bluuebunny/crossref_metadata_2025_split huggingface dataset:
031 Investigating motor evoked potentials as a biomarker for disease severity in hereditary spastic paraplegia
Authors: Siow Sue-Faye , Sue Carolyn , Kumar Kishore , Coward Sharon , Lofts Amy , Ng Karl 
Published: May 2018

IntroductionHereditary spastic paraplegia (HSP) encompasses a diverse group of neurodegenerative disorders that results in significant disability with no curative or disease-modifying treatment. The lack of standardised biomarkers of disease severity has limited the evaluation of potential therapeutic agents. Our aim is to investigate motor evoked potentials (MEPs) as a marker of HSP disease severity.MethodsWe studied 21 subjects (10 male, 11 female; mean age 54.3±13.8 years) with a clinical diagnosis of HSP (10 SPG4, 4 SPG7, 1 SPG3A, 1 SPG 30, 5 genetically undetermined). All patients underwent transcranial magnetic stimulation to measure central motor conduction time (CMCT), resting motor threshold (rMT) and MEP amplitude from the tibialis anterior (TA), abductor hallucis (AH) and abductor digiti minimi (ADM). Clinical disease severity was assessed with the Spastic Paraplegia Rating Scale (SPRS). Pearson correlation coefficient was used to assess correlation between variables, significance was defined as P value<0.05.ResultsTA CMCT was prolonged in 16/21 subjects (76%). AH CMCT was absent in 3/18 subjects (16.7%) and prolonged in 9/18 subjects (50%). ADM CMCT was measured in 19 subjects; all were normal. There was no significant correlation between SPRS scores and MEP amplitude, rMT or CMCT for TA or AH. There was also no significant correlation between these MEP measures and disease duration or patient age. Subgroup analysis of SPG4 HSP (10 subjects) revealed significant correlation between TA and AH CMCT with disease duration (r=0.841, p=0.001; r=0.930, p=0.001) but not SPRS scores.ConclusionLower limb CMCT was absent or prolonged in the majority of subjects. Despite being potentially useful as a diagnostic biomarker for HSP, this study only showed a correlation between lower limb CMCT and disease duration in the SPG4 subgroup. Further genotype-specific studies utilising larger numbers may clarify the relationship between MEP markers and clinical features.
004 Mechanisms of nerve dysfunction in inflammatory neuropathies
Authors: Garg Nidhi , Park Susanna B , Howells James , Yiannikas Con , Vucic Steve , Noto Yu-ichi , Krishnan Arun V , Spies Judith , Mathey Emily K , Pollard John D , Kiernan Matthew C 
Published: May 2018

IntroductionImmune-mediated neuropathies are a cause of disability and an immense cost to the healthcare system. They include chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN) and the neuropathy associated with IgM antibodies against myelin-associated glycoprotein (MAG). CIDP is extremely heterogeneous with marked variability in treatment responsiveness. Patients with MMN often respond to treatment but progressive weakness and wasting typically ensues over time. No therapy has consistently proven effective in anti-MAG neuropathy. The present series of studies were undertaken to improve understanding of disease mechanisms in these neuropathies, a critical step before targeted treatment approaches can be developed.MethodsPatients fulfilling Peripheral Nerve Society criteria for CIDP or MMN and patients positive for anti-MAG IgM underwent comprehensive clinical assessments, neurophysiology, serological testing and structural assessments.ResultsThe patient cohort consisted of 80 patients (51 CIDP, 14 MMN, 15 MAG). 6% of CIDP patients tested positive for anti-neurofascin 155 (NF155) and 4% for anti-contactin 1 IgG4. Anti-NF155 neuropathy was characterised by diffuse nerve enlargement and an axonal excitability profile consistent with severe disruption of the paranodal seal. CIDP patients testing negative for IgG4 antibodies also demonstrated significant nerve enlargement compared with healthy subjects. Axonal excitability profiles differed in those with and without median nerve conduction block. MMN was characterised by patchy nerve enlargement, marked increases in super-excitability and enlarged motor unit size. In contrast, anti-MAG neuropathy patients demonstrated a proximal pattern of nerve enlargement and an axonal excitability profile characterised by reduced super-excitability consistent with increased juxta-paranodal fast potassium channel conductance.ConclusionPatterns of nerve enlargement and neurophysiological profiles differ in the immune-mediated neuropathies providing insights into molecular mechanisms. These results provide templates that can guide treatment approaches. The combination of directed autoantibody assays and measures of axonal function can be used to monitor disease progression and therapeutic response.
