Davide Poggiali

The Parallel Analysis of Phase Sensitive Inversion Recovery (PSIR) and Double Inversion Recovery (DIR) Images Significantly Improves the Detection of Cortical Lesions in Multiple Sclerosis (MS) since Clinical Onset

Background Double inversion recovery (DIR) detects only a minority (<20%) of cortical lesions (CL) in multiple sclerosis (MS). Phase-sensitive inversion recovery (PSIR) was suggested to be substantially superior to DIR in the detection of cortical lesions (CL). These two sequences might be complementary. Objectives To analyze CL frequency and type in MS patients having different disease duration and disability, including patients at clinical onset, and to discern more correctly the artifacts, by combining DIR and PSIR images. Patients and Methods 40 patients were enrolled in the study: 10 clinically isolated syndrome/early relapsing remitting MS (CIS/eRRMS), 24 relapsing remitting MS (RRMS), 6 secondary progressive MS (SPMS). DIR and PSIR images were jointly used to classify lesions as purely intracortical (IC), leukocortical (LC) and juxtacortical (JC). Results PSIR disclosed CL in 100% of the patients and was capable of identifying more than four times lesions (455.5%, p<0.00001), especially IC (mean numbers: 36.5 in CIS/eRRMS, 45.0 in RRMS and 52.3 in SPMS) and LC (mean numbers: 10.9 in CIS/eRRMS, 20.1 in RRMS and 25.3 in SPMS), compared to DIR (p<0.00001). CL number was significantly higher in SPMS compared to RRMS (p<0.0001). Artifacts were more accurately identified by comparing the two sequences. Conclusions Our study confirms the higher ability of PSIR in disclosing and classifying CL. The presence of CL in all CIS patients further points out the relevance of cortical pathology in MS. Whether the parallel analysis of DIR and PSIR images may be useful for diagnostic purposes, especially when a diagnosis of MS is suspected but not confirmed by routine MRI, needs to be evaluated in larger patient series. The analysis of the cortex by DIR and PSIR may also allow a better stratification of the patients for prognostic and counseling purposes, as well as for their inclusion in clinical studies.

Cortical relapses in multiple sclerosis

Background: Multiple sclerosis (MS) is a white and grey matter disease of the central nervous system (CNS). It is recognized that cortical damage (i.e. focal lesions and atrophy) plays a role in determining the accumulation of physical and cognitive disability that is observed in patients with progressive MS. To date, an association of cortical lesions with clinical relapses has not been described. Results: We report clinical and magnetic resonance imaging (MRI) findings of five relapsing–remitting MS (RRMS) patients who had clinical relapses characterized by the acute appearance of cortical symptoms, due to the development of large, snake-like, cortical inflammatory lesions. Symptoms were: acute Wernicke’s aphasia mimicking stroke; agraphia with acalculia, not associated to a motor deficit nor linguistic disturbance; hyposthenia of the left arm, followed by muscle twitching of the hand, spreading to arm and face; acute onset of left lower limb paroxysmal hypertonia; and temporal lobe status epilepticus, with psychotic symptoms. Conclusions: Cortical relapses may occur in MS. MRI examination in MS should include sequences, such as double inversion recovery (DIR) or phase sensitive inversion recovery (PSIR), that are aimed at visualizing cortical lesions, especially in the presence of symptoms of cortical dysfunction. Our observation further stresses and extends the clinical relevance of cortical pathology in MS.

MRI-detectable cortical lesions in the cerebellum and their clinical relevance in multiple sclerosis

Background: The demonstration of cortical lesions (CL) in the cerebellum by magnetic resonance imaging (MRI) is hampered by technical and anatomical constraints. Objective: To investigate the occurrence of cerebellar CL and their correlation with cerebellar-related disability by combining Double Inversion Recovery (DIR) and Phase Sensitive Inversion Recovery (PSIR) MRI images in multiple sclerosis (MS) patients. Material and methods: 40 MS patients (10 CIS/eRRMS, 24 RRMS, 6 SPMS), having a wide range of disability and disease duration, were enrolled. DIR and PSIR images were obtained with a 3T-MRI. Results: Cerebellar white matter lesions (WML) and/or CL were observed in 33/40 patients (82.5%) among which 14/40 had only CL. CL were demonstrated in 26/40 patients by DIR and in 31/40 by PSIR, and their number increased from CIS/eRRMS to SPMS. PSIR disclosed a significantly higher number of CL compared to DIR (RRMS: p=0.0008; SPMS: p=0.002). CL number correlates with the cerebellar Expanded Disability Status Score (EDSS) score (r=0.72, p<0.0001). No correlation was observed between supra-tentorial and cerebellar CL. Conclusions: CL are detected by PSIR in the cerebellum of the majority of MS patients, are more than WML, increase with disease progression and strongly correlate with the cerebellar EDSS. Thus, the observation of CL in the cerebellum of MS at clinical onset might be useful for prognostic and therapeutic aims.

