Papers by Friedemann Paul
Neurology, Jan 26, 2018
We aimed to evaluate racial differences in the clinical features of neuromyelitis optica spectrum... more We aimed to evaluate racial differences in the clinical features of neuromyelitis optica spectrum disorder. This retrospective review included 603 patients (304 Asian, 207 Caucasian, and 92 Afro-American/Afro-European), who were seropositive for anti-aquaporin-4 antibody, from 6 centers in Denmark, Germany, South Korea, United Kingdom, United States, and Thailand. Median disease duration at last follow-up was 8 years (range 0.3-38.4 years). Asian and Afro-American/Afro-European patients had a younger onset age than Caucasian patients (mean 36, 33, and 44 years, respectively; < 0.001). During the disease course, Caucasian patients (23%) had a lower incidence of brain/brainstem involvement than Asian (42%) and Afro-American/Afro-European patients (38%) ( < 0.001). Severe attacks (visual acuity ≤0.1 in at least one eye or Expanded Disability Status Scale score ≥6.0 at nadir) at onset occurred more frequently in Afro-American/Afro-European (58%) than in Asian (46%) and Caucasian (...
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Expert opinion on investigational drugs, 2018
In the short time since 2014, three pivotal, worldwide studies in neuromyelitis optica spectrum d... more In the short time since 2014, three pivotal, worldwide studies in neuromyelitis optica spectrum disorders have been launched: eculizumab, SA237 and inebelizumab, each based on a unique mechanism. Areas covered: In this review, we provide a discussion on the trial data available for each drug, a brief description of the trial design, and our expert opinion on the potential benefits and risks. Expert opinion: Eculizumab, a C5 complement inhibitor, may prove useful in the treatment of intractable cases of NMOSD, but physicians must be aware of the known risk of meningococcal infection. SA237, an interleukin-6 receptor blocker, may be effective at reducing relapse risk, and also has the potential to reduce neuropathic pain in NMOSD. Inebelizumab, a B cell depleting agent, has never been tested in NMOSD, but based on extensive evidence of efficacy with B cell depletion using rituximab, inebelizumab is expected to work at least as well.
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Multiple sclerosis and related disorders, Jan 23, 2018
MOG antibody disease is an autoimmune disease of the central nervous system associated with a ser... more MOG antibody disease is an autoimmune disease of the central nervous system associated with a serological antibody against MOG, myelin oligodendrocyte glycoprotein. MOG is a glycoprotein expressed on the outer membrane of myelin and solely found within the central nervous system, including in the brain, optic nerves and spinal cord. Clinically, the disease resembles neuromyelitis optica spectrum disorders in the predilection for relapses of optic neuritis and transverse myelitis. In addition, acute disseminated encephalomyelitis (ADEM) is a well-recognized phenotype of MOG antibody disease in children. In recent studies around the world where MOG testing is available, up to 42% of NMOSD patients who test seronegative for the AQP4 antibody test positive for MOG antibodies. MOG antibody disease has thus recently emerged as a distinct entity carved out of the patient population diagnosed with NMOSD. In this review, we examine the history of the MOG antibody and its relevance to demyeli...