042 Chronic inflammatory demyelinating polyneuropathy presenting as focal amyotrophy
Authors: El-Wahsh Shadi , Cordato Dennis , Yiannikas Con 
Published: May 2018

IntroductionWe aimed to report a rare case of chronic inflammatory demyelinating polyneuropathy (CIDP) presenting as focal lower limb amyotrophy.CaseA 65 year old man presented with a 12 month history of painless, left anterior thigh wasting. Examination revealed marked left quadriceps and mild left hamstring and tibial wasting (Image 1). He had MRC grade 4/5 left hip flexion and 3/5 knee extension weakness, with normal power elsewhere. His left knee jerk was absent. Remaining reflexes were retained. There was reduced left L5 pinprick and light touch sensation. His neurological exam was otherwise normal. Blood tests, including creatine kinase, blood glucose, and autoimmune panel, were normal. Anti-neuronal, anti-ganglioside and anti-MAG antibodies were negative. Trace IgM lambda para-proteinaemia was detected. Cerebrospinal fluid was unremarkable [protein 0.37 g/L (n<0.45), glucose 4.1 mmol/L (2.5–4.5), leukocytes 0×106/L]. Nerve conduction studies showed normal lower limb motor velocities with reduced left peroneal motor amplitudes and mildly prolonged sural sensory latencies bilaterally. Electromyography showed chronic denervation of bilateral L3-S1 innervated muscles without fibrillation potentials. Posterior tibial somatosensory evoked potential studies demonstrated absent lumbar responses and prolonged cortical latencies. Muscle biopsy confirmed chronic denervation without evidence of myopathy or vasculitis. The patient declined sural nerve biopsy. MRI revealed bilateral multifocal lumbosacral plexopathy with increased T2 signal and thickening of multiple nerves, including femoral, lateral femoral cutaneous and L5 nerve roots (Image 2). CT chest, abdomen and pelvis, and whole body PET scan were normal. High-dose oral prednisone and induction intravenous immunoglobulin (IVIG) therapy followed by 4-weekly maintenance IVIG and low-dose prednisolone were commenced for a presumed diagnosis of CIDP.ConclusionIn this patient, the presence of multifocal nerve thickening on MRI was consistent with an inflammatory neuropathy. The normal PET scan and CSF studies made other diagnoses, such as neuro-lymphoma, less likely. CIDP should be considered in atypical presentations such as focal amyotrophy.
