Myeloid cell iron uptake pathways and paramagnetic rim formation in multiple sclerosis.

In multiple sclerosis (MS), sustained inflammatory activity can be visualized by iron-sensitive magnetic resonance imaging (MRI) at the edges of chronic lesions. These paramagnetic rim lesions (PRLs) are associated with clinical worsening, although the cell type-specific and molecular pathways of iron uptake and metabolism are not well known. We studied two postmortem cohorts: an exploratory formalin-fixed paraffin-embedded (FFPE) tissue cohort of 18 controls and 24 MS cases and a confirmatory snap-frozen cohort of 6 controls and 14 MS cases. Besides myelin and non-heme iron imaging, the haptoglobin-hemoglobin scavenger receptor CD163, the iron-metabolizing markers HMOX1 and HAMP as well as immune-related markers P2RY12, CD68, C1QA and IL10 were visualized in myeloid cell (MC) subtypes at RNA and protein levels across different MS lesion areas. In addition, we studied PRLs in vivo in a cohort of 98 people with MS (pwMS) via iron-sensitive 3 T MRI and haptoglobin genotyping by PCR. CSF samples were available from 38 pwMS for soluble CD163 (sCD163) protein level measurements by ELISA. In postmortem tissues, we observed that iron uptake was linked to rim-associated C1QA-expressing MC subtypes, characterized by upregulation of CD163, HMOX1, HAMP and, conversely, downregulation of P2RY12. We found that pwMS with [Formula: see text] 4 PRLs had higher sCD163 levels in the CSF than pwMS with [Formula: see text] 3 PRLs with sCD163 correlating with the number of PRLs. The number of PRLs was associated with clinical worsening but not with age, sex or haptoglobin genotype of pwMS. However, pwMS with Hp2-1/Hp2-2 haplotypes had higher clinical disability scores than pwMS with Hp1-1. In summary, we observed upregulation of the CD163-HMOX1-HAMP axis in MC subtypes at chronic active lesion rims, suggesting haptoglobin-bound hemoglobin but not transferrin-bound iron as a critical source for MC-associated iron uptake in MS. The correlation of CSF-associated sCD163 with PRL counts in MS highlights the relevance of CD163-mediated iron uptake via haptoglobin-bound hemoglobin. Also, while Hp haplotypes had no noticeable influence on PRL counts, pwMS carriers of a Hp2 allele might have a higher risk to experience clinical worsening.

Cerebrospinal fluid-related tissue damage in multiple sclerosis patients with iron rim lesions.

BACKGROUND: In multiple sclerosis (MS), iron rim lesions (IRLs) are associated with pronounced tissue damage, higher disease severity and have been suggested as an imaging marker of chronic active inflammation behind the blood-brain barrier indicating progression. Furthermore, chronic intrathecal compartmentalized inflammation has been suggested to be a mediator of a cerebrospinal fluid (CSF)-related tissue damage. OBJECTIVE: To investigate CSF markers of intrathecal inflammation in patients with at least one IRL compared to patients without IRLs and to investigate tissue damage in lesions and normal-appearing white matter (NAWM) with proximity to CSF spaces. METHODS: A total of 102 patients (51 with at least 1 IRL and 51 age-/sex-matched patients without IRL) scanned with the same 3T magnetic resonance imaging (MRI) and having CSF analysis data were included. RESULTS: Patients with at least one IRL had higher disability scores, higher lesion volumes, lower brain volumes and a higher intrathecal immunoglobulin G (IgG) synthesis. Apparent diffusion coefficient (ADC) values in IRLs were higher compared to non-IRLs. We observed a negative linear correlation of ADC values in all tissue classes and distance to CSF, which was stronger in patients with high IgG quotients. CONCLUSION: IRLs are associated with higher intrathecal IgG synthesis. CSF-mediated intrathecal smouldering inflammation could explain a CSF-related gradient of tissue damage.

Multiple sclerosis iron rim lesions are linked to impaired cervical spinal cord integrity using the T1/T2-weighted ratio.