Analytical and experimental FWHM of a gamma camera: theoretical and practical issues

Introduction. It is well known that resolution on a gamma camera varies as a function of distance, scatter and the camera’s characteristics (collimator type, crystal thickness, intrinsic resolution etc). Manufacturers frequently provide only a few pre-calculated resolution values (using a line source in air, 10–15 cm from the collimator surface and without scattering). However, these are typically not obtained in situations resembling a clinical setting. From a diagnostic point of view, it is useful to know the expected resolution of a gamma camera at a given distance from the collimator surface for a particular setting in order to decide whether it is worth scanning patients with “small lesion” or not. When dealing with absolute quantification it is also mandatory to know precisely the expected resolution and its uncertainty in order to make appropriate corrections. Aim. Our aims are: to test a novel mathematical approach, the cubic spline interpolation, for the extraction of the full width at half maximum (FWHM) from the acquisition of a line source (experimental resolution) also considering measurement uncertainty; to compare it with the usually adopted methods such as the gaussian approach; to compare it with the theoretical resolution (analytical resolution) of a gamma camera at different distances; to create a web-based educational program with which to test these theories. Methods. Three mathematical methods (direct calculation, global interpolation using gaussian and local interpolation using splines) for calculating FWHM from a line source (planar scintigraphy) were tested and compared. A NEMA Triple Line Source Phantom was used to obtain static images both in air and with different scattering levels. An advanced, open-source software (MATLAB/Octave and PHP based) was created “ad hoc” to obtain and compare FWHM values and relative uncertainty. Results and Conclusion. Local interpolation using splines proved faster and more reliable than the usually-adopted Gaussian interpolation. The proposed freely available software proved effective in assessing both FWHM and its uncertainty.

Trans-synaptic degeneration in the optic pathway. A study in clinically isolated syndrome and early relapsing-remitting multiple sclerosis with or without optic neuritis

Objective Increasing evidence suggest that neuronal damage is an early and diffuse feature of Multiple Sclerosis (MS) pathology. Analysis of the optic pathway may help to clarify the mechanisms involved in grey matter damage in MS. Purpose of our study was to investigate the relationship between inflammation and neurodegeneration and to achieve evidence of trans-synaptic degeneration in the optic pathway in MS at clinical onset. Methods 50 clinically isolated syndromes/early relapse-onset MS (CIS/eRRMS) with mean disease duration of 4.0±3.5 months, 28 MRI healthy controls (HC) and 31 OCT-HC were studied. Ten patients had optic neuritis at presentation (MSON+), 40 presented with other symptoms (MSON-). MRI examination included 3D-T1, 3D-FLAIR and 3D-DIR sequences. Global cortical thickness (gCTh), pericalcarin CTh (pCTh) and white matter volume (WMV) were analysed by means of Freesurfer on 3D-T1 scans. Optic radiation morphology (OR) and volume (ORV) were reconstructed on the base of the Jülich’s Atlas. White matter lesion volume (WMLV), OR-WMLV and percent WM damage (WMLV/WMV = WMLV% and OR-WMLV/ORV = ORWMLV%) were obtained by 3D-FLAIR image segmentation. 3D-DIR sequences were applied to identify inflammatory lesions of the optic nerve. Optic coherence tomography (OCT) protocol included the analysis of global peripapillary retinal nerve fiber layer (g-RNFL) and the 6 fundus oculi’s sectors (temporal, T-RNFL; temporal superior, TS-RNFL; nasal superior, NS-RNFL; nasal, N-RNFL; nasal inferior, NI-RNFL, temporal inferior, TI-RNFL). The retina of both eyes was analyzed. The eyes of ON+ were further divided into affected (aON+) or not (naON+). Results No difference in CTh was found between CIS/eRRMS and HC, and between MSON+ and MSON-. Moreover, MSON+ and MSON- did not differ for any WM lesion load parameter. The most significant correlations between RNFL thickness and optic radiation WM pathology were found in MSON+. In these patients, the temporal RNFL inversely correlated to ipsilateral optic radiation WM lesion load (T-RNFL: r -0.7, p<0.05; TS-RNFL: r -0.7, p<0.05), while nasal RNFL inversely correlated to contralateral optic radiation WM lesion load (NI: r -0.8, p<0.01; NS-RNFL: r -0.8, p<0.01). Conclusions Our findings suggest that in MSON+ the optic pathway is site of a diffuse pathological process that involves both directly and via trans-synaptic degeneration the RNFL.