043 Rheumatoid leptomeningitis: an acute presentation of neuropsychiatric disturbance
Authors: Lubomski Michal , Sy Joanne , Buckland Michael , Lee Andie S , Richards Bethan , Thompson Elizabeth , Fulham Michael , Halmagyi Michael 
Published: May 2018

IntroductionWe report a case of an isolated acute neuropsychiatric presentation due to rheumatoid meningitis (RM), successfully treated with steroids and rituximab.CaseA 41 year old man with a chronic headache and acute neuropsychiatric disturbance including impulsivity, grandiose delusions and agitation on a background of no known psychiatric history. Incidentally, he reported migratory palindromic, large and small joint polyarthritis over the preceding 18 months accompanied by headache, symptomatically treated with indomethacin. He had no prior diagnosis of rheumatoid arthritis (RA) or other connective tissue disorder. Serum and cerebrospinal fluid (CSF) cyclic citrullinated peptide antibodies were strongly positive, with a normal serum rheumatoid factor. An interferon-gamma release assay was positive, suggestive of prior tuberculosis (TB) exposure. CSF examination was unremarkable with an MRI brain demonstrating asymmetric features of leptomeningeal thickening and enhancement over both cerebral cortices, suggesting an inflammatory or infiltrative leptomeningitis. Lymphoma, IgG4–related disease, granulomatous diseases such as TB, granulomatosis with polyangiitis, neurosarcoidosis, neurosyphilis and meningeal metastasis were considered as differential diagnoses. A leptomeningeal and brain biopsy showed necrotising inflammation with ill-defined granulomas and a dense lymphoplasmacytic infiltrate. No organisms were identified. Mycobacterial polymerase chain reaction and cultures over three months were negative. RM was the favoured histological diagnosis. Empirical treatment for prior TB exposure was commenced in conjunction with steroids. Subsequent addition of iv rituximab resulted in sustained improvement of neuropsychiatric and joint symptoms.ConclusionThis report illustrates for the first time isolated acute neuropsychiatric disturbances attributable to RM without a prior history of RA that was responsive to rituximab. Clinicians should consider infiltrative and inflammatory leptomeningeal causes, particularly with asymmetric meningeal thickening and enchantment on MRI and should commit to a tissue biopsy when no other systemic connective tissue, infective or neoplastic causes are identified.
044 Durable clinical efficacy of alemtuzumab in patients with active rrms in the absence of continuous treatment: 7-year follow-up of CARE-MS I patients (Topaz Study)
Authors: McCombe Pamela , Boyko Alexey N , DeSeze Jérôme , Hartung Hans-Peter , Havrdova Eva , Inshasi Jihad Said , Montalban Xavier , Pozzilli Carlo , Selmaj Krzysztof W , Vermersch Patrick , Melanson Maria , Daizadeh Nadia , Rodriguez Claudio E , Wijmeersch Bart Van ,   on behalf of the CARE-MS I, CAMMS03409, and TOPAZ Investigators
Published: May 2018

IntroductionIn CARE-MS I (NCT00530348), alemtuzumab 12 mg/day (baseline: 5 days; 12 months later: 3 days) improved clinical/MRI outcomes versus SC IFNB-1a over 2 years (y) in treatment-naive relapsing-remitting MS (RRMS) patients. Efficacy was durable in a 4-y extension (NCT00930553; 95% enrolled, 92% completed), wherein patients could receive as-needed alemtuzumab retreatment for relapse/MRI activity or other disease-modifying therapies (DMTs) per investigator’s discretion. Patients completing the extension could enrol in the 5-y TOPAZ study (NCT02255656) for further evaluation. Here we examine efficacy/safety through Y7 in alemtuzumab-treated patients from CARE-MS I.MethodsIn TOPAZ, patients can receive alemtuzumab retreatment (≥12 months apart) or other DMTs (both per investigator’s discretion). MRI scans are performed annually. Assessments: annualised relapse rate (ARR); stable/improved Expanded Disability Status Scale (EDSS) from core study baseline; 6 month confirmed disability worsening (CDW); 6 month confirmed disability improvement (CDI); no evidence of disease activity (NEDA); adverse events (AEs).Results299/321 patients (93%) completed TOPAZ Y1 (Y7 after initiating alemtuzumab). ARR remained low (Y7: 0.13); 60% were relapse-free in Y3–7. The percentage of patients with stable/improved EDSS remained high (Y7: 78%). Through Y7, 74% were free from 6 month CDW, 37% achieved 6 month CDI, and the majority achieved NEDA each year (Y7: 61%). 59% received no additional treatment (alemtuzumab or other DMT) after the initial 2 courses. Overall AE incidence, infusion-associated reactions, and infections decreased over time. Thyroid AE incidence peaked in Y3 (15%) and then declined.ConclusionAlemtuzumab efficacy was maintained for 7 years in treatment-naive patients, despite 59% receiving no additional treatment since the initial 2 courses. 37% of patients also showed disability improvement. The alemtuzumab safety profile remained consistent; overall AE incidence decreased over time. Alemtuzumab may provide a unique treatment approach for RRMS patients, offering durable efficacy in the absence of continuous treatment.Study supportSanofi and Bayer HealthCare Pharmaceuticals.