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Neurology(R) neuroimmunology & neuroinflammation, 2017
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Radiology, 2017
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EPMA Journal, 2016
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Journal of Magnetic Resonance Imaging, 2015
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Multiple Sclerosis Journal, 2016
Background: Previous studies have postulated an association between dentate nucleus T1 hyperinten... more Background: Previous studies have postulated an association between dentate nucleus T1 hyperintensity and multiple sclerosis (MS)-related progressive neurodegeneration. Therefore, MS patients have been excluded from most studies investigating brain deposition of gadolinium-based contrast agents (GBCAs). Objective: To study the hypothesis that dentate nucleus T1 hyperintensity in MS patients is associated with GBCA administration. Methods: In a cohort of 97 MS patients, the dentate-to-pons signal intensity ratio (DPSIR) was calculated for 265 consecutive T1-weighted magnetic resonance (MR) scans (including sessions with and without the administration of GBCA). Patients exclusively received either gadopentetate dimeglumine (Gd-DTPA, linear) or gadobutrol (Gd-BT-DO3A, macrocyclic). Results: In patients receiving Gd-DTPA, DPSIR increased significantly between the first and the last scan (+0.009, p
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Multiple Sclerosis, 2010
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Objective: To characterize paramagnetic MRI phase signal abnormalities in neuromyelitis optica sp... more Objective: To characterize paramagnetic MRI phase signal abnormalities in neuromyelitis optica spectrum disorder (NMOSD) vs multiple sclerosis (MS) lesions in a cross-sectional study. Methods: Ten patients with NMOSD and 10 patients with relapsing-remitting MS underwent 7-tesla brain MRI including supratentorial T2*-weighted imaging and supratentorial susceptibility weighted imaging. Next, we analyzed intra-and perilesional paramagnetic phase changes on susceptibility weighted imaging filtered magnetic resonance phase images. Results: We frequently observed paramagnetic rim-like (75 of 232 lesions, 32%) or nodular (32 of 232 lesions, 14%) phase changes in MS lesions, but only rarely in NMOSD lesions (rim-like phase changes: 2 of 112 lesions, 2%, p , 0.001; nodular phase changes: 2 of 112 lesions, 2%, p , 0.001). Conclusions: Rim-like or nodular paramagnetic MRI phase changes are characteristic for MS lesions and not frequently detectable in NMOSD. Future prospective studies should ask whether these imaging findings can be used as a biomarker to distinguish between NMOSD-and MS-related brain lesions. GLOSSARY ICC 5 intraclass correlation; MS 5 multiple sclerosis; NMOSD 5 neuromyelitis optica spectrum disorder; SWI 5 susceptibility weighted imaging; T2*w 5 T2*-weighted. Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) are distinct autoimmune CNS diseases with sometimes overlapping clinical phenotypes. 1 Since treatment options for these 2 CNS diseases differ considerably, 1 the distinction between NMOSD and MS is of high clinical relevance. Recently, new international consensus diagnostic criteria were proposed for NMOSD emphasizing the role of MRI and aquaporin-4 immunoglobulin G antibody testing. 2 Notwithstanding this success, the distinction of NMOSD vs MS can still be challenging in current clinical practice. Ultra-high field MRI at 7 tesla (T) has improved the detection and morphologic characterization of brain lesions by visualizing a central intralesional vein and a T2*-weighted (T2*w) hypointense rim around many MS lesions. 3,4 Contrarily, these imaging features are only rarely depictable in NMOSD lesions. 3,4 At 3T, susceptibility-induced MRI phase signal changes were reported to be specific for MS in contrast to other neurologic disorders such as migraine, antiphospholipid syndrome, and Parkinson disease. 5 Inspired by these findings, we rescanned previously reported patients with NMOSD at 7T 3 and included additional NMOSD cases to describe MRI phase signal changes in NMOSD vs MS lesions in a cross-sectional study.
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Journal of Neurology, Neurosurgery & Psychiatry, 2016
Antibodies to cell surface central nervous system proteins help to diagnose conditions which ofte... more Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD). Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1). Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays. The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples. The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.
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Movement Disorders Clinical Practice, 2014
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Multiple Sclerosis Journal, 2014
The pathogenesis of multiple sclerosis (MS) involves alterations to multiple pathways and process... more The pathogenesis of multiple sclerosis (MS) involves alterations to multiple pathways and processes, which represent a significant challenge for developing more-effective therapies. Systems biology approaches that study pathway dysregulation should offer benefits by integrating molecular networks and dynamic models with current biological knowledge for understanding disease heterogeneity and response to therapy. In MS, abnormalities have been identified in several cytokine-signaling pathways, as well as those of other immune receptors. Among the downstream molecules implicated are Jak/Stat, NF-Kb, ERK1/3, p38 or Jun/Fos. Together, these data suggest that MS is likely to be associated with abnormalities in apoptosis/cell death, microglia activation, blood-brain barrier functioning, immune responses, cytokine production, and/or oxidative stress, although which pathways contribute to the cascade of damage and can be modulated remains an open question. While current MS drugs target some of these pathways, others remain untouched. Here, we propose a pragmatic systems analysis approach that involves the large-scale extraction of processes and pathways relevant to MS. These data serve as a scaffold on which computational modeling can be performed to identify disease subgroups based on the contribution of different processes. Such an analysis, targeting these relevant MS-signaling pathways, offers the opportunity to accelerate the development of novel individual or combination therapies.
