Publications by authors named "Michael Linnebank"

113 Publications

Improved functional and histochemical outcomes in l-DOPA plus tolcapone treated VMAT2-deficient mice.

Neuropharmacology 2020 12 7;181:108353. Epub 2020 Oct 7.

Neurology Department, University Hospital Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland; University Center of Competence Sleep & Health Zurich, University of Zurich, Zurich, Switzerland; Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland. Electronic address:

Parkinson disease is typically treated with L-3,4-dihydroxyphenylalanine (or levodopa) co-prescribed with concentration stabilizers to prevent undesired motor fluctuations. However, the beneficial role of the chronic combined therapy on disease progression has not been thoroughly explored. We hypothesized that tolcapone, a catechol-O-methyl-transferase inhibitor, co-administered with levodopa may offer beneficial long-term disease-modifying effects through its dopamine stabilization actions. Here, we followed vesicular monoamine transporter 2-deficient and wild-type mice treated twice daily per os with vehicle, levodopa (20 mg/kg), tolcapone (15 mg/kg) or levodopa (12.5 mg/kg) + tolcapone (15 mg/kg) for 17 weeks. We assessed open field, bar test and rotarod performances at baseline and every 4th week thereafter, corresponding to OFF-medication weeks. Finally, we collected coronal sections from the frontal caudate-putamen and determined the reactivity level of dopamine transporter. Vesicular monoamine transporter 2-deficient mice responded positively to chronic levodopa + tolcapone intervention in the bar test during OFF-periods. Neither levodopa nor tolcapone interventions offered significant improvements on their own. Similarly, chronic levodopa + tolcapone intervention was associated with partially rescued dopamine transporter levels, whereas animals treated solely with levodopa or tolcapone did not present this effect. Interestingly, 4-month progression of bar test scores correlated significantly with dopamine-transporter-label density. Overall, we observed a moderate functional and histopathological improvement effect by chronic dopamine replacement when combined with tolcapone in vesicular monoamine transporter 2-deficient mice. Altogether, chronic stabilization of dopamine levels by catechol-O-methyl-transferase inhibition, besides its intended immediate actions, arises as a potential long-term beneficial approach during the progression of Parkinson disease.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108353DOI Listing
December 2020

Impaired speed-dependent modulation of the gait pattern in multiple sclerosis.

J Neurol 2020 Oct 4;267(10):2998-3007. Epub 2020 Jun 4.

Spinal Cord Injury Center, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland.

Background: Walking dysfunction is common in people with multiple sclerosis (MS). Besides walking speed or endurance, one crucial feature of ambulatory function is the ability to adjust the gait pattern according to walking speed which relies on the integrity of spinal motor centres, their reciprocal connections to supraspinal networks and peripheral sensory input.

Objective: To investigate the capacity of people with MS to modify their gait pattern in response to changes in walking speed.

Methods: 3D gait analysis during free treadmill walking was performed in 35 people with MS and 20 healthy controls. Twelve kinematic parameters ranging from basic spatiotemporal measures to complex indicators of intralimb coordination were assessed at different absolute and relative walking speeds.

Results: Cadence, double-limb support time, trunk movements and especially measures of intralimb coordination demonstrated significantly less speed-dependent modifications in MS than in controls. These limitations were more prominent in subjects with stronger MS-related impairment (worse outcome in clinical walking tests, higher Expanded Disability Status Scale).

Conclusion: The incapacity to modify specific elements of the walking pattern according to walking speed contributes to gait dysfunction in people with MS limiting activities of daily living. Gait modulation may serve as sensitive marker of walking function in MS.

Trial Registration: Clinicaltrials.gov, NCT01576354; first posted April 12, 2012.
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http://dx.doi.org/10.1007/s00415-020-09965-3DOI Listing
October 2020

Repeated assessment of key clinical walking measures can induce confounding practice effects.

Mult Scler 2020 10 13;26(11):1298-1302. Epub 2019 May 13.

Spinal Cord Injury Centre, Balgrist University Hospital, Zurich, Switzerland/Department of Neurology, University Hospital Zurich, Zurich, Switzerland.

Accurate functional outcome measures are critical for both clinical trials and routine patient assessments. Many functional outcomes improve with test repetition, a phenomenon that can confound the findings of longitudinal assessments. In this viewpoint, we tackle the poorly considered issue of practice effects in prevailing clinical walking tests based on current literature, while also presenting the original data from our own work, in which we investigated practice effects in the timed 25-foot walk (T25FW), timed-up and go (TUG), and 2-minute walk test (2MWT). In these tests, performed on 3 consecutive days in 10 patients with multiple sclerosis and 40 healthy controls, we observed significant practice effects in several established walking outcomes, including a 9.0% improvement in patients' TUG performance ( = 0.0146). Pre-training in these walking tests prior to baseline measurement may mitigate practice effects, thereby improving the accuracy and value of their repeated use in research and clinical settings.
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http://dx.doi.org/10.1177/1352458519845839DOI Listing
October 2020

Familiarization with treadmill walking: How much is enough?

Sci Rep 2019 03 26;9(1):5232. Epub 2019 Mar 26.

Spinal Cord Injury Center, Balgrist University Hospital, Forchstrasse 340, Zurich, Switzerland.