051 Systematic review of CT angiographic ‘spot sign’ for predicting mortality
Authors: Krishnadas Natasha , Phan Thanh G , Lai Vivian WY , Batt Michael J , Chandra Ronil V , Srikanth Velandai , Ma Henry 
Published: May 2018

IntroductionTo study whether presence of the CT angiographic ‘spot sign’ for spontaneous intracerebral haemorrhage (ICH) expansion is predictive of mortality.MethodPubMed, Medline, conference proceedings and manuscript references up to June 2017 were searched for studies reporting “computed tomography angiography” and “spot sign” or “intracerebral haemorrhage” and “spot sign”. Positive (PLR) and negative (NLR) likelihood ratios were calculated using MetaDisc. The PLR needs to be ≥5 and NLR ≤0.1 for a test to be clinically useful.ResultsThere have not been previous systematic reviews correlating the spot sign to clinical outcome. There were 36 studies describing 6888 patients and 32 clinical outcome measures. However, there were only three outcome measures with sufficient comparability across the studies. PLR, and NLR for in-hospital mortality by spot sign were 2.47 (95% CI 1.59–3.82) and 0.62 (95%CI 0.46–0.82) with a plateau of 2.7 and 0.6 respectively across 10 studies. PLR and NLR for 3 month mortality by haematoma expansion were 0.41 (95%CI 0.35–0.47) and 0.8 (95%CI 0.78–0.83) with a plateau of 2.0 and 0.8 respectively across 8 studies.ConclusionOverall, there is limited data available on clinical outcomes stratified by the ‘spot sign’. Based on the available information, the PLR and NLR did not meet respective thresholds of 5 and 0.1 required to have clinical utility.
006 Effect of apolipoprotein e ε4 allele on medial temporal lobe atrophy in ischaemic stroke patients
Authors: Khlif Mohamed Salah , Werden Emilio , Egorova Natalia , Khan Wasim , Brodtmann Amy 
Published: May 2018

IntroductionApolipoprotein E (APOE) ε4 allele is a known risk factor for the development of cognitive impairment. APOE ε4 carriers have been reported as having lower hippocampal volume in Alzheimer’s disease, mild cognitive impairment, and in healthy cohorts,1 but this is not well investigated in stroke. Here, we compared the regional volume in the medial temporal lobe in ischaemic stroke survivors, with and without the ε4 allele, three (time point 1, t1) and twelve (t2) months after stroke.Methods21 APOE ε4 carriers and 21 non-carriers, matched for lesion size and location and for neurological impairment as measured by NIHSS, were sampled from the CANVAS study, a longitudinal imaging study in stroke survivors.2 A mixed-effect linear model was used to analyse the effect of the ε4 allele on hippocampal, entorhinal, and para-hippocampal volumes, adjusting for age, sex, years of education, and total intracranial volume. Volumes were estimated using the longitudinal stream in FreeSurfer 5.3.ResultsThe left hippocampal (pt1=0.038, pt2=0.040) and entorhinal (pt1=0.044, pt2=0.038) volumes were significantly lower in the ε4-carrier group at each time point. The right entorhinal (pt1=pt2=0.002) and para-hippocampal (pt1=0.018, pt2=0.020) volumes were also significantly lower in the ε4-carrier group, but there was no difference in the right hippocampal volume (pt1=pt2=0.055) between the two groups. The group-time interaction was significant for the left para-hippocampal cortex (p=0.019): ε4 non-carriers showed a significant volume increase (p=0.018) between t1 and t2.ConclusionThese findings suggest that stroke survivors who carry the APOE-ε4 allele will experience greater atrophy in the medial temporal lobe in the twelve months following their stroke.References1. Manning EN, et al. e4 Is Associated with Disproportionate Progressive Hippocampal Atrophy in AD. PLoS ONE2014;9(5):e97608.2. Brodtmann A, et al. Charting cognitive and volumetric trajectories after stroke: Protocol for the Cognition And Neocortical Volume After Stroke (CANVAS) study. Int J Stroke2014;9(6):824–828.