Effects of disease modifying therapies on brain and grey matter atrophy in relapsing remitting multiple sclerosis

BackgroundProgressive brain atrophy is a major feature of multiple sclerosis (MS) pathology and is actually considered a major determinant of the progressive accumulation of physical and cognitive disability in MS patients. Although brain atrophy may have different pathological substrates, several lines of evidence suggest that in disease modifying drug (DMD)-treated MS patients, the higher is the anti-inflammatory effect of the DMD the lower is the progression of brain volume loss, grey matter atrophy and the accumulation of disability.Areas coveredMagnetic resonance imaging (MRI)-based measurements of inflammation (focal white matter and grey matter lesions) and neurodegeneration (decrease in brain volume, cortical and deep grey matter atrophy) are currently included among the primary or secondary end-points of Phase II and III randomized clinical trials (RCT). This review summarizes literature data on the effects of DMDs on either whole brain or grey matter atrophy emerged from RCT and from post-marketing studies.CommentaryTaken all together, literature data show that DMDs are capable to reduce significantly brain inflammation and, although with different degrees of effectiveness, to slow down global brain and/or grey matter atrophy progression. Moreover, the comparison between early and delayed treatments clearly points out that the most relevant effects on brain and grey matter atrophy are observed when DMDs are initiated in the very early disease phases.

Raincloud plots: a multi-platform tool for robust data visualization

Across scientific disciplines, there is a rapidly growing recognition of the need for more statistically robust, transparent approaches to data visualization. Complementary to this, many scientists have called for plotting tools that accurately and transparently convey key aspects of statistical effects and raw data with minimal distortion. Previously common approaches, such as plotting conditional mean or median barplots together with error-bars have been criticized for distorting effect size, hiding underlying patterns in the raw data, and obscuring the assumptions upon which the most commonly used statistical tests are based. Here we describe a data visualization approach which overcomes these issues, providing maximal statistical information while preserving the desired ‘inference at a glance’ nature of barplots and other similar visualization devices. These “raincloud plots” can visualize raw data, probability density, and key summary statistics such as median, mean, and relevant confidence intervals in an appealing and flexible format with minimal redundancy. In this tutorial paper, we provide basic demonstrations of the strength of raincloud plots and similar approaches, outline potential modifications for their optimal use, and provide open-source code for their streamlined implementation in R, Python and Matlab ( ). Readers can investigate https://github.com/RainCloudPlots/RainCloudPlots the R and Python tutorials interactively in the browser using Binder by Project Jupyter.

Enlarged Virchow Robin spaces associate with cognitive decline in multiple sclerosis

The clinical significance of Virchow Robin spaces (VRS) in inflammatory brain disorders, especially in multiple sclerosis (MS), is still undefined. We analysed enlarged VRS (eVRS) by means of phase sensitive inversion recovery (PSIR) MRI sequence and investigated their association with inflammation or brain atrophy, and to clinical or physical disability. Forty-three MS patients (21 clinically isolated syndrome suggestive of MS [CIS], 15 RRMS, 7 progressive [PMS]) and 10 healthy controls (HC) were studied. 3DT1, 3DFLAIR and 2DPSIR images were obtained with a 3T MRI scanner. eVRS number and volume were calculated by manual segmentation (ITK-SNAP). Freesurfer was used to assess brain parenchymal fraction (BPF). All patients underwent clinical (EDSS) and cognitive (Rao’s BRB and DKEFS) evaluation. eVRS number and volume resulted significantly higher on 2D-PSIR compared to both 3D-T1 (p<0.001) and 3D-FLAIR (p<0.001) and were significantly increased in CIS compared to HC (p<0.05), in PMS and RRMS compared to CIS (p<0.001) and in male versus female patients (p<0.05). eVRS volume increased significantly with disease duration (r = 0.6) but did not correlate with EDSS. eVRS significantly correlated with SPARTd (r = -0.47) and DKEFSfs (r = -0.46), especially when RRMS and PMS were merged in a single group (r = 0.89, p = 0.002 and r = 0.66, p = 0.009 respectively), while no correlation was found with BPF (r = 0.3), gadolinium-enhancing lesions (r = 0.2) and WMT2 lesion volume (r = 0.2). 2DPSIR allowed the detection of an impressive higher number of eVRS compared to 3DT1 and 3DFLAIR. eVRS associate with SPARTd and DKEFSfs failure in relapse-onset MS, suggesting they may contribute to cognitive decline in MS.