bluuebunny/crossref_metadata_2025_split huggingface dataset:
021 Clinical implications of cortical dysfunction in motor neuron disease: a combined structural and functional approach
Authors: Dharmadasa Thanuja , Simon Neil G , Wang Chenyu , Vucic Steve , Kiernan Matthew C 
Published: May 2018

IntroductionMotor neuron disease (MND) is characterised by progressive failure of upper (UMN) and lower motor neurons (LMN). UMN dysfunction remains difficult to detect clinically, and the influence of cortical change on disease progression and prognosis remains unclarified. This study quantitatively assessed cortical dysfunction in vivo using a novel combined structural and functional approach.MethodsForty-one newly diagnosed MND patients and 30 controls prospectively underwent 3T diffusion tensor magnetic resonance imaging (DTI) to assess cerebral white matter structural integrity. DTI measures including apparent diffusion coefficient (ADC) and functional anisotropy (FA) were analysed using statistical parametric mapping. Threshold tracking transcranial magnetic stimulation (TT-TMS) studies were additionally performed across all four limbs to concurrently assess the functional integrity of the motor cortex. All patients underwent detailed clinical and cognitive assessment.ResultsCortical abnormalities were prominent, with FA significantly reduced (p<0.01) and ADC enhanced (p<0.03) along the primary motor tracts in all MND patients, suggestive of primary axonal degeneration. These changes correlated with clinical function and disease duration. TT-TMS revealed evidence of cortical hyper-excitability over the motor cortex corresponding with clinical site-of-onset (p<0.05). Structural (FA) and functional (cortical hyper-excitability) changes correlated across all extremities. Patients without clinical UMN signs also showed evidence of UMN dysfunction, identifying subclinical change. Subgroup analysis identified the greatest changes in bulbar-onset patients (p<0.03).ConclusionThis multimodal technique identified UMN dysfunction in patients prior to clinically detectable change, which may contribute to earlier diagnosis. More significant cortical involvement in bulbar-onset patients aligns with their poorer survival, highlighting the cortically driven determination of clinical progression and prognosis. Further clinical translation of such patterns may therefore lend insight into pathophysiological disease mechanisms and may influence stratification for clinical trials. Overall, this can serve as a robust biomarker for earlier diagnosis, disease progression and prognosis.
035 Interferon beta induced thrombotic microangiopathy in multiple sclerosis: a clinical-pathological report
Authors: Yam Charmaine , Fok Anthony , McLean Catriona , Butler Ernest , Kempster Peter 
Published: May 2018

IntroductionThrombotic microangiopathy (TMA) has been described with long-term interferon-beta (IFN-β). We report a case of biopsy-proven TMA in a patient with multiple sclerosis (MS) who had been having IFN-β−1a injections for twenty years. These biopsy findings were similar to previously described lung histological changes in IFN β- induced pulmonary arterial hypertension (PAH).CaseA 57 year old woman with relapsing-remitting multiple sclerosis had been administering IFN-β−1a injections for twenty years. Her BMI was 21 and she was on a dose of 44 mcg three times per week. She presented with acute pulmonary oedema, renal failure, malignant hypertension, micro-angiopathic haemolytic anaemia and thrombocytopenia after one week of increasing dyspnoea. A renal biopsy showed malignant hypertensive nephropathy and microangiopathy consistent with TMA. Alternative TMA syndromes including haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura were excluded. Renal function stabilised after the IFN was ceased but never returned to the baseline level.ResultsHer renal biopsy showed glomerular capillary thrombus deposition, endothelial reactivity, vessel necrosis and wall duplication with luminal thrombus. Fibromuscular proliferation, focal fibrinoid necrosis and luminal thrombus was also present within arterioles. These microvascular histopathological findings resemble vessel changes observed seen in lung biopsies in human IFN β mediated PAH, and those described in transgenic mouse models engineered to overproduce Type 1 IFN.1 2 Our patient was on treatment for twenty years at a dose exceeding 50 mcg per week. Both are postulated risk factors for the development of TMA.2ConclusionOur report highlights similarities between microvascular changes seen in IFN-induced TMA and those observed in pulmonary arterial hypertension associated with IFN therapy. This suggests a shared pathophysiological mechanism. Kavanagh et al had described a dose-dependent spectrum of renal microvascular disease in his mouse model.2 The duration and high dosage for weight of IFN Β supports a cumulative drug toxicity effect.References. Fok A, Williams T, McLean C, Butler E. Interferon beta- 1a long-term therapy related to pulmonary arterial hypertension in multiple sclerosis patients. Mult Scler2016Oct;22(11):1495–1498.. Kavanagh D, McGlasson S, Jury A, et al. Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature. Blood2016Aug;05–715987.
054 Disability improvement is observed in each functional system in alemtuzumab-treated patients with active RRMS: results from CARE-MS II extension
Authors: Macdonell Richard AL , Aburashed Rany A , Alroughani Raed , Dive Dominique , Izquierdo Guillermo , Kim Ho-Jin , Lycke Jan , Pozzilli Carlo , Sharrack Basil , Vermersch Patrick , Wiendl Heinz , Lysandropoulos Andreas , Chung Luke , Daizadeh Nadia , Hunter Samuel F ,   on behalf of the CARE-MS II and CAMMS03409 Investigators
Published: May 2018