Treadmill-based gait analysis is widely used to investigate walking pathologies and quantify treatment effects on locomotion. Differential sensorimotor conditions during overground vs. treadmill walking necessitate initial familiarization to treadmill walking. Currently, there is no standardized treadmill acclimatization protocol and insufficient familiarization potentially confounds analyses. We monitored initial adaptations to treadmill walking in 40 healthy adults. Twenty-six walking parameters were assessed over 10 minutes with marker-based kinematic analysis and acclimatization profiles were generated. While 16 walking parameters demonstrated initial acclimatization followed by plateau performance, ten parameters remained stable. Distal lower limb control including ankle range of motion, toe trajectory and foot clearance underwent substantial adaptations. Moreover, intralimb coordination and gait variability also demonstrated acclimatization, while measures of symmetry and interlimb coordination did not. All parameters exhibiting a plateau after acclimatization did so within 6-7 minutes (425 strides). Older participants and those naïve to treadmill walking showed adaptations with higher amplitudes but over similar timescales. Our results suggest a minimum of 6 minutes treadmill acclimatization is required to reach a stable performance, and that this should suffice for both older and naïve healthy adults. The presented data aids in optimizing treadmill-based gait analysis and contributes to improving locomotor assessments in research and clinical settings.
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http://dx.doi.org/10.1038/s41598-019-41721-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435738PMC
March 2019

Probing Corticospinal Control During Different Locomotor Tasks Using Detailed Time-Frequency Analysis of Electromyograms.

Front Neurol 2019 29;10:17. Epub 2019 Jan 29.

Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.

Locomotion relies on the fine-tuned coordination of different muscles which are controlled by particular neural circuits. Depending on the attendant conditions, walking patterns must be modified to optimally meet the demands of the task. Assessing neuromuscular control during dynamic conditions is methodologically highly challenging and prone to artifacts. Here we aim at assessing corticospinal involvement during different locomotor tasks using non-invasive surface electromyography. Activity in tibialis anterior (TA) and gastrocnemius medialis (GM) muscles was monitored by electromyograms (EMGs) in 27 healthy volunteers (11 female) during regular walking, walking while engaged in simultaneous cognitive dual tasks, walking with partial visual restriction, and skilled, targeted locomotion. Whereas EMG intensity of the TA and GM was considerably altered while walking with partial visual restriction and during targeted locomotion, dual-task walking induced only minor changes in total EMG intensity compared to regular walking. Targeted walking resulted in enhanced EMG intensity of GM in the frequency range associated with Piper rhythm synchronies. Likewise, targeted walking induced enhanced EMG intensity of TA at the Piper rhythm frequency around heelstrike, but not during the swing phase. Our findings indicate task- and phase-dependent modulations of neuromuscular control in distal leg muscles during various locomotor conditions in healthy subjects. Enhanced EMG intensity in the Piper rhythm frequency during targeted walking points toward enforced corticospinal drive during challenging locomotor tasks. These findings indicate that comprehensive time-frequency EMG analysis is able to gauge cortical involvement during different movement programs in a non-invasive manner and might be used as complementary diagnostic tool to assess baseline integrity of the corticospinal tract and to monitor changes in corticospinal drive as induced by neurorehabilitation interventions or during disease progression.
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http://dx.doi.org/10.3389/fneur.2019.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361808PMC
January 2019

Assessment of Clinically Meaningful Improvements in Self-Reported Walking Ability in Participants with Multiple Sclerosis: Results from the Randomized, Double-Blind, Phase III ENHANCE Trial of Prolonged-Release Fampridine.

CNS Drugs 2019 01;33(1):61-79

Biogen, Cambridge, MA, USA.

Background: Walking impairment is a hallmark of multiple sclerosis (MS). It affects > 90% of individuals over time, reducing independence and negatively impacting health-related quality of life, productivity, and daily activities. Walking impairment is consistently reported as one of the most distressing impairments by individuals with MS. Prolonged-release (PR)-fampridine previously has been shown to improve objectively measured walking speed in walking-impaired adults with MS. The impact of PR-fampridine from the perspective of the individual with MS warrants full and detailed examination.

Objective: The objective of this study was to evaluate whether PR-fampridine has a clinically meaningful effect on self-reported walking ability in walking-impaired participants with MS.

Methods: ENHANCE was a phase III, randomized, double-blind, placebo-controlled study of PR-fampridine 10 mg twice daily in walking-impaired individuals age 18-70 years with either relapsing or progressive forms of MS and an Expanded Disability Status Scale (EDSS) score of 4.0-7.0 at screening. Participants were stratified by EDSS score (≤ 6.0 or 6.5-7.0) at randomization to ensure a balanced level of disability in the treatment groups. The primary endpoint was the proportion of participants with a mean improvement in the 12-item Multiple Sclerosis Walking Scale (MSWS-12) score exceeding the predefined threshold for clinically meaningful improvement (≥ 8 points) over 24 weeks. Secondary endpoints included the proportion with ≥ 15% improvement in Timed Up and Go (TUG) speed, and mean changes in Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS), Berg Balance Scale (BBS), and ABILHAND scores over 24 weeks.

Results: In total, 636 participants with MS were randomized (PR-fampridine, n = 317; placebo, n = 319; modified intention-to-treat sample: PR-fampridine, n = 315; placebo, n = 318). At baseline in the PR-fampridine and placebo groups, 46% and 51% had a progressive form of MS, median [range] EDSS scores were 6.0 [4.0-7.0] and 5.5 [4.0-7.0], mean [range] MSWS-12 scores were 63.6 [0-100] and 65.4 [0-100], and mean [range] TUG speed was 0.38 [0.0-1.0] and 0.38 [0.0-1.2] feet/s, respectively. A significantly higher percentage of PR-fampridine-treated participants (136/315 [43.2%]) had clinically meaningful improvement in MSWS-12 score over 24 weeks versus placebo (107/318 [33.6%]; odds ratio 1.61 [95% confidence interval 1.15-2.26]; p = 0.006). For PR-fampridine versus placebo, significantly more participants had a ≥ 15% improvement in TUG speed, and there was significantly greater mean improvement in MSIS-29 PHYS score (p < 0.05); numerical improvements that were not statistically significant were observed in BBS/ABILHAND. Adverse events that were more common in the PR-fampridine group than placebo group (difference ≥ 3%) by Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term were urinary tract infection and insomnia. There were no seizures reported.

Conclusions: PR-fampridine treatment resulted in sustained, clinically meaningful improvements over 24 weeks in self-reported walking and functional ability in walking-disabled participants with MS. CLINICALTRIALS.

