[Neuropsychological and MRI diagnostics in secondary progressive multiple sclerosis]. / Neuropsychologische und Magnetresonanztomographie(MRT)-Diagnostik bei sekundär progredienter Multipler Sklerose.

BACKGROUND: Multiple sclerosis is a disease continuum with an initial relapsing remitting course (RRMS) and secondary progression (SPMS) at later stages. Most of the hitherto approved treatments do not adequately control for the phase of secondary progression. Thus, early detection of SPMS conversion is a key issue to initiate SPMS-tailored treatment. In this context, assessment of cognitive functions and magnetic resonance imaging (MRI) both play an important role in the longitudinal follow-up of MS patients. OBJECTIVE: To elucidate the importance of cognitive testing and MRI for prediction and detection of SPMS conversion as well as to discuss strategies for disease monitoring and for optimizing treatment in standard clinical care, particularly in outpatient settings. MATERIAL AND METHODS: Review article based on a nonsystematic literature review. RESULTS: Standardized cognitive testing can support early diagnosis of SPMS and facilitate disease monitoring. Annual application of sensitive screening tests, such as the Symbol Digit Modalities Test (SDMT) and Brief Visual Memory Test-Revised (BVMT­R) or the entire Brief International Cognitive Assessment for MS (BICAMS) test battery are recommended in this context. The MRI evidence of persistent inflammatory activity within 3 years of diagnosis as well as evidence of cortical lesions are predictive for SPMS conversion. Standardized MRI monitoring for markers of progression can substantiate clinical and neurocognitive signs of SPMS conversion. CONCLUSION: Multidisciplinary patient care involving careful clinical examination, neuropsychological testing and MRI monitoring is of great significance for the prediction of SPMS conversion and diagnostics. This enables early treatment adaptation, since pharmacological interventions in SPMS differ from those in RRMS. Continuous clinical, neuropsychological and MRI vigilance enable stringent monitoring of treatment outcomes with respect to neuroinflammatory and neurodegenerative activity as well as treatment-related complications.

Facing privacy in neuroimaging: removing facial features degrades performance of image analysis methods.

BACKGROUND: Recent studies have created awareness that facial features can be reconstructed from high-resolution MRI. Therefore, data sharing in neuroimaging requires special attention to protect participants' privacy. Facial features removal (FFR) could alleviate these concerns. We assessed the impact of three FFR methods on subsequent automated image analysis to obtain clinically relevant outcome measurements in three clinical groups. METHODS: FFR was performed using QuickShear, FaceMasking, and Defacing. In 110 subjects of Alzheimer's Disease Neuroimaging Initiative, normalized brain volumes (NBV) were measured by SIENAX. In 70 multiple sclerosis patients of the MAGNIMS Study Group, lesion volumes (WMLV) were measured by lesion prediction algorithm in lesion segmentation toolbox. In 84 glioblastoma patients of the PICTURE Study Group, tumor volumes (GBV) were measured by BraTumIA. Failed analyses on FFR-processed images were recorded. Only cases in which all image analyses completed successfully were analyzed. Differences between outcomes obtained from FFR-processed and full images were assessed, by quantifying the intra-class correlation coefficient (ICC) for absolute agreement and by testing for systematic differences using paired t tests. RESULTS: Automated analysis methods failed in 0-19% of cases in FFR-processed images versus 0-2% of cases in full images. ICC for absolute agreement ranged from 0.312 (GBV after FaceMasking) to 0.998 (WMLV after Defacing). FaceMasking yielded higher NBV (p = 0.003) and WMLV (p ≤ 0.001). GBV was lower after QuickShear and Defacing (both p < 0.001). CONCLUSIONS: All three outcome measures were affected differently by FFR, including failure of analysis methods and both "random" variation and systematic differences. Further study is warranted to ensure high-quality neuroimaging research while protecting participants' privacy. KEY POINTS: • Protecting participants' privacy when sharing MRI data is important. • Impact of three facial features removal methods on subsequent analysis was assessed in three clinical groups. • Removing facial features degrades performance of image analysis methods.

Predicting clinical progression in multiple sclerosis after 6 and 12 years.

