Expert recommendations to personalization of medical approaches in treatment of multiple sclerosis: an overview of family planning and pregnancy

Multiple sclerosis is the most common chronic autoimmune disease of the central nervous system which preferentially affects females at childbearing age. For this reason, patients and treating physicians were frequently confronted with questions concerning family planning, pregnancy and birth. Preventive and personalized treatment approaches are considered, because topics as heredity, risk of congenital malformations, influence of pregnancy on MS and aspects of drug therapy during the period of conception, pregnancy, puerperium and lactation have to be discussed. Here, we provide an overview about the current state of knowledge regarding these issues

Magnetic resonance elastography reveals altered brain viscoelasticity in experimental autoimmune encephalomyelitis

Cerebral magnetic resonance elastography (MRE) measures the viscoelastic properties of brain tissues in vivo. It was recently shown that brain viscoelasticity is reduced in patients with multiple sclerosis (MS), highlighting the potential of cerebral MRE to detect tissue pathology during neuroinflammation. To further investigate the relationship between inflammation and brain viscoelasticity, we applied MRE to a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). EAE was induced and monitored by MRE in a 7-tesla animal MRI scanner over 4 weeks. At the peak of the disease (day 14 after immunization), we detected a significant decrease in both the storage modulus (G') and the loss modulus (G″), indicating that both the elasticity and the viscosity of the brain are reduced during acute inflammation. Interestingly, these parameters normalized at a later time point (day 28) corresponding to the clinical recovery phase. Consistent with this, we observed a clear correlation between viscoelastic tissue alteration and the magnitude of perivascular T cell infiltration at both day 14 and day 28. Hence, acute neuroinflammation is associated with reduced mechanical cohesion of brain tissues. Moreover, the reduction of brain viscoelasticity appears to be a reversible process, which is restored when inflammation resolves. For the first time, our study has demonstrated the applicability of cerebral MRE in EAE, and showed that this novel imaging technology is highly sensitive to early tissue alterations resulting from the inflammatory processes. Thus, MRE may serve to monitor early stages of perivascular immune infiltration during neuroinflammation

Time domain and spectral domain optical coherence tomography in multiple sclerosis: a comparative cross-sectional study

Conventional time domain optical coherence tomography has been established for the in vivo assessment of retinal axonal loss in multiple sclerosis. The innovative spectral domain imaging is superior to the conventional technique with respect to data acquisition speed, resolution and reproducibility. However, until now comparability of the two techniques has not been investigated in multiple sclerosis. In this study involving 55 multiple sclerosis patients, data obtained using both techniques (Stratus time domain optical coherence tomography and Cirrus spectral domain optical coherence tomography, Carl Zeiss Meditec) showed an excellent correlation (Pearson's r = 0.926, p < 0.001). However, owing to considerable differences in absolute retinal nerve fibre layer measurements (mean +/- standard deviation 8.1 microm +/- 6.2, range -12 to 23 microm), results from the two devices are not interchangeable

Venous drainage in multiple sclerosis: A combined MRI and ultrasound study

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) was proposed as the causal trigger for developing multiple sclerosis (MS). However, current data are contradictory and a gold standard for venous flow assessment is missing. OBJECTIVE: To compare structural magnetic resonance venography (MRV) and dynamic extracranial color-coded duplex sonography (ECCS) in a cohort of patients with MS. METHODS: We enrolled 40 patients (44 ± 10 years). All underwent contrast-enhanced MRV for assessment of internal jugular vein (IJV) and azygos vein (AV) narrowing, graded into 3 groups: 0%-50%, 51%-80%, and >80%. ECCS analysis of blood flow direction, cross-sectional area (CSA), and blood volume flow (BVF) in both IJV and vertebral veins (VV) occurred in the supine and upright body position. RESULTS: MRV identified 1 AV narrowing. IJV analysis yielded 12 patients for group 1 (30%), 19 patients for group 2 (48%), and 9 patients for group 3 (22%). By ECCS criteria, 4 patients (10%) presented with venous drainage abnormalities. Jugular BVF was different only between groups 1 and 3 (616 ± 133 vs 381 ± 213 mL/min, p = 0.02). No other parameters in supine position and none of the parameters in the upright body position, apart from the IJV-BVF decrease in groups 1 and 3 (479 ± 172 vs 231 ± 144 mL/min, p = 0.01), were different. CONCLUSIONS: Our ECCS data contradict the postulated 100% prevalence of CCSVI criteria in MS. MRV seems more sensitive to detect IJV narrowing compared to ECCS. A measurable hemodynamic effect only exists in vessel narrowings >80%. Our combined data argue against a causal relationship of venous narrowing and MS, favoring the rejection of the CCSVI hypothesis