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), iron rim lesions (IRLs) are characterized by pronounced tissue matrix damage. The T1/T2-weighted (T1/T2w) ratio represents a postprocessing MRI approach to investigate tissue integrity, but studies investigating spinal cord pathology are missing until now. The aim of this study was to characterize tissue integrity using the T1/T2w ratio in lesions and the normal-appearing white and gray matter (NAWM, NAGM) in the spinal cord and brain in MS patients with and without brain IRLs. METHODS: Forty MS patients (20 patients with at least one brain IRL and 20 age- and sex-matched patients without IRLs) were included. Normalized cross-sectional area (nCSA) of the upper cervical cord was calculated in addition to T1/T2w values and standard brain and spinal cord MRI parameters. RESULTS: Patients with IRLs had higher disability scores, a smaller nCSA, and a higher cervical T2 lesion volume. T1/T2w values of brain IRLs were significantly lower compared to non-IRLs (p < .001). Furthermore, T1/T2w values of lesions were significantly lower compared to the NAGM and NAWM, both in the brain and the spinal cord (p < .05 for all comparisons). T1/T2w values of the NAGM and NAWM in the brain and spinal cord did not statistically differ between the IRL group and the non-IRL group. CONCLUSION: IRLs constitute an imaging marker of disease severity. T1/T2w ratio maps represent an interesting technique to capture diffuse tissue properties. Calculation of T1/T2w ratio maps of the spinal cord might provide additional insights into the pathophysiological processes of MS.

Exploring (peri-) lesional and structural connectivity tissue damage through T1/T2-weighted ratio in iron rim multiple sclerosis lesions.

OBJECTIVE: In multiple sclerosis (MS), iron rim lesions (IRLs) on magnetic resonance imaging (MRI) are associated with pronounced intralesional tissue damage. The aim of this study was to investigate (peri-)lesional and structural connectivity tissue damage in IRLs compared to non-IRLs. MATERIAL AND METHODS: MRI was acquired on a 3 T system. Tissue integrity was assessed using the T1/T2-weighted (T1/T2w) ratio. Furthermore, we assessed the impact on structural network connectivity accounting for differences in lesion volumes and T1/T2w values. RESULTS: Seventy-six patients (38 with at least one IRL and 38 age- and sex-matched patients without IRLs) were included. In the IRL-group, T1/T2w ratios of IRLs were significantly lower compared to non-IRLs (p < 0.05). When comparing the T1/T2w ratios in non-IRLs between the IRL-group and non-IRL group, there was no significant difference (p = 0.887). We observed a centrifugal decrease in microstructural damage from lesions to the perilesional white matter. In the IRL-group, T1/T2w ratios in the perilesional white matter 3-8 mm distant to the lesion were significantly lower in IRLs compared to non-IRLs. We found no significant differences in the amount of network disruption between both lesion types (p = 0.122). CONCLUSION: T1/T2w represents an interesting candidate to capture a pronounced intra- and perilesional tissue damage of IRLs. However, our preliminary results suggest that a pronounced tissue damage might not result in a higher disruption to structural connectivity networks in IRLs.

Impact of disease-modifying therapies on evolving tissue damage in iron rim multiple sclerosis lesions.

We investigated the impact of disease-modifying therapies (DMTs) on the evolving tissue damage in iron rim multiple sclerosis lesions using a novel post-processing magnetic resonance imaging (MRI) approach, the T1/T2 ratio. In this study, on baseline and 1-year follow-up, T1/T2 ratios of iron rim lesions (IRLs) in patients starting DMT (dimethyl fumarate, fingolimod, ocrelizumab) did not statistically differ compared to patients without DMT. At the second follow-up, T1/T2 ratios were significantly lower in IRLs in patients without DMT (p = 0.002), suggesting that DMTs have a beneficial delayed effect on lesion evolution and tissue matrix damage in IRLs.

Spatial distribution of multiple sclerosis iron rim lesions and their impact on disability.