BACKGROUND AND PURPOSE: To predict disability and cognition in multiple sclerosis (MS) after 6 and 12 years, using early clinical and imaging measures. METHODS: A total of 115 patients with MS were selected and followed up after 2 and 6 years, with 79 patients also being followed up after 12 years. Disability was measured using the Expanded Disability Status Scale (EDSS); cognition was measured only at follow-up using neuropsychological testing. Predictors of interest included EDSS score, baseline brain and lesion volumes and their changes over 2 years, baseline age, clinical phenotype, sex and educational level. RESULTS: Higher 6-year EDSS score was predicted by early EDSS score and whole-brain volume changes and baseline diagnosis of primary progressive MS (adjusted R2  = 0.56). Predictors for 12-year EDSS score included larger EDSS score changes and higher T1-hypointense lesion volumes (adjusted R2  = 0.38). Year 6 cognition was predicted by primary progressive MS phenotype, lower educational level, male sex and early whole-brain atrophy (adjusted R2  = 0.26); year 12 predictors included male sex, lower educational level and higher baseline T1-hypointense lesion volumes (adjusted R2  = 0.14). CONCLUSIONS: Patients with early signs of neurodegeneration and a progressive disease onset were more prone to develop both disability progression and cognitive dysfunction. Male sex and lower educational level only affected cognitive dysfunction, which remains difficult to predict and probably needs more advanced imaging measures.

The course of apathy in late-life depression treated with electroconvulsive therapy; a prospective cohort study.

OBJECTIVES: Apathy, a lack of motivation, is frequently seen in older individuals, with and without depression, with substantial impact on quality of life. This prospective cohort study of patients with severe late-life depression treated with electroconvulsive therapy (ECT) aims to study the course of apathy and the predictive value of vascular burden and in particular white matter hyperintensities on apathy course. METHODS: Information on apathy (defined by a score of >13 on the Apathy Scale), depression severity, vascular burden, and other putative confounders was collected in at 2 psychiatric hospitals on patients with late-life depression (aged 55 to 87 years, N = 73). MRI data on white matter hyperintensities were available in 52 patients. Possible risk factors for apathy post-ECT were determined using regression analyses. RESULTS: After treatment with ECT, 52.0% (26/50) of the depression remitters still suffered from clinically relevant apathy symptoms. In the entire cohort, more patients remained apathetic (58.9%) than depressed (31.5%). Presence of apathy post-ECT was not associated with higher age, use of benzodiazepines, or severity of apathy and depression at baseline. Less response in depressive symptomatology after ECT predicted post-treatment apathy. The presence of vascular disease, diabetes mellitus and smoking, and white matter hyperintensities in the brain was not associated with post-treatment apathy. CONCLUSIONS: Apathy may perpetuate in individual patients, despite remission of depressive symptoms. In this cohort of patients with late-life depression, post-ECT apathy is not associated with white matter hyperintensities.

[Diagnosis of multiple sclerosis: revision of the McDonald criteria 2017]. / Diagnose der Multiplen Sklerose: Revision der McDonald-Kriterien 2017.

Multiple sclerosis (MS) is the most common chronic autoimmune disorder of the central nervous system (CNS) largely affecting young adults. The diagnosis of MS is based on two pillars: 1) detection of the spatial and temporal dissemination of focal neurological deficits and 2) exclusion of important differential diagnoses. The current revision of the diagnostic criteria (McDonald 2017) also follows these principles, takes new data on magnetic resonance imaging (MRI) into account and reintroduces the role of cerebrospinal fluid (CSF) diagnostics for relapsing-remitting forms. The main priority is a reliable diagnosis as early as possible with the aim of a timely initiation of course-adapted treatment. Some of the concrete innovations are the consideration of cortical MRI lesions (equivalent to juxtacortical foci), the elimination of a distinction between asymptomatic and symptomatic MRI lesions and consideration of characteristic CSF findings for the criterion of temporal dissemination. Relapsing MS can be diagnosed at the time of the first attack by the detection of CSF-specific oligoclonal bands and the MRI detection of a typical local lesion distribution (even without simultaneous detection of a contrast-enhancing lesion). For the primary progressive course, for which a first treatment option has recently been approved, the known definition remains unaltered. With respect to the differential diagnosis there is a clear demarcation from Devic's syndrome, now known as neuromyelitis optica spectrum disorders (NMOSD), as recent insights indicate a separate disease entity caused by an autoimmune response against the astrocytic aquaporin 4 (AQP4) water channel. Finally, future studies will have to provide a definition for secondary progressive MS courses and clarify how to handle diseases characterized by antibodies against myelin oligodendrocyte glycoprotein (MOG) or patients with radiologically isolated syndrome (RIS), i. e. incidental MRI-based detection of CNS lesions in the absence of any clinical event. In summary, McDonald 2017 is within the conceptual structure of its predecessor and simplifies an early diagnosis, thus paving the way to early treatment of MS.

