Philipp Eisele

Brain atrophy and lesion load predict long term disability in multiple sclerosis

Objective To determine whether brain atrophy and lesion volumes predict subsequent 10 year clinical evolution in multiple sclerosis (MS). Design From eight MAGNIMS (MAGNetic resonance Imaging in MS) centres, we retrospectively included 261 MS patients with MR imaging at baseline and after 1–2 years, and Expanded Disability Status Scale (EDSS) scoring at baseline and after 10 years. Annualised whole brain atrophy, central brain atrophy rates and T2 lesion volumes were calculated. Patients were categorised by baseline diagnosis as primary progressive MS (n=77), clinically isolated syndromes (n=18), relapsing–remitting MS (n=97) and secondary progressive MS (n=69). Relapse onset patients were classified as minimally impaired (EDSS=0–3.5, n=111) or moderately impaired (EDSS=4–6, n=55) according to their baseline disability (and regardless of disease type). Linear regression models tested whether whole brain and central atrophy, lesion volumes at baseline, follow-up and lesion volume change predicted 10 year EDSS and MS Severity Scale scores. Results In the whole patient group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS and disease modifying treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10 year EDSS with R2=0.74 in the whole group and R2=0.72 in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients (R2=0.68), lesion volumes in moderately impaired relapse onset patients (R2=0.21) and whole brain atrophy in primary progressive MS (R2=0.34). Conclusions This large multicentre study points to the complementary predictive value of atrophy and lesion volumes for predicting long term disability in MS.

MRI monitoring of pathological changes in the spinal cord in patients with multiple sclerosis

The spinal cord is a clinically important site that is affected by pathological changes in most patients with multiple sclerosis; however, imaging of the spinal cord with conventional MRI can be difficult. Improvements in MRI provide a major advantage for spinal cord imaging, with better signal-to-noise ratio and improved spatial resolution. Through the use of multiplanar MRI, identification of diffuse and focal changes in the whole spinal cord is now routinely possible. Corroborated by related histopathological analyses, several new techniques, such as magnetisation transfer, diffusion tension imaging, functional MRI, and proton magnetic resonance spectroscopy, can detect non-focal, spinal cord pathological changes in patients with multiple sclerosis. Additionally, functional MRI can reveal changes in the response pattern to sensory stimulation in patients with multiple sclerosis. Through use of these techniques, findings of cord atrophy, intrinsic cord damage, and adaptation are shown to occur largely independently of focal spinal cord lesion load, which emphasises their relevance in depiction of the true burden of disease. Combinations of magnetisation transfer ratio or diffusion tension imaging indices with cord atrophy markers seem to be the most robust and meaningful biomarkers to monitor disease evolution in early multiple sclerosis.

Reduced Diffusion in a Subset of Acute MS Lesions: A Serial Multiparametric MRI Study

BACKGROUND AND PURPOSE: MRI studies have focused on newly developing MS lesions to characterize the early pathology of the disease. DWI is highly sensitive to acute and chronic tissue changes in MS. We characterized the development of acute MS lesions by using DWI in a multiparametric MRI protocol. MATERIALS AND METHODS: Seventy-two consecutive patients presenting with a new symptom with definite MS or a CIS suggestive of central nervous system demyelination were screened with MRI. Patients who showed an acute MRI lesion with a reduction of ADC were studied with serial MRI for up to 4 months after presentation. RESULTS: Ten of 72 screened patients who showed a lesion with a reduced ADC were each examined 4–7 times, resulting in 52 examinations in total. We identified a characteristic sequence of signal-intensity changes: 1) days 0–7: slight T2 hyperintensity and prominent ADC reduction (maximum, −66%), faint or no enhancement on postcontrast T1-weighted images; 2) days 7–10: prominent T2 hyperintensity and contrast enhancement, ADC normalization/pseudonormalization; 3) up to 4 weeks: elevated ADC values, prominent enhancement on postcontrast images; 4) after 4 weeks: partial reversibility of T2 hyperintensity, ADC elevation, and resolution of contrast enhancement. CONCLUSIONS: In a subgroup of patients with MS presenting soon after new symptom onset, a transient reduction of the ADC delineated a short and very early phase of MS lesion evolution. Subsequent pseudonormalization of the ADC occurred along with signs of the development of vasogenic edema.

Investigation of leptomeningeal enhancement in MS: a postcontrast FLAIR MRI study.