061 Ocrelizumab reduces disability progression independent of relapse activity in patients with relapsing multiple sclerosis (RMS) (ENCORE)
Authors: Kappos Ludwig , Wolinsky Jerry S , Giovannoni Gavin , Arnold Douglas L , Lublin Fred , Wang Qing , Model Fabian , Wei Wei , Garren Hideki , Manfrini Marianna , Belachew Shibeshih , Hauser Stephen 
Published: May 2018

IntroductionOcrelizumab-(OCR) showed superior efficacy vs interferon beta-1a-(IFNβ1a) in OPERA I/II trials in RMS. Confirmed disability progression-(CDP) based on composite of Expanded Disability Status Scale-(EDSS), timed 25-foot walk-(T25FW) and 9-hole peg test-(9HPT) may better characterise aspects of disability progression than EDSS alone and has improved sensitivity for assessing progression in secondary progressive MS-(SPMS).MethodsRMS patients, including relapsing SPMS patients, in OPERA I/II-(NCT01247324/NCT01412333) received IV-OCR 600 mg (q24w) or SC-IFNβ1a 44 µg (tiw) over 96 weeks. CCDP was defined as disability progression measured by EDSS (increase ≥1.0 or 0.5 if baseline >5.5) or ≥20% T25FW increase or ≥20% 9 HPT increase, confirmed after ≥12/≥24 weeks. Definition-1 of CCDP-IRA=reference EDSS/T25FW/9HPT was re-baselined at first available assessment ≥30 days, after each relapse and no relapse should occur between baseline and initial disability progression [IDP], and within 30 days post-IDP and 30 days prior to IDP confirmation. Definition-2=period of no relapse for 30 days post-IDP confirmation. Subgroup analysis included patients at potentially higher SPMS risk based on baseline-EDSS ≥4.0 and pyramidal Kurtzke Functional Systems Score ≥2.ResultsIn the pooled intention-to-treat (ITT) cohort (n=1,656), risk reduction (RR; OCR vs IFNβ1a) for 12-/24 week CCDP was 34% (30.7% vs 21.5%; p<0.001) and 31% (22.6% vs 16.1%; p=0.002). The 12-/24 week CCDP-IRA RRs for Definition-1 were 24% (25.4% vs 19.6%; p=0.010) and 22% (19.2% vs 14.9%; p=0.046); and for Definition-2, 25% (25.4% vs 19.5%; p=0.008) and 23% (19.2% vs 14.8%; p=0.039). In the subgroup at higher SPMS risk, 12-/24 week RRs for CCDP-IRA (Definition-2) were 40% (31.2% vs 19.1%; p=0.022) and 36% (26.9% vs 16.6%; p=0.064). All CCDP-IRA components in the ITT and subgroups followed similar trends.ConclusionResults show that considerable disability progression in RMS occurs independently of protocol-defined relapses. Ocrelizumab significantly reduced progression vs IFNβ1a in the OPERA ITT population of RMS patients and more so in the subgroup at higher SPMS risk.