Can we overcome the 'clinico-radiological paradox' in multiple sclerosis?

The association between common neuroradiological markers of multiple sclerosis (MS) and clinical disability is weak, a phenomenon known as the clinico-radiological paradox. Here, we investigated to which degree it is possible to predict individual disease profiles from conventional magnetic resonance imaging (MRI) using multivariate analysis algorithms. Specifically, we conducted cross-validated canonical correlation analyses to investigate the predictive information contained in conventional MRI data of 40 MS patients for the following clinical parameters: disease duration, motor disability (9-Hole Peg Test, Timed 25-Foot Walk Test), cognitive dysfunction (Paced Auditory Serial Addition Test), and the expanded disability status scale (EDSS). It turned out that the information in the spatial patterning of MRI data predicted the clinical scores with correlations of up to 0.80 (p < 10(-9)). Maximal predictive information for disease duration was identified in the precuneus and somatosensory cortex. Areas in the precuneus and precentral gyrus were maximally informative for motor disability. Cognitive dysfunction could best be predicted using data from the angular gyrus and superior parietal lobe. For EDSS, the inferior frontal gyrus was maximally informative. In conclusion, conventional MRI is highly predictive of clinical disability in MS when pattern-based algorithms are used for prediction. Thus, the so-called clinico-radiological paradox is not apparent when using suitable analysis techniques

Multiple sclerosis lesions and irreversible brain tissue damage: a comparative ultrahigh-field strength magnetic resonance imaging study

BACKGROUND: In current clinical practice, T2-weighted magnetic resonance imaging (MRI) is commonly applied to quantify the accumulated multiple sclerosis (MS) lesion load, whereas T1-weighted sequences are used to differentiate edema, blood-brain barrier breakdown by contrast enhancement, and irreversible brain tissue damage (commonly called "black holes" owing to the loss of signal intensity in T1-weighted sequences). Black holes are histopathologically associated with axonal loss and severe tissue destruction. In addition, double inversion recovery techniques were developed to improve the sensitivity to cortical lesions. OBJECTIVE: To demonstrate the potential of ultrahigh-field 3-dimensional T1-weighted imaging using magnetization-prepared rapid acquisition and multiple gradient-echoes (MPRAGE) to detect and characterize white and gray matter pathology in MS. DESIGN: Comparative study. SETTING: The patients with MS were recruited from the outpatient clinics of the NeuroCure Clinical Research Center and underwent 7-T brain MRI at the Berlin Ultrahigh Field Facility, both of which are in Berlin, Germany. Patients  Twenty patients with relapsing-remitting MS and 14 healthy controls underwent 7-T brain MRI, using a 24-channel receive head coil, and a subgroup of 18 patients with relapsing-remitting MS also underwent 1.5-T brain MRI. The imaging protocol included 2-dimensional T2-weighted fast low-angle shot (FLASH) and turbo inversion recovery magnitude (TIRM) sequences. For 3-dimensional T1-weighted imaging, the MPRAGE sequence was used. Each sequence was initially examined independently in separate analyses by an investigator blinded to all other data. In a second study, all detected lesions were retrospectively analyzed in a side-by-side comparison of all sequences. RESULTS: By use of 7-T T2-weighted FLASH imaging, 604 cerebral lesions were detected in the patients with relapsing-remitting MS (mean, 30.2 lesions per patient [range, 2-107 lesions per patient]), but none were detected in healthy controls. Cortical pathology was visible in 10 patients (6 cortical lesions and 37 leukocortical lesions). Within the 7-T acquisitions, each lesion detected at T2-weighted sequences and/or double inversion recovery sequences was also clearly delineated on corresponding MPRAGE sequences in side-by-side analysis. However, at 1.5 T, the MPRAGE images depicted only 452 of 561 lesions visualized in T2-weighted sequences and/or double inversion recovery sequences. In contrast, when analyzing each sequence separately, we found that the 7-T MPRAGE depicted more lesions than the 7-T FLASH (728 lesions vs 584 lesions), and almost twice as many as the 1.5-T MPRAGE (399 lesions). The 7-T MPRAGE also improved the detection of cortical and leukocortical lesions (15 lesions vs 58 lesions). CONCLUSIONS: At ultrahigh-field strength, T1-weighted MPRAGE is highly sensitive in detecting MS plaques within the white and the gray brain parenchyma. Our results indicate structural damage beyond demyelination in every lesion depicted, which is in accordance with postmortem histopathological studies. The 7-T MPRAGE clearly delineated every cortical lesion that was visualized by any other MRI sequence at 1.5 or 7 T