Gov Identifier: NCT02219932.
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http://dx.doi.org/10.1007/s40263-018-0586-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328522PMC
January 2019

Prolonged-release fampridine in multiple sclerosis: clinical data and real-world experience. Report of an expert meeting.

Ther Adv Neurol Disord 2018 5;11:1756286418803248. Epub 2018 Oct 5.

Center of Clinical Neuroscience, Department of Neurology, MS Center Dresden, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.

Prolonged-release (PR) fampridine is the only approved medication to improve walking in multiple sclerosis (MS), having been shown to produce a clinically meaningful improvement in walking ability in the subset of MS patients with Expanded Disability Status Scale 4-7. Recent responder subgroup analyses in the phase III ENHANCE study show a large effect size in terms of an increase of 20.58 points on the patient-reported 12-item MS Walking Scale in the 43% of patients classified as responders to PR-fampridine, corresponding to a standardized response mean of 1.68. Use of PR-fampridine in clinical practice varies across Europe, depending partly on whether it is reimbursed. A group of European MS experts met in June 2017 to discuss their experience with using PR-fampridine, including their views on the patient population for treatment, assessment of treatment response, re-testing and re-treatment, and stopping criteria. This article summarizes the experts' opinions on how PR-fampridine can be used in real-world clinical practice to optimize the benefits to people with MS with impaired walking ability.
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http://dx.doi.org/10.1177/1756286418803248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174649PMC
October 2018

Profiling walking dysfunction in multiple sclerosis: characterisation, classification and progression over time.

Sci Rep 2018 03 21;8(1):4984. Epub 2018 Mar 21.

Department of Neurology, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland.

Gait dysfunction is a common and relevant symptom in multiple sclerosis (MS). This study aimed to profile gait pathology in gait-impaired patients with MS using comprehensive 3D gait analysis and clinical walking tests. Thirty-seven patients with MS walked on the treadmill at their individual, sustainable speed while 20 healthy control subjects walked at all the different patient's paces, allowing for comparisons independent of walking velocity. Kinematic analysis revealed pronounced restrictions in knee and ankle joint excursion, increased gait variability and asymmetry along with impaired dynamic stability in patients. The most discriminative single gait parameter, differentiating patients from controls with an accuracy of 83.3% (χ test; p = 0.0001), was reduced knee range of motion. Based on hierarchical cluster and principal component analysis, three principal pathological gait patterns were identified: a spastic-paretic, an ataxia-like, and an unstable gait. Follow-up assessments after 1 year indicated deterioration of walking function, particularly in patients with spastic-paretic gait patterns. Our findings suggest that impaired knee/ankle control is common in patients with MS. Personalised gait profiles and clustering algorithms may be promising tools for stratifying patients and to inform patient-tailored exercise programs. Responsive, objective outcome measures are important for monitoring disease progression and treatment effects in MS trials.
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http://dx.doi.org/10.1038/s41598-018-22676-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862880PMC
March 2018

Nogo-A antibodies enhance axonal repair and remyelination in neuro-inflammatory and demyelinating pathology.

Acta Neuropathol 2017 09 23;134(3):423-440. Epub 2017 Jun 23.

Brain Research Institute, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.

Two hallmarks of chronic multiple sclerosis lesions are the absence of significant spontaneous remyelination and primary as well as secondary neurodegeneration. Both characteristics may be influenced by the presence of inhibitory factors preventing myelin and neuronal repair. We investigated the potential of antibodies against Nogo-A, a well-known inhibitory protein for neuronal growth and plasticity, to enhance neuronal regeneration and remyelination in two animal models of multiple sclerosis. We induced a targeted experimental autoimmune encephalomyelitis (EAE) lesion in the dorsal funiculus of the cervical spinal cord of adult rats resulting in a large drop of skilled forelimb motor functions. We subsequently observed improved recovery of forelimb function after anti-Nogo-A treatment. Anterograde tracing of the corticospinal tract revealed enhanced axonal sprouting and arborisation within the spinal cord gray matter preferentially targeting pre-motor and motor spinal cord laminae on lesion level and above in the anti-Nogo-A-treated animals. An important additional effect of Nogo-A-neutralization was enhanced remyelination observed after lysolecithin-induced demyelination of spinal tracts. Whereas remyelinated fiber numbers in the lesion site were increased several fold, no effect of Nogo-A-inhibition was observed on oligodendrocyte precursor proliferation, migration, or differentiation. Enhancing remyelination and promoting axonal regeneration and plasticity represent important unmet medical needs in multiple sclerosis. Anti-Nogo-A antibodies hold promise as a potential new therapy for multiple sclerosis, in particular during the chronic phase of the disease when neurodegeneration and remyelination failure determine disability evolution.
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http://dx.doi.org/10.1007/s00401-017-1745-3DOI Listing
September 2017

Minimum toe clearance: probing the neural control of locomotion.

Sci Rep 2017 05 15;7(1):1922. Epub 2017 May 15.

Spinal Cord Injury Center, University Hospital Balgrist, Forchstrasse 340, 8008, Zurich, Switzerland.

Minimum toe clearance (MTC) occurs during a highly dynamic phase of the gait cycle and is associated with the highest risk of unintentional contact with obstacles or the ground. Age, cognitive function, attention and visual feedback affect foot clearance but how these factors interact to influence MTC control is not fully understood. We measured MTC in 121 healthy individuals aged 20-80 under four treadmill walking conditions; normal walking, lower visual field restriction and two Stroop colour/word naming tasks of two difficulty levels. Competition for cognitive and attentional resources from the Stroop task resulted in significantly lower mean MTC in older adults, with the difficult Stroop task associated with a higher frequency of extremely low MTC values and subsequently an increased modelled probability of tripping in this group. While older adults responded to visual restriction by markedly skewing MTC distributions towards higher values, this condition was also associated with frequent, extremely low MTC values. We reveal task-specific, age-dependent patterns of MTC control in healthy adults. Age-related differences are most pronounced during heavy, distracting cognitive load. Analysis of critically-low MTC values during dual-task walking may have utility in the evaluation of locomotor control and fall risk in older adults and patients with motor control deficits.
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http://dx.doi.org/10.1038/s41598-017-02189-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432520PMC
May 2017

High EDSS can predict risk for upper urinary tract damage in patients with multiple sclerosis.