John Cunningham virus conversion in relation to natalizumab concentration in multiple sclerosis patients.

BACKGROUND AND PURPOSE: Infection with the John Cunningham virus (JCV) is required for the development of progressive multifocal leukoencephalopathy, the feared complication of natalizumab treatment in multiple sclerosis patients. The JCV seroconversion rate seems higher in natalizumab treated patients than in the normal population, with an unknown cause. METHODS: Natalizumab concentration was correlated to JCV antibody status and seroconversion in a large cohort of multiple sclerosis patients. RESULTS: One hundred and thirty-five patients were included. No correlation was found between natalizumab concentration and JCV status, JCV seroconversion or JCV index. CONCLUSIONS: Higher natalizumab concentrations do not explain the increased JCV seroconversion rate in natalizumab treated patients.

[Imaging of primary muscular diseases : What do neurologists expect from radiologists?] / Bildgebung primärer Muskelerkrankungen : Was erwartet der Neurologe vom Radiologen?

Imaging, in particular magnetic resonance imaging (MRI), has in recent years increasingly become a crucial tool for the diagnostics of inherited and acquired muscular diseases. The aim of imaging in neuromuscular disorders goes beyond the detection and quantification of degenerative muscular changes, such as fatty degeneration and includes recognition of very early signs of muscular pathologies presenting as muscular edema. Therefore, imaging is a valuable diagnostic method to support the clinical diagnosis and to narrow down the differential diagnoses, leading to specific additional diagnostic tests in order to establish the correct diagnosis. Although advances in MRI hardware and technology have led to a faster, more accurate and advanced image acquisition allowing whole body examination in a feasible fashion, the standardization of image acquisition and interpretation remains a challenge. The aim of this review article is to address the important and clinically relevant issues concerning the role of imaging of neuromuscular diseases in order to facilitate a good interdisciplinary management for the diagnostics and monitoring of neuromuscular diseases.

Muscle imaging in inherited and acquired muscle diseases.

In this review we discuss the use of conventional (computed tomography, magnetic resonance imaging, ultrasound) and advanced muscle imaging modalities (diffusion tensor imaging, magnetic resonance spectroscopy) in hereditary and acquired myopathies. We summarize the data on specific patterns of muscle involvement in the major categories of muscle disease and provide recommendations on how to use muscle imaging in this field of neuromuscular disorders.

High cumulative JC virus seroconversion rate during long-term use of natalizumab.

BACKGROUND AND PURPOSE: John Cunningham virus (JCV) seropositivity is a risk factor for the development of natalizumab-associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients. When JCV seronegative patients seroconvert, their risk of developing PML increases. Limited longitudinal data exist about the seroconversion rate amongst natalizumab-treated relapsing-remitting MS (RRMS) patients. Our objective was to evaluate the seroconversion rate in a large Dutch cohort of natalizumab-treated RRMS patients. Seroconversion was defined as at least two consecutive seropositive serum samples (or cessation of therapy after a single seropositive sample because of seropositivity) after initial seronegative testing. METHODS AND RESULTS: In our study of 179 patients for whom longitudinal blood samples were available over a long period (median 4.2 years), anti-JCV antibody indices were measured in 933 available samples. Eighty-six patients (48.0%) tested seronegative initially. Of these 86 seronegative patients, 23 patients (26.7%) seroconverted during follow-up. The annualized seroconversion rate was 7.1%. Seroconversion occurred between 9 and 90 months (median 43 months) of treatment. The rate of seroconversion was independent of follow-up duration. No significant increase was seen in the anti-JCV antibody index in the non-converting patients during the follow-up. CONCLUSION: The annualized seroconversion rate of 7.1% in patients using natalizumab, cumulatively leading to more than 25% of seronegative patients becoming seropositive in 4 years, is of clinical relevance and should be taken into account in the risk assessment when considering the start of natalizumab therapy.