BACKGROUND: In multiple sclerosis (MS), iron rim lesions (IRLs) on magnetic resonance imaging (MRI) have been suggested as an imaging marker of disease progression. However, the exact mechanisms how they contribute to disability are yet not completely known. Strategic lesion location may be an important factor concerning the impact of focal lesions on clinical disability. Therefore, the aim of this study was to investigate the spatial distribution of IRLs compared to non-IRLs and their impact on disability. METHODS: We retrospectively identified 67 patients with at least one IRL on MRI and 67 age- and sex-matched patients without IRLs. We compared the spatial distribution of lesions between both groups and between IRLs and non-IRLs in patients with IRLs. Furthermore, we assessed the relationship between lesion localisation and disability on a voxel-by-voxel basis and investigated the impact on structural network disruptions. RESULTS: Patients with IRLs had higher disability scores (median Expanded Disability Status Scale score (range): 3.0 (0 - 8.5) versus 1.5 (0 - 6.5); p = 0.001; median pyramidal functional system score (range): 1.0 (0 - 5) versus 0 (0 - 4); p = 0.003), significantly lower brain volumes (mean normal-appearing grey matter volume: 749.66 ± 60.58 versus 785.83 ± 53.71 mL; mean normal-appearing white matter volume: 723.58 ± 60.13 versus 753.25 ± 69.61 mL; mean deep grey matter volume: 33.21 ± 4.19 versus 35.85 ± 4.89 mL; p < 0.05 for all comparisons) and a significantly higher total T2 lesion volume (mean: 9.96 ± 11.6 versus 4.31 ± 8.9 mL; p < 0.001). We found no neuroanatomical regions that were more often affected by IRLs. Furthermore, comparing the overall network disruption in the IRL group, IRLs caused less network disruption/mL lesion size compared to non-IRLs (1.54% / mL versus 2.0% / mL; p < 0.05). CONCLUSION: IRLs are associated with higher disability scores. However, our results suggest that a higher disability is not explained by the sheer topography of IRLs or their network disruption.

MRI predictors for the conversion from contrast-enhancing to iron rim multiple sclerosis lesions.

BACKGROUND: In multiple sclerosis (MS), iron rim lesions (IRLs) are characterized by progressive tissue matrix damage. Therefore, early identification could represent an interesting target for therapeutic intervention to minimize evolving tissue damage. The aim of this study was to identify magnetic resonance imaging (MRI) parameters predicting the conversion from contrast-enhancing to IRLs. METHODS: We retrospective identified MS patients scanned on the same 3 T MRI system presenting at least one supratentorial contrast-enhancing lesion (CEL) and a second MRI including susceptibility-weighted images after at least 3 months. On baseline MRI, pattern of contrast-enhancement was categorized as "nodular" or "ring-like", apparent diffusion coefficient (ADC) maps were assessed for the presence of a peripheral hypointense rim. Lesion localization, quantitative volumes (ADC, lesion volume) and the presence of a central vein were assessed. RESULTS: Eighty-nine acute contrast-enhancing lesions in 54 MS patients were included. On follow-up, 16/89 (18%) initially CELs converted into IRLs. CELs that converted into IRLs were larger and demonstrated significantly more often a ring-like contrast-enhancement pattern and a peripheral hypointense rim on ADC maps. Logistic regression model including the covariables pattern of contrast-enhancement and presence of a hypointense rim on ADC maps showed the best predictive performance (area under the curve = 0.932). DISCUSSION: The combination of a ring-like contrast-enhancement pattern and a peripheral hypointense rim on ADC maps has the ability to predict the evolution from acute to IRLs. This could be of prognostic value and become a target for early therapeutic intervention to minimize the associated tissue damage.

Long-term dynamics of multiple sclerosis iron rim lesions.