Mult Scler 2018 04 3;24(4):529-534. Epub 2017 Apr 3.

Neuro-Urology, Spinal Cord Injury Center & Research, University of Zürich, Balgrist University Hospital, Zürich, Switzerland.

Background: Neurogenic lower urinary tract dysfunction (NLUTD) is very common in patients with multiple sclerosis (MS), and it might jeopardize renal function and thereby increase mortality. Although there are well-known urodynamic risk factors for upper urinary tract damage, no clinical prediction parameters are available.

Objective: We aimed to assess clinical parameters potentially predicting urodynamic risk factors for upper urinary tract damage.

Methods: A consecutive series of 141 patients with MS referred from neurologists for primary neuro-urological work-up including urodynamics were prospectively evaluated. Clinical parameters taken into account were age, sex, duration, and clinical course of MS and Expanded Disability Status Scale (EDSS).

Results: Multivariate modeling revealed EDSS as a clinical parameter significantly associated with urodynamic risk factors for upper urinary tract damage (odds ratio = 1.34, 95% confidence interval (CI) = 1.06-1.71, p = 0.02). Using receiver operator characteristic (ROC) curves, an EDSS of 5.0 as cutoff showed a sensitivity of 86%-87% and a specificity of 52% for at least one urodynamic risk factor for upper urinary tract damage.

Conclusion: High EDSS is significantly associated with urodynamic risk factors for upper urinary tract damage and allows a risk-dependent stratification in daily neurological clinical practice to identify MS patients requiring further neuro-urological assessment and treatment.
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http://dx.doi.org/10.1177/1352458517703801DOI Listing
April 2018

Increasing cognitive load attenuates right arm swing in healthy human walking.

R Soc Open Sci 2017 Jan 25;4(1):160993. Epub 2017 Jan 25.

Spinal Cord Injury Center , University Hospital Balgrist , Forchstrasse 340, 8008 Zurich , Switzerland.

Human arm swing looks and feels highly automated, yet it is increasingly apparent that higher centres, including the cortex, are involved in many aspects of locomotor control. The addition of a cognitive task increases arm swing asymmetry during walking, but the characteristics and mechanism of this asymmetry are unclear. We hypothesized that this effect is lateralized and a Stroop word-colour naming task-primarily involving left hemisphere structures-would reduce right arm swing only. We recorded gait in 83 healthy subjects aged 18-80 walking normally on a treadmill and while performing a congruent and incongruent Stroop task. The primary measure of arm swing asymmetry-an index based on both three-dimensional wrist trajectories in which positive values indicate proportionally smaller movements on the right-increased significantly under dual-task conditions in those aged 40-59 and further still in the over-60s, driven by reduced right arm flexion. Right arm swing attenuation appears to be the norm in humans performing a locomotor-cognitive dual-task, confirming a prominent role of the brain in locomotor behaviour. Women under 60 are surprisingly resistant to this effect, revealing unexpected gender differences atop the hierarchical chain of locomotor control.
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http://dx.doi.org/10.1098/rsos.160993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319362PMC
January 2017

Intrauterine valproate exposure is associated with alterations in hippocampal cell numbers and folate metabolism in a rat model of valproate teratogenicity.

Seizure 2017 Mar 27;46:7-12. Epub 2017 Jan 27.

Helios-Klinik Hagenbrock-Ambrock, Hagen, Germany.

Purpose: Valproate is one of the most commonly used anticonvulsive drugs. Despite its significant benefits, the teratogenicity of valproate is a relevant problem in the treatment of women of childbearing age. In addition to major congenital malformations, such as neural tube defects, reduced intelligence and attention after intrauterine valproate exposure are reported. Until now the mechanisms of teratogenicity of VPA are poorly understood and concepts how to reduce valproate teratogenicity are lacking.

Methods: In a rat model of valproate teratogenicity we examined hippocampal cell structure in 4 week old animals with a stereological approach. As potential mechanisms of VPA teratogenicity we examined histone acetylation by western blotting and metabolites of the folate metabolism as well as global DNA methylation by tandem mass spectrometry in the brain and liver tissue of newborn pups (p0).

Results: We found an increase in the number of neurons in the hippocampal areas CA1/2 (p=0.018) and CA3 (p=0.022), as well as a decreased number of astrocytes in CA1/2 (p=0.004) and CA3 (p=0.003) after intrauterine VPA exposure, as a possible indication of altered cell differentiation during intrauterine VPA exposure. Valproate exposure was also associated with an increase in 5-methyl-tetrahydrofolate (THF) (p=0.002) and a decrease in 5-10-methenyl-THF in the brain of newborn pups, as well as a reduced homocysteine plasma level (p<0.001). The described changes in hippocampal cell numbers and folate metabolism were only significant after high-dose intrauterine VPA exposure indicating a dose-dependent effect. VPA exposure was not associated with changes in histone acetylation or global DNA methylation in brain tissue in newborn pups.

Conclusion: This study shows that intrauterine VPA exposure is associated with changes in hippocampal cell numbers in the CA1/2 and CA3 region and in folate metabolism.
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http://dx.doi.org/10.1016/j.seizure.2017.01.003DOI Listing
March 2017

Cystatin F is a biomarker of prion pathogenesis in mice.

PLoS One 2017 8;12(2):e0171923. Epub 2017 Feb 8.

Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.