[Progressive multifocal leukoencephalopathy]. / Progressive multifokale Leukenzephalopathie.

Progressive multifocal leukoencephalopathy (PML) is a disease of immunosuppressed patients caused by the JC polyomavirus (JCPyV). Due to the elevated risk in patients treated with natalizumab for multiple sclerosis (MS) and also treatment with other biologicals for different indications, the relevance of PML has increased in recent years. This article summarizes the published knowledge on the biology and pathogenesis of PML with a focus on the role of cerebrospinal fluid diagnostics in the work-up for PML and the current PML case definition. Current recommendations regarding risk management are discussed, as are possible therapies and prevention.

Bidirectional trans-synaptic axonal degeneration in the visual pathway in multiple sclerosis.

OBJECTIVE: To investigate the coexistence of anterograde and retrograde trans-synaptic axonal degeneration, and to explore the relationship between selective visual pathway damage and global brain involvement in longstanding multiple sclerosis (MS). METHODS: In this single-centre, cross-sectional study, patients with longstanding MS (N=222) and healthy controls (HC, N=62) were included. We analysed thickness of retinal layers (optical coherence tomography), damage within optic radiations (OR) (lesion volume and fractional anisotropy and mean diffusivity by diffusion tensor imaging) and atrophy of the visual cortex and that of grey and white matter of the whole-brain (structural MRI). Linear regression analyses were used to assess associations between the different components and for comparing patients with and without optic neuritis and HC. RESULTS: In patients with MS, an episode of optic neuritis (MSON) was significantly associated with decreased integrity of the ORs and thinning of the peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell complex (GCC). Lesion volume in the OR was negatively associated with pRNFL and GCC thickness in patients without optic neuritis (MSNON). The pRNFL and GCC showed associations with integrity of the OR, thickness of the primary visual cortex (only in patients with MSON), and also with global white and grey matter atrophy. In HCs, no such relationships were demonstrated. INTERPRETATION: This study provides evidence for presence of bidirectional (both anterograde and retrograde) trans-synaptic axonal degeneration in the visual pathway of patients with MS. Additionally, thinning of the retinal pRNFL and GCC are related to global white and grey matter atrophy in addition to pathology of the visual pathway.

Perivascular spaces in MS patients at 7 Tesla MRI: a marker of neurodegeneration?

BACKGROUND: Virchow-Robin spaces (VRS) are associated with vascular and neurodegenerative disease. In multiple sclerosis (MS), VRS have been associated with neuroinflammation. Ultra-high field imaging may be used to gain insight in these contradictory findings. OBJECTIVE: The objective of this paper is to analyze VRS in MS patients using high-resolution 7 Tesla (T) MRI. Additionally, we investigated whether the widening of VRS is related to inflammatory or neurodegenerative aspects of MS. METHODS: Thirty-four MS patients and 11 healthy controls were examined at 7T. Number and size of VRS were measured on three-dimensional (3D) T1-weighted images, and 3D fluid-attenuated inversion recovery (FLAIR) images were used for MS lesion detection. Brain atrophy was quantified by computing supratentorial brain volume fraction (sBVF). VRS counts were correlated with clinical variables, lesion count and sBVF. RESULTS: MS patients displayed more VRS (median 11) than healthy controls (median four), p = 0.001. VRS size did not differ between both groups. VRS count in MS patients was associated with sBVF (rho = -0.40, p = 0.02), but not with lesion count (p = 0.22). CONCLUSIONS: The 7T MRI reveals increased numbers of VRS in MS. The finding that VRS are associated with supratentorial brain atrophy, but not with lesion count, suggests that VRS might rather serve as a neurodegenerative than an inflammatory marker in MS.

