Caspar F. Pfueller

Distinct lesion morphology at 7-T MRI differentiates neuromyelitis optica from multiple sclerosis

Objective: To investigate distinct white matter and cortical gray matter pathology in neuromyelitis optica spectrum disorders (NMOSDs) and multiple sclerosis (MS) at 7-T MRI in a cross-sectional study. Methods: We included 10 patients with NMOSDs and 18 patients with MS in our 7-T MRI study. The imaging protocol comprised T2*-weighted fast low angle shot and turbo inversion recovery magnitude sequences. White matter and cortical gray matter lesions were assessed with special regard to their (perivascular) localization as well as the expression of a hypointense rim. Results: In total, we detected 140 white matter lesions in 7 of 10 patients with NMOSDs. In contrast to MS plaques, which were nearly exclusively centered by a small vein (92%) and showed a characteristic hypointense rim (23%), white matter changes in patients with NMOSDs were nonspecific in appearance and were only infrequently neighbored by a blood vessel (49 lesions [35%], p = 0.003). Hypointense rims were very rarely detectable (3 lesions [2%], p < 0.001). Cortical pathology was absent in NMOSDs. In our MS cohort, we detected 36 leukocortical, 8 intracortical, and 8 subpial cortical lesions in 7 of 18 patients. Conclusion: The MRI features of white matter and the absence of cortical gray matter findings substantially differentiate NMOSDs from MS and can be used as a potential marker to distinguish these 2 entities. The fact that cortical pathology is common in MS but is not present in patients with NMOSDs may reflect the difference in the underlying pathogenesis.

Fatigue in multiple sclerosis is closely related to sleep disorders: a polysomnographic cross-sectional study:

Background: Sleep disorders can cause tiredness. The relationship between sleep disorders and fatigue in patients with multiple sclerosis (MS) has not yet been investigated systematically. Objective: To investigate the relationship between fatigue and sleep disorders in patients with MS. Methods: Some 66 MS patients 20 to 66 years old were studied by overnight polysomnography. Using a cut-off point of 45 in the Modified Fatigue Impact Scale (MFIS), the entire cohort was stratified into a fatigued MS subgroup (n = 26) and a non-fatigued MS subgroup (n = 40). Results: Of the fatigued MS patients, 96% (n = 25) were suffering from a relevant sleep disorder, along with 60% of the non-fatigued MS patients (n = 24) (p = 0.001). Sleep-related breathing disorders were more frequent in the fatigued MS patients (27%) than in the non-fatigued MS patients (2.5%). Significantly higher MFIS values were detected in all (fatigued and non-fatigued) patients with relevant sleep disorders (mean MFIS 42.8; SD 18.3) than in patients without relevant sleep disorders (mean MFIS 20.5; SD 17.0) (p < 0.001). Suffering from a sleep disorder was associated with an increased risk of fatigue in MS (odds ratio: 18.5; 95% CI 1.6–208; p = 0.018). Conclusion: Our results demonstrate a clear and significant relationship between fatigue and sleep disorders.

Patterns of retinal nerve fiber layer loss in multiple sclerosis patients with or without optic neuritis and glaucoma patients

OBJECTIVE Optical coherence tomography (OCT) has gained increasing attention in multiple sclerosis (MS) research and has been suggested as outcome measure for neuroprotective therapies. However, to date it is not clear whether patterns of retinal nerve fiber layer thickness (RNFLT) loss are different in MS compared to other diseases such as glaucoma and data on RNFLT loss in MS patients with or without optic neuritis (ON/NON) have remained inconsistent or even contradictory. METHODS In this large cross-sectional study we analyzed the patterns of axonal loss of retinal ganglion cells in MS eyes (n=262) with and without history of ON (MS/ON: 73 eyes; MS/NON: 189 eyes) and patients eyes with glaucomatous optic disc atrophy (GA: n=22; 39 eyes) in comparison to healthy control eyes (HC: n=406 eyes). RESULTS We found that significant average and quadrant RNFLT loss is detectable by OCT in both MS and GA patients compared to healthy controls (p<0.01). The age- and gender adjusted average and quadrant RNFLT did not differ significantly between MS and GA patients (p>0.05). Average (p<0.0001) and quadrant (p<0.05) RNFL thinning is significantly more severe in MS/ON versus MS/NON eyes, and the extent of RNFL thinning varies across quadrants in MS/ON eyes with the highest degree of RNFLT loss in the temporal quadrant (p<0.001). CONCLUSION RNFLT reduction across all four quadrants in MS patients as a whole as well as in MS/NON eyes argues for a diffuse neurodegenerative process. Superimposed inflammatory attacks to the optic nerve may cause additional axonal damage with a temporal preponderance. Future studies are necessary to further evaluate the capacity of OCT to depict disease specific damage patterns.