Misfolding of the cellular prion protein (PrPC) into the scrapie prion protein (PrPSc) results in progressive, fatal, transmissible neurodegenerative conditions termed prion diseases. Experimental and epidemiological evidence point toward a protracted, clinically silent phase in prion diseases, yet there is no diagnostic test capable of identifying asymptomatic individuals incubating prions. In an effort to identify early biomarkers of prion diseases, we have compared global transcriptional profiles in brains from pre-symptomatic prion-infected mice and controls. We identified Cst7, which encodes cystatin F, as the most strongly upregulated transcript in this model. Early and robust upregulation of Cst7 mRNA levels and of its cognate protein was validated in additional mouse models of prion disease. Surprisingly, we found no significant increase in cystatin F levels in both cerebrospinal fluid or brain parenchyma of patients with Creutzfeldt-Jakob disease compared to Alzheimer's disease or non-demented controls. Our results validate cystatin F as a useful biomarker of early pathogenesis in experimental models of prion disease, and point to unexpected species-specific differences in the transcriptional responses to prion infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171923PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298286PMC
August 2017

Monitoring long-term efficacy of fampridine in gait-impaired patients with multiple sclerosis.

Neurology 2017 Feb 1;88(9):832-841. Epub 2017 Feb 1.

From the Department of Neurology (L.F., B.Z., S.K. K.R., L.L., D.W., T.S., P.G., J.A.P., M.W., M.L.), University Hospital Zurich; Spinal Cord Injury Center (T.K.), Balgrist University Hospital, Zurich, Switzerland; and Department of Neurology (M.L.), Helios-Klinik Hagen-Ambrock, Hagen, Germany.

Objective: To expand upon the limited knowledge of the long-term effects of prolonged-release (PR) fampridine in patients with multiple sclerosis (PwMS) regarding safety, walking improvements, and changes in drug responsiveness.

Methods: Fifty-three PwMS who completed the FAMPKIN core study were included in this extension trial. Drug efficacy was assessed in an open-label and randomized double-blind, placebo-controlled study design with regular baseline assessments over a period of 2 years using the Timed 25-Foot Walk (T25FW), 6-Minute Walk Test (6MWT), and 12-item MS Walking Scale (MSWS-12) as outcome measures.

Results: The data showed good tolerability and persisting efficacy of PR fampridine during long-term treatment in PwMS. Significant improvements in walking speed, endurance, and self-perceived ambulatory function were observed during open-label (T25FW: +11.5%; 6MWT: 10.7%; MSWS-12: 6.1 points) and double-blind controlled treatment with PR fampridine (T25FW: +13.1%; 6MWT: 11.9%; MSWS-12: 7.4 points). Several patients showed changes in drug responsiveness over time, resulting in an increased proportion of patients exceeding 10% or 20% improvements in walking measures after long-term treatment.

Conclusions: Efficacy and tolerability data confirmed PR fampridine as a valuable long-term treatment for improving ambulatory function in gait-impaired PwMS. Similar results in open-label and double-blind phases reveal that the walking tests used are objective and reliable. The considerable proportion of patients in whom responsiveness to PR fampridine changed over time emphasizes the importance of regular reassessment of drug efficacy in clinical practice to optimize treatment. Such reassessments seem to be particularly important in patients with poor initial drug responses, as this group demonstrated enhanced responsiveness after long-term treatment.

Clinicaltrialsgov Identifier: NCT01576354.

Classification Of Evidence: This study provides Class II evidence that PR fampridine significantly improved gait compared to placebo in a 2-week study in PwMS who had been using PR fampridine for 2 years.
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http://dx.doi.org/10.1212/WNL.0000000000003656DOI Listing
February 2017

Nogo-A Antibodies for Progressive Multiple Sclerosis.

CNS Drugs 2017 Mar;31(3):187-198

Brain Research Institute, University of Zurich, Zurich, Switzerland.

Most of the current therapies, as well as many of the clinical trials, for multiple sclerosis (MS) target the inflammatory autoimmune processes, but less than 20% of all clinical trials investigate potential therapies for the chronic progressive disease stage of MS. The latter is responsible for the steadily increasing disability in many patients, and there is an urgent need for novel therapies that protect nervous system tissue and enhance axonal growth and/or remyelination. As outlined in this review, solid pre-clinical data suggest neutralization of the neurite outgrowth inhibitor Nogo-A as a potential new way to achieve both axonal and myelin repair. Several phase I clinical studies with anti-Nogo-A antibodies have been conducted in different disease paradigms including MS and spinal cord injury. Data from spinal cord injury and amyotrophic lateral sclerosis (ALS) trials accredit a good safety profile of high doses of anti-Nogo-A antibodies administered intravenously or intrathecally. An antibody against a Nogo receptor subunit, leucine rich repeat and immunoglobulin-like domain-containing protein 1 (LINGO-1), was recently shown to improve outcome in patients with acute optic neuritis in a phase II study. Nogo-A-suppressing antibodies could be novel drug candidates for the relapsing as well as the progressive MS disease stage. In this review, we summarize the available pre-clinical and clinical evidence on Nogo-A and elucidate the potential of Nogo-A-antibodies as a therapy for progressive MS.
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http://dx.doi.org/10.1007/s40263-017-0407-2DOI Listing
March 2017

Sudan black: a fast, easy and non-toxic method to assess myelin repair in demyelinating diseases.

Neuropathol Appl Neurobiol 2017 Apr 10;43(3):242-251. Epub 2017 Mar 10.

Brain Research Institute, University of Zurich and Department of Health Sciences and Technology, Zurich, Switzerland.

Aims: The search for novel drugs that enhance myelin repair in entities such as multiple sclerosis has top priority in neurological research, not least because remyelination can hinder further neurodegeneration in neuro-inflammatory conditions. Recently, several new compounds with the potential to boost remyelination have been identified using high-throughput in vitro screening methods. However, assessing their potential to enhance remyelination in vivo using plastic embedded semi-thin sections or electron microscopy, even though being the gold standard for assessing remyelination, is toxic, extremely time-consuming and expensive.

Methods: We screened available myelin dyes for a staining candidate which offers a faster and easier alternative to visualize remyelination in cryo-sections.