Application of serum natalizumab levels during plasma exchange in MS patients with progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab treatment. Restoring immune function by plasmapheresis/immunoadsorption (PLEX/IA) is important for the outcome of PML. We report on four multiple sclerosis (MS) patients whom developed PML during natalizumab treatment, in whom we measured serum natalizumab concentrations before and during PLEX. Depending on the serum natalizumab concentration at the time of PML diagnosis, the number of PLEX treatments necessary to reach subtherapeutic serum natalizumab concentrations is variable. Measuring serum natalizumab concentrations before and during PLEX is helpful to determine the optimum number of PLEX treatments in individual MS patients with PML.

Whole-body high-field MRI shows no skeletal muscle degeneration in young patients with recessive myotonia congenita.

BACKGROUND: Muscle magnetic resonance imaging (MRI) is the most sensitive method in the detection of dystrophic and non-dystrophic abnormalities within striated muscles. We hypothesized that in severe myotonia congenita type Becker muscle stiffness, prolonged transient weakness and muscle hypertrophy might finally result in morphologic skeletal muscle alterations reflected by MRI signal changes. AIM OF THE STUDY: To assess dystrophic and/or non-dystrophic alterations such as fatty or connective tissue replacement and muscle edema in patients with severe recessive myotonia congenita. METHODS: We studied three seriously affected patients with myotonia congenita type Becker using multisequence whole-body high-field MRI. All patients had molecular genetic testing of the muscle chloride channel gene (CLCN1). RESULTS: Molecular genetic analyses demonstrated recessive CLCN1 mutations in all patients. Two related patients were compound heterozygous for two novel CLCN1 mutations, Q160H and L657P. None of the patients showed skeletal muscle signal changes indicative of fatty muscle degeneration or edema. Two patients showed muscle bulk hypertrophy of thighs and calves in line with the clinical appearance. CONCLUSIONS: We conclude that (i) chloride channel dysfunction alone does not result in skeletal muscle morphologic changes even in advanced stages of myotonia congenita, and (ii) MRI skeletal muscle alterations in myotonic dystrophy must be clear consequences of the dystrophic disease process.

Pattern of skeletal muscle involvement in primary dysferlinopathies: a whole-body 3.0-T magnetic resonance imaging study.

OBJECTIVES AND METHODS: Mutations in the gene encoding dysferlin cause limb girdle muscular dystrophy type 2B (LGMD2B), distal Miyoshi myopathy (MM), and a rare form of distal anterior compartment myopathy. To study the correlations between clinical manifestations and muscle imaging changes we conducted a 3.0-T magnetic resonance imaging (MRI) study in six German patients with primary dysferlinopathies defined by absence of dysferlin expression in muscle (MM, n = 3; LGMD2B, n = 2; hyperCKemia without clinical symptoms, n = 1). RESULTS: Patients with manifest myopathy had widespread muscular pathology. In analogy to previous imaging studies, we confirmed an involvement of the anterior and posterior thigh compartments and a predominant involvement of posterior lower legs. However, our whole-body MRI study further provided evidence of signal alterations in the glutei, erector spinae and shoulder girdle muscles. Correlation of clinical findings with imaging demonstrated the potential of MRI to detect subclinical muscle pathology. CONCLUSIONS: Whole-body 3.0-T MRI is a non-invasive method to demonstrate various degrees of skeletal muscle alterations and disease progression in muscular dystrophies. Furthermore, whole-body high-field MRI may serve as a helpful diagnostic tool in differentiating primary dysferlinopathies from other forms of LGMD and distal myopathies.

Long-term disease activity and disability progression in relapsing-remitting multiple sclerosis patients on natalizumab.