064 Expert consensus on standards for multiple sclerosis care: results from a modified delphi process
Authors: Butzkueven Helmut , Hobart Jeremy , Bowen Amy , Eberhard Lucy , Pepper George , Giovannoni Gavin 
Published: May 2018

IntroductionThe importance of prompt intervention in multiple sclerosis (MS) was described in the widely endorsed report, Brain health: time matters in multiple sclerosis.1 The present study aimed to define standards for the timing of key steps in the care pathway.MethodsAn international group of 29 MS neurologists was recruited from regions with high MS prevalence to participate in a modified Delphi process. Across five rounds, they defined ‘core’, ‘achievable’ and ‘aspirational’ time frames (to reflect a minimum, good and high standard of MS care, respectively). A 31-member Reviewing Group of MS nurses, experts with MS and allied healthcare professionals reviewed the results and provided feedback to four Chairs.ResultsConsensus was reached (≥75% agreement; n=21) on core, achievable and aspirational time frames for events spanning the MS care pathway. Here, we will present 21 achievable standards related to referral, diagnosis, treatment decisions, monitoring and managing new symptoms. For example, the Panel agreed that most MS teams should be aiming to1 complete a diagnostic workup for MS within 4 weeks of a patient being referred to a neurologist,2 assess patient eligibility for a suitable disease-modifying therapy within 3 weeks of diagnosis,3 perform follow-up clinical evaluations every 6 months, and4 offer an annual MRI scan.ConclusionThese standards will inform tools for clinics and people with MS and act as a potential future benchmark for established and developing MS clinics across the globe aiming to deliver the highest quality care.Reference. Giovannoni G, et al. Mult Scler Relat Disord2016;9(Suppl 1):S5–S48.
072 Clinical audit of stroke admissions associated with atrial fibrillation and anticoagulation rates
Authors: Khan Zainab , Gopinath Sumana , Levy Stanley 
Published: May 2018

IntroductionAtrial fibrillation (AF) increases the risk of potentially fatal or disabling ischaemic stroke, and a systematic review found <70% of eligible patients with AF are using oral anticoagulants (OACs).1MethodsMedical records of patients admitted with stroke/TIA associated with known or new diagnosis of AF from 1 st July 2016 to 30th June 2017 were reviewed. This data was to be compared to a similar audit conducted in 2009. Data collected included age, sex, history of AF, adequacy of anticoagulation (before and after admission) and vascular risk factors.Results49 patients (29 males, average age 76 years) were included in the study. Incidence of AF was found to be 27.9% in stroke and 8.4% among TIA admissions. Known AF occurred in 34 (82.9%) of the stroke admissions and 8 (100%) of the TIA admissions. Therefore, AF was diagnosed post-stroke in 17.1% of participants. Prior to stroke and TIA 61.9% of patients were receiving anticoagulants. Treatment prior to stroke or TIA consisted of 11 (26.2%) on DOACs, 15 (35.7%) on warfarin, 5 (11.9%) on anti-platelets, and 11 (26.2%) with no anti-thrombotics. Sub-therapeutic INRs (<2.0) upon admission were found in 60% of participants using warfarin. Among the 11 untreated patients, 1 patient was non-compliant, 1 had recent SAH, but no explanation was found for the remaining 9 participants. Anticoagulation rates improved on discharge with 40 (81.6%) patients prescribed either DOACs or warfarin.ConclusionAnticoagulation rates have improved since 2009 (61.9% vs 41%) in stroke/TIA admissions associated with AF. However, use of anticoagulants in this population remains inadequate. Furthermore, 60% of patients on warfarin had sub-therapeutic INRs upon admission. There is still a need for improved screening for AF, with only a slight decrease in rates of new diagnosis of AF compared to the 2009 audit (from 22% to 17.1%).Reference. Ogilvie IM, Newton N, Welner SA, Cowell W, Lip G. Underuse of Oral Anticoagulants in Atrial Fibrillation: A Systematic Review. The American Journal of Medicine2009;124(7):11. https://doi.org/10.1016/j.amjmed.2009.11.025