Results: We identified sudan black as a candidate with excellent myelin resolution and we show that our adapted sudan black staining can demonstrate myelin repair in rodent spinal cord cryosections as reliable as in semithin sections, but much faster, easier, less toxic and less expensive. Besides that, it can resolve the small myelinated axons in the corpus callosum. The staining can yet readily be combined with immunostainings which can be challenging in semithin sections. We validated the method in human spinal cord tissue as well as in experimental demyelination of the rat spinal cord by a lysolecithin time course experiment. As proof-of-principle, we demonstrate that sudan black is able to reliably detect the remyelination enhancing properties of benztropine.

Conclusion: Our adapted sudan black staining can be used to rapidly and non-toxically screen for remyelinating therapies in demyelinating diseases.
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http://dx.doi.org/10.1111/nan.12373DOI Listing
April 2017

Direct, long-term intrathecal application of therapeutics to the rodent CNS.

Nat Protoc 2017 Jan 15;12(1):104-131. Epub 2016 Dec 15.

Brain Research Institute, University of Zurich, Zurich, Switzerland.

Systemic application of therapeutics to the CNS tissue often results in subtherapeutic drug levels, because of restricted and selective penetration through the blood-brain barrier (BBB). Here, we give a detailed description of a standardized technique for intrathecal drug delivery in rodents, analogous to the technique used in humans. The intrathecal drug delivery method bypasses the BBB and thereby offers key advantages over oral or intravenous administration, such as maximized local drug doses with minimal systemic side effects. We describe how to deliver antibodies or drugs over several days or weeks from a s.c. minipump and a fine catheter inserted into the subdural space over the spinal cord (20 min operative time) or into the cisterna magna (10 min operative time). Drug levels can be sampled by quick and minimally invasive cerebrospinal fluid (CSF) collection from the cisterna magna (5 min procedure time). These techniques enable targeted application of any compound to the CNS for therapeutic studies in a wide range of CNS disease rodent models. Basic surgery skills are helpful for carrying out the procedures described in this protocol.
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http://dx.doi.org/10.1038/nprot.2016.151DOI Listing
January 2017

Novel cases of amyotrophic lateral sclerosis after treatment of cerebral arteriovenous malformationss.

Swiss Med Wkly 2016 12;146:w14361. Epub 2016 Nov 12.

Department of Neurology, University of Rostock and German Centre for Neurodegenerative Diseases/ DZNE, Rostock, Germany.

Previous case studies reported nine patients with cerebral arteriovenous malformations (AVM) who developed amyotrophic lateral sclerosis (ALS) after AVM embolisation. Here, we describe three novel cases of ALS which developed 13-34 years after treatment, including embolisation, of cerebral AVM. This study provides further arguments supporting the thesis that embolisation of cerebral AVM might influence the risk of later ALS development.
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http://dx.doi.org/10.4414/smw.2016.14361DOI Listing
September 2017

The relevance of cortical lesions in patients with multiple sclerosis.

BMC Neurol 2016 Oct 21;16(1):204. Epub 2016 Oct 21.

Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland.

Background: Recent studies suggest that cortical lesions in multiple sclerosis (MS) substantially contribute to clinical disease severity. The present study aimed at investigating clinical, neuroanatomical, and cognitive correlates of these cortical lesions with a novel approach, i.e. by comparing two samples of relapsing-remitting multiple sclerosis (RRMS) patients, one group with and the other without cortical lesions.

Methods: High-resolution structural MRI was acquired from 42 RRMS patients and 43 controls (HC). The patient group was dichotomized based on the presence versus absence of DIR-hyperintense cortex-involving lesions, resulting in a cortical lesion group (CL, n = 32) and a non-cortical lesion group (nCL, n =10). Cognitive functioning was assessed in all participants with a comprehensive neuropsychological battery, covering mnestic, executive, and attentional functions.

Results: Highest densities of cortical lesions in the CL group were observed in the bilateral parahippocampal gyrus. Relative to HC, patients with cortical lesions - but not those without - showed significant global cortical thinning and mnestic deficits. The two patient groups did not differ from each other regarding demographic and basic disease characteristics such as EDSS scores.

Conclusion: The appearance of cortical lesions in MS patients is associated with cortical thinning as well as mnestic deficits, which might be key characteristics of a 'cortically dominant' MS subtype.
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http://dx.doi.org/10.1186/s12883-016-0718-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073896PMC
October 2016

Considerations on long-term immuno-intervention in the treatment of multiple sclerosis: an expert opinion.

Expert Opin Pharmacother 2016 Oct 15;17(15):2085-95. Epub 2016 Sep 15.

f Dermatologische Klinik Universitätsspital Zürich , Zurich , Switzerland.

Introduction: As management of multiple sclerosis (MS) requires life-long treatment with disease-modifying agents, any risks associated with long-term use should be considered when evaluating therapeutic options.

Areas Covered: Immune cells of the innate and adaptive immune systems play various roles in the pathogenesis of MS. MS therapies affect the immune system, each with a unique mode of action, and consequently possess different long-term safety profiles. Rare, but serious safety concerns, including an increased risk of infection and cancer, have been associated with immunosuppressant use. The risks associated with newer immunosuppressive agents, which target specific elements of MS disease pathophysiology, are not yet fully established as the duration of clinical trials is relatively short and post-marketing experience is limited. Non-immunosuppressants used to treat MS have well-defined safety profiles established over a large number of patient-years demonstrating them to be well-tolerated long-term treatment options. When considering the long-term use of disease-modifying agents for treating MS, classification as immunosuppressants or non-immunosuppressants can be useful when evaluating potential risks associated with chronic use.

Expert Opinion: A successful therapeutic strategy for any serious, chronic disease such as MS should weigh effectiveness versus long-term safety of available treatments.
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http://dx.doi.org/10.1080/14656566.2016.1232712DOI Listing
October 2016

Modulating Arm Swing Symmetry with Cognitive Load: A Window on Rhythmic Spinal Locomotor Networks in Humans?