Correlation of self-assessed fatigue and alertness in multiple sclerosis

Background: Fatigue is the most common symptom in multiple sclerosis patients, but is difficult to measure; quantification thus relies on self-assessed questionnaires. Objective: To evaluate a battery of neuropsychological tests regarding their capacity to objectify self-reported fatigue. Methods: We assessed the correlation between age, gender, education, Kurtzke’s Expanded Disability Status Scale, depression, fatigue and neuropsychological testing using a cross-sectional approach in 110 multiple sclerosis patients. Fatigue was measured with the Fatigue Severity Scale. Cognition was measured using a series of neuropsychological tests including three subtests of the Test of Attentional Performance, the Brief Repeatable Battery of Neuropsychological Tests and the Faces Symbol Test. Results: According to the Fatigue Severity Scale 51.4% of the cohort were fatigued (scores ≥4). Age, education and depression showed a significant correlation with the Fatigue Severity Scale. Only 5.5% of the cohort exhibited cognitive impairment in the Brief Repeatable Battery of Neuropsychological Tests scores. After correction for age, education, Expanded Disability Status Scale and depression, Fatigue Severity Scale scores were an independent predictor of performance in the alertness subtest of the Test of Attentional Performance (standardized coefficient beta = 0.298, p = 0.014). Conclusion: The alertness subtest of the Test of Attentional Performance may offer an objective method of evaluating self-reported fatigue, and may therefore — in addition to the Fatigue Severity Scale — be a suitable tool for the assessment of multiple sclerosis patients complaining of fatigue.

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.

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 Neuro Cure 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-TFLASH (728 lesions vs 584 lesions), and almost twice as many as the 1.5-T MPRAGE (399 lesions). The 7-TMPRAGE 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.

Lipopolysaccharide Injection Induces Relapses of Experimental Autoimmune Encephalomyelitis in Nontransgenic Mice via Bystander Activation of Autoreactive CD4+ Cells

Infections sometimes associate with exacerbations of autoimmune diseases through pathways that are poorly understood. Ag-specific mechanisms such as cross-reactivity between a microbial Ag and a self-Ag have received no direct support. In this study, we show that injection of LPS induces experimental autoimmune encephalomyelitis in TCR-transgenic mice and relapse of encephalomyelitis in normal mice. This form of treatment induces proliferation and cytokine production in a fraction of effector/memory Th lymphocytes in vitro via physical contact of Th cells with CD4− LPS-responsive cells. TCR-mediated signals are not necessary; rather what is required is ligation of costimulatory receptors on Th cells by costimulatory molecules on the CD4− cells. This form of bystander activation provides an Ag-independent link between infection and autoimmunity that might fit the clinical and epidemiological data on the connection between infection and autoimmunity better than the Ag-specific models.

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 µm ± 6.2, range -12 to 23 µm), results from the two devices are not interchangeable.

Impairment of contrast visual acuity as a functional correlate of retinal nerve fibre layer thinning and total macular volume reduction in multiple sclerosis

Objectives To analyse the association between retinal nerve fibre layer thickness (RNFLT) and total macular volume (TMV) as measured by optical coherence tomography, and contrast sensitivity (CS) measured by Functional Acuity Contrast Testing (FACT) in relapsing-remitting multiple sclerosis; and to investigate whether FACT testing by a contrast box device is feasible in multiple sclerosis (MS). Methods fact was performed using the Optec 6500 P vision testing system with best correction under photopic and mesopic conditions without glare. The Area Under the Log Contrast Sensitivity Function (AUC) was calculated. RNFLT and TMV were assessed by Stratus optical coherence tomography. All participants underwent visual acuity testing (Snellen), spherical refractive error testing and cylindrical refractive error testing. Results 85 relapsing-remitting multiple sclerosis patients (170 eyes) and 35 healthy controls (HC, 70 eyes) were measured. AUC Day and Night were lower in MS than in HC (p<0.001) when correcting for age, as were mean RNFLT and TMV (p<0.001 and p=0.018, respectively). Both RNFLT and TMV predicted contrast sensitivity in MS (AUC Day: standardised coefficient β=0.277, p<0.001, and β=0.262, p<0.001, respectively; AUC Night: β=0.202, p=0.009 and β=0.222, p=0.004, respectively, linear regressions). In HC, there was no correlation between RNFLT or TMV and contrast sensitivity. Conclusion (1) Contrast sensitivity is reduced in MS versus HC; (2) RNFL and TMV as morphological measures of retinal axonal loss are predictors of contrast sensitivity as a functional visual parameter in MS but not in HC; and (3) FACT with the contrast box is a novel, feasible and rapid method to assess contrast sensitivity in MS.

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.