BACKGROUND: Several studies have pointed out that seemingly chronic multiple sclerosis (MS) lesions may also be in inflammatory states. In pathological studies, up to 40% of chronic MS lesions are characterized as "chronic active" or "smoldering" lesions that are characterized by a rim of iron-laden proinflammatory macrophages/microglial cells at the lesion edge with low-grade continuous myelin breakdown. In vivo, these lesions can be visualized as "iron rim lesions" (IRLs) on susceptibility-weighted imaging (SWI). The aim of this study was to investigate the long-term dynamics of IRLs in vivo for a more detailed evolution of dynamic lesion volume changes occurring over time. METHODS: We retrospectively identified patients with MS who were followed for at least 36 months (up to 72 months) and underwent at least an annual MRI on the same 3 Tsystem. Using Voxel-Guided Morphometry (VGM) we investigated regional volume changes within lesions and correlated these findings with SWI for the presence of a characteristic hypointense lesion rim. To estimate tissue damage, apparent diffusion coefficient (ADC) values for every lesion at baseline and follow-up MRIs were determined. RESULTS: Forty-three patients were included in the study. Overall, we identified 302 supratentorial non-confluent MS lesions (52 persistent IRLs, nine transient IRLs, 228 non-IRLs and 13 acute contrast-enhancing lesions). During follow-up, persistent IRLs significantly enlarged, whereas non-IRLs showed a tendency to shrink. At baseline MRI, ADC values were significantly higher in persistent IRLs (1.23 × 10-3 mm/s2) compared to non-IRLs (1.01 × 10-3 mm/s2; p < 0.001), but not compared to transient IRLs (1.06 × 10-3 mm/s2; p = 0.15) and contrast-enhancing lesions (1.15 × 10-3 mm/s2; p = 1.0). During follow-up, ADC values significantly increased more often in persistent IRLs compared to all other lesion types (p < 0.0001). CONCLUSIONS: Our long-term data demonstrate that persistent IRLs enlarge during disease duration, whereas non-IRLs show a tendency to shrink. Furthermore, IRLs are associated with sustained tissue damage, supporting the notion that IRLs could represent a new imaging biomarker in MS.

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.

The neuroradiology of progressive multifocal leukoencephalopathy: a clinical trial perspective.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the CNS caused by the JC virus, which infects white and grey matter cells and leads to irreversible demyelination and neuroaxonal damage. Brain MRI, in addition to the clinical presentation and demonstration of JC virus DNA either in the CSF or by histopathology, is an important tool in the detection of PML. In clinical practice, standard MRI pulse sequences are utilized for screening, diagnosis and monitoring of PML, but validated imaging-based outcome measures for use in prospective, interventional clinical trials for PML have yet to be established. We review the existing literature regarding the use of MRI and PET in PML and discuss the implications of PML histopathology for neuroradiology. MRI not only demonstrates the localization and extent of PML lesions, but also mirrors the tissue destruction, ongoing viral spread, and resulting inflammation. Finally, we explore the potential for imaging measures to serve as an outcome in PML clinical trials and provide recommendations for current and future imaging outcome measure development in this area.

Intrathecal activation of CD8+ memory T cells in IgG4-related disease of the brain parenchyma.

IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder signified by aberrant infiltration of IgG4-restricted plasma cells into a variety of organs. Clinical presentation is heterogeneous, and pathophysiological mechanisms of IgG4-RD remain elusive. There are very few cases of IgG4-RD with isolated central nervous system manifestation. By leveraging single-cell sequencing of the cerebrospinal fluid (CSF) of a patient with an inflammatory intracranial pseudotumor, we provide novel insights into the immunopathophysiology of IgG4-RD. Our data illustrate an IgG4-RD-associated polyclonal T-cell response in the CSF and an oligoclonal T-cell response in the parenchymal lesions, the latter being the result of a multifaceted cell-cell interaction between immune cell subsets and pathogenic B cells. We demonstrate that CD8+ T effector memory cells might drive and sustain autoimmunity via macrophage migration inhibitory factor (MIF)-CD74 signaling to immature B cells and CC-chemokine ligand 5 (CCL5)-mediated recruitment of cytotoxic CD4+ T cells. These findings highlight the central role of T cells in sustaining IgG4-RD and open novel avenues for targeted therapies.

