially in the gray matter. MUCCA is the main MRI-derived parameter for explaining clinical disability in NMO and MS, and may serve as a potential biomarker for further clinical trials, especially in NMO.