[Potential Impact of Public Communication on Emergency Presentations due to Headache during the Covid-19 Pandemic]. / Epidemiologische Untersuchung zu möglichen Auswirkungen öffentlicher Kommunikation im Rahmen der COVID-19-Pandemie auf Notfallvorstellungen von Kopfschmerzpatient*innen.

Headache is a frequent presenting symptom in the emergency department. While most cases are of benign aetiology, it is crucially important to identify potentially dangerous underlying disorders. We hypothesized an increase in headache-related emergency presentations after venous thrombosis of cerebral sinuses had been identified as a rare side effect of vaccination with adenovirus vector-based Coronavirus-disease 2019 (COVID-19) vaccines and that information had been publicly communicated by the Paul Ehrlich Institute. Data from patients with the diagnosis of primary headache disorders or unspecified headache presenting to the Interdisciplinary Emergency Department of the University Medicine Mannheim were retrospectively analysed. Based on vaccination dashboard data published by the Federal Ministry of Health, calendar weeks 14-30 and 47-48, on the one hand, and 1-13 and 31-46, on the othe, were categorized into a variable "vaccination epoch" (14-30, 47-48: high vaccination activity if≥3 million weekly vaccinations in Germany; 1-13, 31-46: low vaccination activity if<3 million weekly vaccinations). The number of patients with headache was the dependent variable. A Poisson regression was performed to analyze whether the frequency of events, i. e., patient presentations, was a function of year (2019, 2021), epoch (high, low) and an interaction of year and epoch - the latter reflecting an impact of vaccination activity during the pandemic and expressed as incidence rate ratio. Compared to 2019, there was a more than 70% increase in presentations due to headache during periods of high vaccination activity in 2021 (p<0.001; 95% confidence interval 1.272-2.316), in 25% of presentations in 2021, patients considered their headache as vaccination-associated. Public communication and resulting nocebo effects may, among other factors, have contributed to our observation of increased numbers of emergency headache presentations, illustrating the impact of public distribution of medical information on practical aspects of emergency care during crises.

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.

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.

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.

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.