TSPO PET imaging of natalizumab-associated progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a severe infection of the CNS caused by the polyomavirus JC that can occur in multiple sclerosis patients treated with natalizumab. Clinical management of patients with natalizumab-associated PML is challenging not least because current imaging tools for the early detection, longitudinal monitoring and differential diagnosis of PML lesions are limited. Here we evaluate whether translocator protein (TSPO) PET imaging can be applied to monitor the inflammatory activity of PML lesions over time and differentiate them from multiple sclerosis lesions. For this monocentre pilot study we followed eight patients with natalizumab-associated PML with PET imaging using the TSPO radioligand 18F-GE-180 combined with frequent 3 T MRI. In addition we compared TSPO PET signals in PML lesions with the signal pattern of multiple sclerosis lesions from 17 independent multiple sclerosis patients. We evaluated the standardized uptake value ratio as well as the morphometry of the TSPO uptake for putative PML and multiple sclerosis lesions areas compared to a radiologically unaffected pseudo-reference region in the cerebrum. Furthermore, TSPO expression in situ was immunohistochemically verified by determining the density and cellular identity of TSPO-expressing cells in brain sections from four patients with early natalizumab-associated PML as well as five patients with other forms of PML and six patients with inflammatory demyelinating CNS lesions (clinically isolated syndrome/multiple sclerosis). Histological analysis revealed a reticular accumulation of TSPO expressing phagocytes in PML lesions, while such phagocytes showed a more homogeneous distribution in putative multiple sclerosis lesions. TSPO PET imaging showed an enhanced tracer uptake in natalizumab-associated PML lesions that was present from the early to the chronic stages (up to 52 months after PML diagnosis). While gadolinium enhancement on MRI rapidly declined to baseline levels, TSPO tracer uptake followed a slow one phase decay curve. A TSPO-based 3D diagnostic matrix taking into account the uptake levels as well as the shape and texture of the TSPO signal differentiated >96% of PML and multiple sclerosis lesions. Indeed, treatment with rituximab after natalizumab-associated PML in three patients did not affect tracer uptake in the assigned PML lesions but reverted tracer uptake to baseline in the assigned active multiple sclerosis lesions. Taken together our study suggests that TSPO PET imaging can reveal CNS inflammation in natalizumab-associated PML. TSPO PET may facilitate longitudinal monitoring of disease activity and help to distinguish recurrent multiple sclerosis activity from PML progression.

Exploring joint patterns of brain structure and function in inflammatory bowel diseases using multimodal data fusion.

BACKGROUND: A growing number of neuroimaging studies suggest distinct neural changes in inflammatory bowel diseases (IBDs). Whether such changes may show similar spatial patterns across distinct neural features within and between specific IBD is unclear. To address this question, we used multivariate multimodal data fusion analysis to investigate structure/function modulation in remitted patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Patients with IBD (n = 46; n = 31 with CD, n = 15 with UC) in stable remission and 17 healthy controls (HC) underwent structural magnetic resonance imaging (sMRI) and resting-state functional magnetic resonance imaging (rs-fMRI) as well as cognitive testing. Anxiety, depression, and fatigue were assessed using self-rating questionnaires. sMRI data were analyzed via voxel-based morphometry (VBM) and rs-fMRI data via amplitude of low-frequency fluctuations (ALFFs) and regional homogeneity (ReHo). Detection of cross-information between VBM, ALFF, and ReHo was conducted by means of a joint independent component analysis (jICA), followed by group-inference statistics. KEY RESULTS: Joint independent component analysis detected structural alterations in middle frontal and temporal regions (VBM), and functional changes in the superior frontal gyrus (ReHo) and the medial as well as inferior frontal, inferior temporal, rectal, and subcallosal gyrus (ALFF). One joint component of extracted features of the three modalities differed significantly between IBD patients and controls (p = 0.03), and most distinctly between HC and patients with UC. CONCLUSIONS AND INFERENCES: Using a multivariate data fusion technique, this study provides further evidence to brain alterations in IBD. The data suggest distinct neural differences between CD and UC, particularly in frontotemporal regions.

Design of TRUST, a non-interventional, multicenter, 3-year prospective study investigating an integrated patient management approach in patients with relapsing-remitting multiple sclerosis treated with natalizumab.