BACKGROUND: Natalizumab is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). Data on clinical and imaging measures predictive of disease activity and progression during treatment is limited. OBJECTIVE: To determine clinical and imaging predictors of long-term inflammatory disease activity and disability progression in RRMS patients on natalizumab. METHODS: Patients (n = 135) were selected from our prospective observational natalizumab cohort and monitored using brain MRI and extensive clinical testing. Progression and improvement on the Expanded Disability Status Scale (EDSS), no evidence of disease activity (NEDA) and no evidence of progression or active disease (NEPAD) status were determined using measurements after the initial phase of inflammation and the early anti-inflammatory impact of natalizumab. RESULTS: EDSS progression was seen in 43.7% of patients and EDSS improvement in 17.8%. Median follow-up was 4.9 years (IQR 3.6-6.0). Patients with a longer disease duration at natalizumab initiation have a higher hazard for earlier EDSS progression (HR 1.05, CI 1.00-1.09, p = 0.037) and a higher pre-baseline relapse rate predicted a longer NEPAD status (HR 1.70, CI 1.06-2.72, p = 0.028). CONCLUSION: The results suggest that starting natalizumab early, during active inflammatory disease results in a more favourable outcome. When taking into account early inflammation and the impact of natalizumab on disease activity during the initial treatment phase, a higher than expected proportion of patients showed disability progression.

MR imaging of the prostate at 3.0T with external phased array coil - preliminary results.

INTRODUCTION: Among all imaging modalities, MRI of the prostate has the highest sensitivity to predict extracapsular tumor spread, seems to have added value for the preoperative treatment planning. It is an adjunct tool in patients with high suspicion of prostate cancer and so far negative TRUS-guided biopsies. Due to the higher intrinsic signal, it is expected that 3.0T enables to image the prostate without endorectal coil. Aim of this study was to evaluate the diagnostic accuracy of phased array coil 3.0T MRI in patients with suspicion of prostate cancer. MATERIAL AND METHODS: A high spatial resolution T2-w 3.0T pulse sequence (0.47 x 0.47 x 3mm voxel size) was performed in 26 patients prior to US-guided biopsy. Qualitative analysis comprised visual signal to noise, tissue contrasts and motion artifacts. MR diagnoses were correlated with histology. Diagnostic indices for the detection of prostate cancer in the peripheral zone were calculated. RESULTS: Histopathologic examination revealed pro?state cancer in 12 and benign prostate disorders in 14 patients. Motion artifacts due to peristalsis were rated moderate. Mean visual signal to noise was high. Contrast between peripheral and central zone of the prostate was excellent. MRI had 4 false negative and 2 false positive diagnoses (sensitivity 66.7 %, specificity 86.7 % diagnostic accuracy 76.9%). CONCLUSION: At 3.0T, diagnostic indices for cancer detection seem to be comparable to data reported about endorectal 1.5T MRI. Thus 3.0 T offers new options for MR imaging of the prostate in selected patients who cannot or are not willing to be examined with the endorectal coil.

Double inversion recovery brain imaging at 3T: diagnostic value in the detection of multiple sclerosis lesions.

BACKGROUND AND PURPOSE: To prospectively determine the sensitivity in the detection of multiple sclerosis (MS) lesions by using double inversion recovery (DIR), fluid-attenuated inversion recovery (FLAIR), and T2-weighted turbo spin-echo (T2 TSE) MR imaging at 3T. METHODS: Seventeen patients presenting with a clinically isolated syndrome (CIS) suggestive of MS, 9 patients with definite MS, and 6 healthy control subjects were included. Imaging was performed on a 3T MR system using DIR, FLAIR, and T2 TSE sequences. Lesions were counted and classified according to 5 anatomic regions: infratentorial, periventricular, deep white matter, juxtacortical, and mixed white matter-gray matter. The sensitivity at DIR was compared with the corresponding sensitivity at FLAIR and T2 TSE sequence. The contrast between lesions and normal-appearing gray matter, normal-appearing white matter, and CSF was determined for all sequences. RESULTS: Because of higher lesion-white matter contrast, the DIR showed a higher number of lesions compared with the FLAIR (7% gain, P = 0.04) and the T2 TSE (15% gain, P = 0.01). The higher sensitivity was also significant for the infratentorial region compared with the FLAIR (56% gain, P = 0.02) and the T2 TSE (44% gain, P = 0.02). Compared with the FLAIR, no significant changes of the lesion load measurements were observed in the supratentorial brain: slightly higher numbers of periventricular and mixed gray matter-white matter lesions on the DIR were counterbalanced by a slightly reduced sensitivity regarding juxtacortical lesions. CONCLUSION: DIR brain imaging at 3T provides the highest sensitivity in the detection of MS lesions especially in the infratentorial region.