Objective: To investigate possible leptomeningeal contrast enhancement using postcontrast fluid-attenuated inversion recovery (FLAIR) MRI as an additional marker of inflammation in patients with multiple sclerosis (MS). Methods: A cohort of 112 patients (73 women) with clinically definitive MS or a clinically isolated syndrome suggestive of CNS demyelination were included. A pathologic control group of 5 stroke patients was also examined. MRI was performed on a 3T system including FLAIR, T2-weighted, T1-weighted–contrast injection, followed by T1-weighted and FLAIR. Results: Of the 112 patients, 39 had an acute relapse at the time of MRI. In total, 96 contrast-enhancing lesions were identified on postcontrast T1-weighted images. The pathologic control group demonstrated the sensitivity of postcontrast FLAIR images demonstrating leptomeningeal enhancement in all cases. In contrast, only 1 out of 112 examined patients with MS showed a single area of abnormal leptomeningeal contrast enhancement. Conclusions: In contrast to intraparenchymal blood–brain barrier (BBB) dysfunction that is frequently seen in patients with MS, BBB dysfunction of leptomeningeal vessels is usually not detectable in patients with early MS.

Lack of increased signal intensity in the dentate nucleus after repeated administration of a macrocyclic contrast agent in multiple sclerosis: An observational study.

AbstractRecently, several studies reported increased signal intensity (SI) in the dentate nucleus (DN) after repeated application of gadolinium-based contrast agents (GBCAs), suggesting a deposition of gadolinium in this location. Patients with relapsing–remitting multiple sclerosis (RRMS) frequently show increased permeability of the blood–brain barrier as part of the inflammatory process in the brain parenchyma, which theoretically might increase the risk of gadolinium deposition. In this retrospective study, we investigated a possible increasing SI in the DN after repeated administrations of the macrocyclic contrast agent gadoterate meglumine.Forty-one RRMS patients (33 women, mean age 38 years) with at least 6 prior gadolinium-enhanced examinations (single dose gadoterate meglumine) were identified. A total of 279 unenhanced T1-weighted examinations were analyzed.SI ratio differences did not differ between the first and last MRI examination, neither for the DN-to-pons ratio (P = 0.594) nor for the DN-to-cerebellum ratio (P = 0.847). There was no correlation between the mean DN-to-pons, or between the mean DN-to-cerebellum SI ratio and the number of MRI examinations (P = 0.848 and 0.891), disease duration (P = 0.676 and 0.985), and expanded disability status scale (EDSS) (P = 0.639 and 0.945).We found no signal increases in the DN after a minimum of 6 injections of the macrocyclic GBCA gadoterate meglumine in RRMS patients. This warrants further investigations in regard to the true pathophysiologic basis of intracerebral gadolinium deposition.

Acute Marchiafava-Bignami disease with extensive diffusion restriction and early recovery: case report and review of the literature.

Marchiafava‐Bignami disease (MBD) is a neurological disorder that has been found to be associated with chronic alcoholism and malnutrition. MBD classically results in acute edema and demyelination of the corpus callosum. Edema of the complete corpus callosum has been described to be an unfavorable prognostic factor. We present an acute onset of MBD with diffusion restriction of the complete corpus callosum and symmetric bilateral extension into the semioval center, that almost completely resolved clinically as well as in MRI only 3 days later. With early detection and treatment, the prognosis of MBD may be good even in cases with severe diffusion restriction of the complete corpus callosum.

Heterogeneity of acute multiple sclerosis lesions on sodium (23Na) MRI

Background: Advanced magnetic resonance imaging (MRI) techniques provide a window into pathological processes in multiple sclerosis (MS). Nevertheless, to date only few studies have performed sodium MRI in MS. Objectives: We analysed total sodium concentration (TSC) in hyperacute, acute and chronic lesions in MS with 23Na MRI. Methods: 23Na MRI and 1H MRI were performed in 65 MS patients and 10 healthy controls (HC). Mean TSC was quantified in all MS lesions with a diameter of >5 mm and in the normal appearing white and grey matter (NAWM, NAGM). Results: TSC in the NAWM and the NAGM of MS patients was significantly higher compared to HC (WM: 37.51 ± 2.65 mM versus 35.17 ± 3.40 mM; GM: 43.64 ± 2.75 mM versus 40.09 ± 4.64 mM). Acute and chronic MS lesions showed elevated TSC levels of different extent (contrast-enhancing lesions (49.07 ± 6.99 mM), T1 hypointense lesions (45.06 ± 6.26 mM) and remaining T1 isointense lesions (39.88 ± 5.54 mM)). However, non-enhancing hyperacute lesions with a reduced apparent diffusion coefficient showed a TSC comparable to the NAWM (37.22 ± 4.62 mM). Conclusions: TSC is not only a sensitive marker of the severity of chronic tissue abnormalities in MS but is also highly sensitive to opening of the blood–brain barrier and vasogenic tissue oedema in contrast-enhancing lesions.