BACKGROUND: Natalizumab provides rapid and high-efficacy control of multiple sclerosis disease activity with long-term stabilization. However, the benefits of the drug are countered by a risk of developing progressive multifocal leukoencephalopathy in patients infected with the John Cunningham Virus. Close monitoring is required in patients with increased progressive multifocal leukoencephalopathy risk receiving natalizumab in the long-term for an optimal benefit-risk evaluation. Standardized high-quality monitoring procedures may provide a superior basis for individual benefit and risk evaluation and thus improve treatment decisions. The non-interventional study TRUST was designed to capture natalizumab effectiveness under real-life conditions and to examine alternate approaches for clinical assessments, magnetic resonance imaging monitoring and use of biomarkers for progressive multifocal leukoencephalopathy risk stratification. METHODS/DESIGN: TRUST is a non-interventional, multicenter, prospective cohort study conducted at approximately 200 German neurological centers. The study is intended to enroll 1260 relapsing-remitting multiple sclerosis patients with ongoing natalizumab therapy for at least 12 months. Patients will be followed for a period of 3 years, irrespective of treatment changes after study start. Data on clinical, subclinical and patient-centric outcomes will be documented in order to compare the effectiveness of continuous versus discontinued natalizumab treatment. Furthermore, the type and frequency of clinical, magnetic resonance imaging and biomarker assessments, reasons for continuation or discontinuation of therapy and the safety profile of natalizumab will be collected to explore the impact of a systematic patient management approach and its potential impact on patient outcome. Specifically, the role of biomarkers, the use of expert opinions, the impact of high-frequency magnetic resonance imaging assessment for early progressive multifocal leukoencephalopathy detection and the role of additional radiological and clinical expert advice will be explored. DISCUSSION: TRUST was initiated in spring 2014 and enrollment is anticipated to be completed by mid 2016. Annual interim analyses will deliver continuous information and transparency with regard to the patient cohorts and the completeness and quality of data as well as closely monitor any safety signals in the natalizumab-treated cohort. The study's results may provide insights into opportunities to improve the benefit-risk assessment in clinical practice and support treatment decisions.

MRI Characteristics of the Evolution of Supratentorial Recent Small Subcortical Infarcts.

OBJECTIVE: Morphological changes of recent small subcortical infarcts are not well defined. The purpose of the present study was to describe the MRI characteristics of the evolution for this stroke subtype. METHODS: We conducted a retrospective review of patients diagnosed with definite supratentorial recent small subcortical infarcts according to the ASCO classification with baseline and follow-up MRI (≥90 days of stroke onset). We investigated the incidence of cavity formation, the infarct volume change, and the positional relationship between infarct lesions and preexisting white matter hyperintensities (WMHs) of presumed vascular origin. RESULTS: We identified 62 patients with a median age of 71 years (range: 30-87). Median follow-up period was 26 months (range: 3-99). Cavity formation was observed in 38 infarct lesions (61%). Eighteen lesions (29%) were partially adjacent to WMHs and 7 (11%) were fused into WMHs. In a multiple logistic regression analysis, age [odds ratio per 5-year increase: 1.34; 95% confidence interval (CI): 1.03-1.80; p = 0.03] and baseline infarct volume (odds ratio per 1-ml increase: 4.7; 95% CI: 1.6-19.7; p = 0.003) were independent predictors of cavity formation. There was a significant volume reduction between baseline and follow-up infarct lesions (median volume reduction rate: 44%). CONCLUSION: More than one-third of recent small subcortical infarcts do not lead to cavity formation and 40% of infarct lesions overlap with WMHs. Our data indicate the continuity between recent small subcortical infarcts and WMHs.

Presumptive progressive multifocal leukoencephalopathy in multiple sclerosis after natalizumab therapy.

BACKGROUND AND PURPOSE: To describe a patient with relapsing remitting MS who was treated with natalizumab for 36 months. First symptoms of presumptive progressive multifocal leukoencephalopathy (PML) appeared 14 weeks after her last natalizumab infusion. METHODS: Neurological examination, MRI and CSF analysis were performed. RESULTS: The lack of anti-inflammatory treatment response, clinical course, and serial MRI examinations showed lesion development typical for PML on diffusion-weighted and FLAIR MRI. CSF analysis for JC virus was tested negative twice. CONCLUSIONS: This case represents a presumptive PML after discontinuation of natalizumab treatment-similar to the definition established for PML in HIV patients.

Magnetic resonance imaging pattern in natalizumab-associated progressive multifocal leukoencephalopathy.