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JAMA neurology, Jan 26, 2015
Brain parenchymal lesions are frequently observed on conventional magnetic resonance imaging (MRI... more Brain parenchymal lesions are frequently observed on conventional magnetic resonance imaging (MRI) scans of patients with neuromyelitis optica (NMO) spectrum disorder, but the specific morphological and temporal patterns distinguishing them unequivocally from lesions caused by other disorders have not been identified. This literature review summarizes the literature on advanced quantitative imaging measures reported for patients with NMO spectrum disorder, including proton MR spectroscopy, diffusion tensor imaging, magnetization transfer imaging, quantitative MR volumetry, and ultrahigh-field strength MRI. It was undertaken to consider the advanced MRI techniques used for patients with NMO by different specialists in the field. Although quantitative measures such as proton MR spectroscopy or magnetization transfer imaging have not reproducibly revealed diffuse brain injury, preliminary data from diffusion-weighted imaging and brain tissue volumetry indicate greater white matter than...
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Journal of Neurotrauma, 2015
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Nature Reviews Neurology, 2014
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International journal of molecular sciences, 2015
Quality of Life (QoL) is decreased in multiple sclerosis (MS), but studies about the impact of sl... more Quality of Life (QoL) is decreased in multiple sclerosis (MS), but studies about the impact of sleep disorders (SD) on health-related quality of Life (HRQoL) are lacking. From our original cohort, a cross-sectional polysomnographic (PSG) study in consecutive MS patients, we retrospectively analysed the previously unpublished data of the Nottingham Health Profile (NHP). Those MS patients suffering from sleep disorders (n = 49) showed significantly lower HRQoL compared to MS patients without sleep disorders (n = 17). Subsequently, we classified the patients into four subgroups: insomnia (n = 17), restless-legs syndrome, periodic limb movement disorder and SD due to leg pain (n = 24), obstructive sleep apnea (n = 8) and patients without sleep disorder (n = 17). OSA and insomnia patients showed significantly higher NHP values and decreased HRQoL not only for the sleep subscale but also for the "energy" and "emotional" area of the NHP. In addition, OSA patients also s...
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Neuropsychiatric disease and treatment, 2015
There are few studies describing periodic limb movement syndrome (PLMS) in rapid eye movement (RE... more There are few studies describing periodic limb movement syndrome (PLMS) in rapid eye movement (REM) sleep in patients with narcolepsy, restless legs syndrome, REM sleep behavior disorder, and spinal cord injury, and to a lesser extent, in insomnia patients and healthy controls, but no published cases in multiple sclerosis (MS). The aim of this study was to investigate PLMS in REM sleep in MS and to analyze whether it is associated with age, sex, disability, and laboratory findings. From a study of MS patients originally published in 2011, we retrospectively analyzed periodic limb movements (PLMs) during REM sleep by classifying patients into two subgroups: PLM during REM sleep greater than or equal to ten per hour of REM sleep (n=7) vs less than ten per hour of REM sleep (n=59). A univariate analysis between PLM and disability, age, sex, laboratory findings, and polysomnographic data was performed. MS patients with more than ten PLMs per hour of REM sleep showed a significantly high...
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Investigative Opthalmology & Visual Science, 2015
To evaluate whether the densities of corneal subbasal nerves and epithelial immune dendritiform c... more To evaluate whether the densities of corneal subbasal nerves and epithelial immune dendritiform cells (DCs) are comparable between a set of three representative standard images of in vivo confocal microscopy (IVCM) and the wide-field mapped composite IVCM images. This prospective, cross-sectional, and masked study included 110 eyes of 58 patients seen in a neurology clinic who underwent laser-scanning IVCM (Heidelberg Retina Tomograph 3) of the central cornea. Densities of subbasal corneal nerves and DCs were compared between the average of three representative standard images and the wide-field mapped composite images, which were reconstructed by automated mapping. There were no statistically significant differences between the average of three representative standard images (0.16 mm2 each) and the wide-field composite images (1.29 ± 0.64 mm2) in terms of mean subbasal nerve density (17.10 ± 6.10 vs. 17.17 ± 5.60 mm/mm2, respectively, P = 0.87) and mean subbasal DC density (53.2 ± 67.8 vs. 49.0 ± 54.3 cells/mm2, respectively, P = 0.43). However, there were notable differences in subbasal nerve and DC densities between these two methods in eyes with very low nerve density or very high DC density. There are no significant differences in the mean subbasal nerve and DC densities between the average values of three representative standard IVCM images and wide-field mapped composite images. Therefore, these standard images can be used in clinical studies to accurately measure cellular structures in the subbasal layer.
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Papers by Friedemann Paul