J Neurotrauma 2017 05 12;34(10):1897-1902. Epub 2016 Oct 12.

1 Spinal Cord Injury Center, University Hospital Balgrist , Zurich, Switzerland .

In healthy subjects, changes in arm swing symmetry while walking are observed when a cognitive dual task is added, with a tendency toward left-dominant arm swing as cognitive load increases. We applied a modified Stroop word/color naming paradigm to investigate this effect in spinal cord injured (SCI) patients. Six patients with cervical SCI (cSCI), 6 with thoracic injuries (tSCI; all 12 patients American Spinal Injury Association [ASIA] Injury Score [AIS]D), and 12 healthy, matched controls underwent three-dimensional 3D gait analysis while walking normally at a comfortable speed (NW) and when performing an additional congruent (CS) and incongruent (IS) Stroop task. An arm swing symmetry index (ASI)-in which positive values indicate proportionally more movement on the left and vice versa-was calculated. Even in the baseline NW condition, all three subject groups showed larger arm movements on the left. In controls, ASI increased (NW, 13.7 ± 6.3; CS, 16.6 ± 6.4; IS, 19.6 ± 7.8) as the task became more demanding. A larger shift in tSCI patients (NW, 15.8 ± 6.0; CS, 23.4 ± 3.8; IS, 30.7 ± 4.4) was driven by a significant reduction in right wrist trajectory (p = 0.014), whereas cSCI patients showed a small reduction in mean ASI with high variability (NW, 14.2 ± 10.7; CS, 9.3 ± 13.5; IS, 6.0 ± 12.9). The effect of the IS task on ASI compared to baseline (NW) was significantly different between tSCI (+12.5 ± 6.3) and cSCI (-8.2 ± 6.0) patients (p = 0.011). Disruption of the long propriospinal connections coordinating arm and leg movements during walking may explain the heightened sensitivity to manipulation of cognitive load in tSCI, whereas the more robust automaticity in cSCI may be attributed to impaired supraspinal inputs in the context of preserved intraspinal pathways.
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http://dx.doi.org/10.1089/neu.2016.4554DOI Listing
May 2017

Homocysteine metabolism is associated with cerebrospinal fluid levels of soluble amyloid precursor protein and amyloid beta.

J Neurochem 2016 10 30;139(2):324-332. Epub 2016 Sep 30.

Department of Psychiatry, Division of Old Age Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.

Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. The objective of this study was to investigate the relationships between cerebral amyloid production and both blood and cerebrospinal fluid (CSF) markers of the homocysteine metabolism. We assessed CSF concentrations of soluble APPα, soluble APPβ, and amyloid β1-42 (Aβ1-42), as well as plasma levels of homocysteine (Hcys), total vitamin B12, and folate, and CSF concentrations of homocysteine (Hcys-CSF), 5-methyltetrahydrofolate (5-MTHF), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) in 59 subjects with normal cognition. Linear regression analyses were performed to assess associations between homocysteine metabolism parameters and amyloid production. The study was approved by the Ethical Committee of the University of Bonn. After controlling for age, gender, APOEe4 status, and albumin ratio (Qalb), higher Aβ1-42 CSF levels were associated with high Hcys and low vitamin B12 plasma levels as well as with high Hcys, high SAH, and low 5-MTHF CSF levels. Higher CSF concentrations of sAPPα and sAPPβ were associated with high SAH levels. The results suggest that disturbed homocysteine metabolism is related to increased CSF levels of sAPP forms and Aβ1-42, and may contribute to the accumulation of amyloid pathology in the brain. Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. We found associations between CSF levels of soluble APP forms and Aβ1-42, and markers of the homocysteine metabolism in both plasma and CSF in adults with normal cognition. Disturbed homocysteine metabolism may represent a target for preventive and early disease-modifying interventions in Alzheimer's disease.
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http://dx.doi.org/10.1111/jnc.13766DOI Listing
October 2016

Teaching NeuroImages: Recurrent oculomotor palsies caused by neurosarcoidosis.

Neurology 2016 07;87(3):e31-2

From the Departments of Neurology (V.K., J.A.P., M.L.), Ophthalmology (A.C., C.G.-K.), and Nuclear Medicine (P.A.), and Institute of Clinical Pathology (K.I.), University Hospital Zurich, Switzerland; Department of Oncological Sciences (V.K.), Tisch Cancer Institute and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY; and HELIOS Klinik Hagen-Ambrock (M.L.), Hagen, Germany.

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http://dx.doi.org/10.1212/WNL.0000000000002865DOI Listing
July 2016

Random number generation deficits in patients with multiple sclerosis: Characteristics and neural correlates.

Cortex 2016 09 21;82:237-243. Epub 2016 May 21.

Department of Neurology, University Hospital Zurich, Zurich, Switzerland. Electronic address:

Human subjects typically deviate systematically from randomness when attempting to produce a sequence of random numbers. Despite an increasing number of behavioral and functional neuroimaging studies on random number generation (RNG), its structural correlates have never been investigated. We set out to fill this gap in 44 patients with multiple sclerosis (MS), a disease whose impact on RNG has never been studied. The RNG task required the paced (1 Hz) generation of the numbers from 1 to 6 in a sequence as random as possible. The same task was administered in 39 matched healthy controls. To assess neuroanatomical correlates such as cortical thickness, lesion load and third ventricle width, all subjects underwent high-resolution structural MRI. Compared to controls, MS patients exhibited an enhanced tendency to arrange consecutive numbers in an ascending order ("forward counting"). Furthermore, patients showed a higher susceptibility to rule breaks (producing out-of-category digits like 7) and to skip beats of the metronome. Clinico-anatomical correlation analyses revealed two main findings: First, increased counting in MS patients was associated with higher cortical lesion load. Second, increased number of skipped beats was related to widespread cortical thinning. In conclusion, our test results illustrate a loss of behavioral complexity in the course of MS, while the imaging results suggest an association between this loss and cortical pathology.
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http://dx.doi.org/10.1016/j.cortex.2016.05.007DOI Listing
September 2016

Cognitive Impairment in Multiple Sclerosis: Clinical Manifestation, Neuroimaging Correlates, and Treatment.