OBJECTIVE: Natalizumab is an effective treatment for patients with multiple sclerosis (MS) that is associated with a risk of progressive multifocal leukoencephalopathy (PML). Recommendations were published in 2006 to improve early diagnosis of PML using magnetic resonance imaging (MRI). However, due to the small number of MS patients initially diagnosed with PML, the imaging criteria could only be derived from PML lesions in patients with human immunodeficiency virus. Therefore, there is an urgent need to assess the MRI characteristics of PML in MS patients to update the existing recommendations. METHODS: In this retrospective review, the first 40 natalizumab-treated MS patients diagnosed with PML in the postmarketing setting were identified, of whom 22 (10 with clinically diagnosed immune reconstitution inflammatory syndrome) fulfilled the inclusion criteria for this study. Magnetic resonance images were analyzed according to predefined criteria by 5 independent readers. RESULTS: The most frequent lesion pattern in early scans from PML patients was that of large (>3 cm, 15 of 18), subcortical (18 of 18), T2 or fluid-attenuated inversion recovery hyperintense (18 of 18), T1-hypointense (17 of 18), and diffusion-hyperintense (15 of 15) lesions, with a sharp border toward the gray matter and an ill-defined border toward the white matter (18 of 18) on T2-weighted images. We could detect contrast enhancement in 41% (7 of 17) of the cases on the first scan at clinical presentation. INTERPRETATION: Attention to characteristic MRI patterns, especially the presence of contrast enhancement, and the subcortical location may have utility in screening and early diagnosis of PML in natalizumab-treated MS patients.

Effect of immunomodulatory medication on regional gray matter loss in relapsing-remitting multiple sclerosis--a longitudinal MRI study.

Prevention of global gray matter (GM) volume changes in multiple sclerosis (MS) are an objective in clinical trials, but the effect of immunomodulatory medication on regional GM atrophy progression is unclear. MRIs from 86 patients with relapsing-remitting MS (RRMS) followed up for 24 months were analyzed using voxel-based morphometry. An analysis of covariance model (cluster threshold, corrected p<0.05) was used to compare GM volumes between baseline and follow-up while stratified by immunomodulatory medication (IM): Interferone INF-beta-1a (n=34), INF-beta-1b (n=16), glatiramer acetate (GA) (n=15), and no-immunomodulatory treatment (n=21). In the INF-beta-1a/1b group (n=50), significant GM volume reductions were observed during follow-up in fronto-temporal, cingulate and cerebellar cortical brain regions, without significant differences between the INF-beta-1a and INF-beta-1b patients. In the GA group and in unmedicated patients, no significant regional GM volume reductions were observed. In contrast to GA, INF-beta-1a/1b treatment was associated with GM volume reductions in hippocampal/parahippocampal and anterior cingulate cortex. This is the first longitudinal study investigating the effects of IMs on GM in RRMS. Results suggest differences in the dynamics of regional GM volume atrophy in differentially treated or untreated RRMS patients.

Gender differences in acute ischemic stroke: etiology, stroke patterns and response to thrombolysis.

BACKGROUND AND PURPOSE: Differences between women and men in relation to stroke are increasingly being recognized. METHODS: From July 2004 until June 2007, 237 acute ischemic stroke (AIS) patients were treated with recombinant tissue plasminogen activator (rtPA) within 3 hours after onset of symptoms in our stroke unit. Baseline characteristics, etiology, CT/MRI stroke patterns, clinical outcome, and complications of women were compared to those of men. RESULTS: Of 237 AIS patients (mean age 70.7 years), 111 (46.8%) were women and 126 (53.2%) were men. Women were older (P=0.001), but history of hyperlipidemia (P=0.03), smoking (P=0.03), and coronary heart disease (P<0.001) was less frequent than in men. Internal carotid artery disease occurred more often in men (P=0.02), whereas atrial fibrillation was observed more often in women (P=0.002). In men borderzone/small embolic and lacunar stroke was found more frequently (39.7 versus 27.2%), whereas women showed a higher percentage of large territorial stroke (72.8 versus 60.3%, P=0.09). Baseline National Institute of Health Stroke Scale scores (12.5 versus 11.3), NIHSS score at discharge (11.0 versus 9.5), 3-month-outcome modified Rankin Scale score, thrombolysis-related (17.1% versus 13.5%) or independent complications (32.4% versus 30.2%), and mortality after 3 months (13.5% versus 9.5%) were similar. CONCLUSIONS: Differences of stroke lesion patterns in genders are paralleled by differences in etiology and risk factor profiles (women, cardioembolism; men, large and small vessel disease). Baseline characteristics, rates of rtPA-related and independent complications, as well as clinical outcomes were not different between women and men with AIS.