DWI Lesion Patterns in Cancer-Related Stroke - Specifying the Phenotype

Background: Due to the lack of specific diagnostic markers, the diagnosis of cancer-related stroke strongly depends on its phenotype. Distinct DWI lesion patterns with involvement of multiple vascular territories have been reported repeatedly in cancer-related stroke but have not been addressed in detail in a selected cohort of prospectively recruited cancer patients with emphasis on hypercoagulable conditions. Patients and Methods: Ischemic stroke patients with known malignant cancer activity, laboratory evidence of strong plasmatic hypercoagulation (D-dimer levels >3 µg/ml) and without competing stroke etiologies according to the recently introduced ASCOD (A - atherosclerosis, S - small vessel disease, C - cardiac pathology, O - other cause, and D - dissection) classification of evidence-rated etiology of stroke subtypes were included in the analysis. Cerebral MRI on admission was reviewed with respect to ischemic lesion patterns. Results: Thirty-two patients met the inclusion criteria. The mean D-dimer levels were 15.39 µg/ml (±10.84). Acute infarction in ≥2 vascular territories was present in 27/32 (84%) patients. (Micro-) embolic scattering of infarction was present in 25/32 (78%) patients. Evidence for previous, potentially oligosymptomatic infarction was found in 16 (50%) patients, demonstrated by the additional presence of subacute or chronic ischemic lesions. Conclusion: When excluding competing embolic and nonembolic stroke etiologies, the pattern of scattered DWI lesions in multiple vascular supply territories strongly dominates the phenotype of cancer-related stroke. Additionally, evidence of recurrent infarction is frequent in this cohort of patients. This is not only important for the diagnosis of cancer-related stroke itself but may prove helpful for the identification of cancer-related stroke patients with unknown malignancy at the time of stroke manifestation and evaluation of strategies for secondary prevention.

Idarucizumab as Antidote to Intracerebral Hemorrhage under Treatment with Dabigatran

Background and Purpose: Non-vitamin K anticoagulants (NOAC) such as dabigatran have become important therapeutic options for the prevention of stroke. Until recently, there were only nonspecific agents to reverse their anticoagulant effects in a case of emergency. Idarucizumab, an antibody fragment targeting dabigatran, is the first specific antidote for a NOAC to be approved, but real-world experience is limited. Methods: We report two cases of patients on dabigatran with acute intracerebral hemorrhage who received idarucizumab. Results: In both cases, idarucizumab promptly reversed the anticoagulant effect of dabigatran and there was no hematoma expansion in follow-up imaging. Conclusions: In addition to clinical and preclinical studies, our cases add to the experience regarding the safety and efficacy of idarucizumab. They show that idarucizumab may be an important safety option for patients on dabigatran in emergency situations.

Investigation of cerebral microbleeds in multiple sclerosis as a potential marker of blood-brain barrier dysfunction.

OBJECTIVE In multiple sclerosis (MS) lesions blood-brain-barrier (BBB) breakdown is a common phenomenon delineating the phase of focal inflammation in developing MS lesions. In other pathologies like cerebral amyloid angiopathy or arteriosclerotic cerebral small vessel disease permanent cerebral microbleeds (CMB) have been shown to be sensitive markers indicating BBB dysfunction. We were interested in the potential role of T(2)*-weighted MRI and CMBs as BBB integrity markers in MS. METHODS A large cohort of 189 MS patients (179 relapsing remitting MS and 10 secondary progressive MS) was investigated on a 3T MRI system with conventional and T(2)*-weighted gradient echo MRI (T(2)*w) sequences. T(2)*w images were analysed for CMBs by experienced raters. RESULTS None of the MS patients showed a CMB. CONCLUSION On T(2)*w MRI the prevalence of CMBs is not higher in MS patients than what is to be expected in young healthy people. In contrast to pathologies with structural vascular changes like small vessel disease or cerebral amyloid angiopathy, CMBs are not seen in MS where the immune reaction is causing a functional change in the BBB.