Semin Neurol 2016 Apr 26;36(2):203-11. Epub 2016 Apr 26.

Unit of Neuropsychology, Department of Neurology, University Hospital Zürich, Zürich, Switzerland.

Cognitive impairment is found in up to 70% of patients with multiple sclerosis (MS). Once thought of as a variant of subcortical dementia with a characteristic set of deficits, we now know that MS-related cognitive impairment can have many faces. This conceptual change in neuropsychology is embedded in a paradigm shift in the neuroscientific understanding of MS over the past 25 years: Partly based on modern neuroimaging techniques, the classical view of MS as an inflammatory demyelinating disease affecting the white matter of the central nervous system has been extended. In particular, many studies have shown that the MS pathology also includes neurodegeneration, and that gray matter structures such as the cerebral cortex can also show focal lesions, atrophy, or both. The authors present an updated summary of the clinical manifestation and neuroimaging correlates of cognitive impairment in MS, and discuss the relatively few treatment options available to date.
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http://dx.doi.org/10.1055/s-0036-1579696DOI Listing
April 2016

Prolonged-release fampridine in multiple sclerosis: Improved ambulation effected by changes in walking pattern.

Mult Scler 2016 10 13;22(11):1463-1475. Epub 2016 Jan 13.

Department of Neurology, University Hospital Zurich, Zurich, Switzerland/ Department of Neurology, HELIOS-Klinik Hagen-Ambrock, Hagen, Germany.

Background: Prolonged-release fampridine (PR-fampridine, 4-aminopyridine) increases walking speed in the timed 25-foot walk test (T25FW) in some patients (timed-walk responders) with multiple sclerosis (MS).

Objective: To explore the effects of PR-fampridine on different aspects of walking function and to identify associated gait modifications in subjects with MS.

Methods: In this prospective, randomized, placebo-controlled, double-blind, phase II study (FAMPKIN; clinicaltrials.gov, NCT01576354), subjects received a 6-week course of oral placebo or PR-fampridine treatment (10 mg, twice daily) before crossing over. Using 3D-motion-analysis, kinematic and kinetic parameters were assessed during treadmill walking (primary endpoint). Clinical outcome measures included T25FW, 6-minute walk test (6MWT), and balance scales. Physical activity in everyday life was measured with an accelerometer device.

Results: Data from 55 patients were suitable for analysis. Seventeen subjects were timed-walk responders under PR-fampridine. For the total study population and for responders, a significant increase in walking speed (T25FW) and distance (6MWT) was observed. Gait pattern changes were found at the single-subject level and correlated with improvements in the T25FW and 6MWT. Physical activity was increased in responders.

Conclusion: PR-fampridine improves walking speed, endurance, and everyday physical activity in a subset of subjects with MS and leads to individual modifications of the gait pattern.
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http://dx.doi.org/10.1177/1352458515622695DOI Listing
October 2016

Cortical thinning in the anterior cingulate cortex predicts multiple sclerosis patients' fluency performance in a lateralised manner.

Neuroimage Clin 2016 14;10:89-95. Epub 2015 Nov 14.

Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland; Department of Neurology, Helios-Klinik Hagen-Ambrock, Ambrocker Weg 60, 58091 Hagen, Germany.

Cognitive impairment is as an important feature of Multiple Sclerosis (MS), and might be even more relevant to patients than mobility restrictions. Compared to the multitude of studies investigating memory deficits or basic cognitive slowing, executive dysfunction is a rarely studied cognitive domain in MS, and its neural correlates remain largely unexplored. Even rarer are topological studies on specific cognitive functions in MS. Here we used several structural MRI parameters - including cortical thinning and T2 lesion load - to investigate neural correlates of executive dysfunction, both on a global and a regional level by means of voxel- and vertex-wise analyses. Forty-eight patients with relapsing-remitting MS and 48 healthy controls participated in the study. Five executive functions were assessed, i.e. verbal and figural fluency, working memory, interference control and set shifting. Patients scored lower than controls in verbal and figural fluency only, and displayed widespread cortical thinning. On a global level, cortical thickness independently predicted verbal fluency performance, when controlling for lesion volume and central brain atrophy estimates. On a regional level, cortical thinning in the anterior cingulate region correlated with deficits in verbal and figural fluency and did so in a lateralised manner: Left-sided thinning was related to reduced verbal - but not figural - fluency, whereas the opposite pattern was observed for right-sided thinning. We conclude that executive dysfunction in MS patients can specifically affect verbal and figural fluency. The observed lateralised clinico-anatomical correlation has previously been described in brain-damaged patients with large focal lesions only, for example after stroke. Based on focal grey matter atrophy, we here show for the first time comparable lateralised findings in a white matter disease with widespread pathology.
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http://dx.doi.org/10.1016/j.nicl.2015.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683425PMC
October 2016

Neurosyphilis presenting as a new onset lateralized movement disorder.

J Clin Neurosci 2015 Oct 6;22(10):1682-3. Epub 2015 Jun 6.

Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, Zurich 8091, Switzerland. Electronic address:

We report a unique and illustrative case of a 52-year-old man with neurosyphilis presenting as subacute hemichorea, and discuss a vascular, metabolic or inflammatory origin. A broad range of neurological findings may be linked to neurosyphilis, potentially complicating its diagnosis. We propose that new onset lateralized movement disorders may constitute the initial clinical presentations of neurosyphilis, and provide evidence for striatal hypermetabolism pointing to direct inflammatory, syphilitic changes as the underlying pathophysiological mechanism. Neurosyphilis is no longer a common disorder, but the prevalence of syphilis is rising again in Western countries and its past reputation as the great imitator should not be forgotten.
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http://dx.doi.org/10.1016/j.jocn.2015.03.038DOI Listing
October 2015