Periventricular venous density in multiple sclerosis is inversely associated with T2 lesion count: a 7 Tesla MRI study

Background: Damage to venules in multiple sclerosis was first described decades ago. Today, ultrahigh magnetic field strength T2*-weighted magnetic resonance imaging (MRI) techniques depict very small cerebral veins in vivo with great anatomical detail. Objective: We aimed to investigate alterations of periventricular small blood vessel appearance in relation to T2 lesion count and distribution in multiple sclerosis and clinically isolated syndrome in comparison with healthy control subjects at 7 Tesla MRI.Methods:We investigated 38 patients (including 16 with early multiple sclerosis and seven with clinically isolated syndrome) and 22 matched healthy controls at 7 Tesla. The protocol included T2*-weighted Fast Low Angle Shot, and T2-weighted Turbo Inversion Recovery Magnitude sequences. We quantified periventricular venous density by a novel region-of-interest-based algorithm, expressing the ratio of 'veins per region-of-interest' as well as of 'periventricular vascular area'. Results: Our study revealed significantly decreased venous density in multiple sclerosis patients compared with healthy controls. Venous alterations were already detectable in clinically isolated syndrome and early multiple sclerosis, although to a smaller extent. Venous density correlated inversely with periventricular and whole-brain T2 lesion count. Furthermore, we found no indication for cerebral venous congestion in multiple sclerosis. Conclusion: High spatially resolving anatomical T2*-weighted MRI revealed vascular alterations in early stages of multiple sclerosis, presumably as a part of widespread haemodynamic and metabolic alterations

Effects of deep repetitive transcranial magnetic stimulation on brain-derived neurotrophic factor serum concentration in healthy volunteers

Objective: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive, safe and efficacious technique for treating various neuropsychiatric disorders, but its underlying mechanisms are poorly understood. A newly developed H-coil allows the stimulation of deeper brain regions. This study is the first to investigate the effects of deep high-frequency rTMS on brain-derived neurotrophic factor (BDNF) serum concentrations in healthy volunteers. We aimed to evaluate the short-term effect of deep rTMS on BDNF serum concentrations. Methods: This was a double-blind, randomized deep high-frequency rTMS study using an H-coil on a cohort of 13 healthy volunteers (NCT01106365). The following stimulation protocols were applied: 18-Hz stimulation of the left dorsolateral prefrontal cortex (PFC), 5-Hz stimulation of the primary motor cortex (MC) and sham stimulation in random order. Blood samples were obtained before, 30 min after and 60 min after each treatment. Results: The BDNF serum concentration decreased significantly after MC and PFC stimulation, but not after sham stimulation. Furthermore, BDNF serum level changes were associated with changes in individual alertness. Conclusion: Although BDNF serum concentrations do not necessarily correlate with BDNF levels in the cerebrospinal fluid or the brain, these results indicate an acute biological effect of deep rTMS on BDNF release, and demonstrate that this change correlates with alertness