IntroductionIn CARE-MS II (NCT00548405), alemtuzumab (12 mg/day, baseline: 5 days; 12 months later: 3 days) significantly improved clinical/MRI outcomes versus subcutaneous interferon beta-1a over 2 years in relapsing-remitting MS patients with inadequate response to prior therapy; significantly greater percentage of alemtuzumab-treated patients achieved 6 month confirmed disability improvement (CDI). Efficacy remained durable in a 4 year extension (NCT00930553). Here we assess alemtuzumab efficacy on disability at the level of functional systems (FS) scores of the Expanded Disability Status Scale (EDSS) over 6 years.MethodsEDSS and individual FS scores were recorded at baseline and quarterly; CDI (≥1.0 point EDSS decrease confirmed over 6 months) was assessed in patients with baseline EDSS score ≥2.0.ResultsOf the 393 patients who entered the extension, 338 (86%) remained on study through Year 6; 50% received neither alemtuzumab retreatment nor other disease-modifying therapy after the initial 2 courses. Through Years 3–6, 76%–80% of patients showed stable (≤0.5 point change) or improved (≥1.0 point decrease) EDSS scores versus core study mean (SD) baseline score of 2.7 (1.2);≥75% were stable/improved in each FS. Through Year 6, 43% achieved 6 month CDI and 96% of patients with CDI had an EDSS score <4. 71% of patients with CDI achieved improvements in >1 FS. Improvements were observed in each FS, most frequently occurring in the sensory (48%), pyramidal (44%), and cerebellar (44%) systems; 21%–25% showed improvements in the brainstem, cerebral, visual, and bowel/bladder FS.ConclusionMost (86%) CARE-MS II patients who entered the extension remained on the study through Year 6;≥75% of alemtuzumab-treated patients had improved/stable scores across all FS over 6 years. Improvements were seen for each FS in patients with 6 month CDI, with 71% showing improvements in >1 FS, indicating a broad treatment effect with alemtuzumab on multiple aspects of disability improvements.Study supportSanofi and Bayer HealthCare Pharmaceuticals.
062 Cadasil presenting with focal and generalised epilepsy due to a novel NOTCH3 mutation
Authors: Chen Benson S , Cleland James C , King Richard I , Anderson Neil E 
Published: May 2018

IntroductionCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by mutations of the NOTCH3 gene. Clinical manifestations include migraine, recurrent ischaemic strokes, and cognitive decline. Seizures are an uncommon early symptom and usually occur after the onset of stroke. We report a CADASIL family with epilepsy as an early clinical symptom due to a novel NOTCH3 mutation.MethodsThe clinical histories of three family members from two generations are reported, alongside para-clinical details including results of magnetic resonance imaging (MRI), electroencephalogram (EEG), and genetic testing.ResultsThe proband developed focal and generalised seizures at age 51. She had a preceding history of cognitive impairment and migraines. The proband’s son developed focal seizures at age 25 involving his left arm and then generalised seizures. He experienced intermittent headaches, without history of stroke or cognitive impairment. His sister (the proband’s daughter) had epilepsy from age 12, characterised by blank spells and generalised seizures. Cognitive decline was noted from age 38, without history of stroke. There was no family history of epilepsy in those without CADASIL. MRI in all three family members showed multifocal T2 FLAIR hyperintensities within the supratentorial white matter, particularly the temporal lobes. EEG was abnormal only in the proband’s son, with paroxysmal bursts of poorly organised 3–4 Hz spike-wave activity. Genetic testing in all three family members found a novel NOTCH3 mutation, c.1337G>A p.(Cys446Tyr).ConclusionWe have identified a novel NOTCH3 mutation in a kindred with epilepsy as an early manifestation of CADASIL without prior history of strokes. The association with epilepsy is unlikely to be coincidental given the strong segregation of epilepsy and CADASIL in this kindred and the clear focal seizure semiology noted in all family members. Whether this mutation represents a distinct new phenotype requires further investigation.
065 A pilot time and motion study for treatments of relapsing remitting multiple sclerosis (RRMS) in australia
Authors: Lechner-Scott Jeanette , Davey Ryan , Davey Peter , Bogeski Goce , Cheah Esther 
Published: May 2018

IntroductionThe time burden of managing relapsing remitting multiple sclerosis (RRMS) for patients and healthcare staff is not well quantified despite its importance in treatment choice. Of interest were three higher efficacy RRMS therapies, cladribine tablets, alemtuzumab, and fingolimod because of their different modes of administration. Time and motion (T and M) surveys have previously been used to quantify time burden by asking respondents about duration of treatment administration. The objective is to determine the time taken by patients, nurses, neurologist and other specialists to treat RRMS with cladribine tablets, alemtuzumab and fingolimod using purposely developed T and M surveys.MethodsWe created two T and M surveys, one for neurologists and nurses, and another for patients. Surveys were informed by product information documents, validated by an MS nurse, and completed by telephone with patients (n=3), neurologists (n=3), and nurses (n=8) from eight MS clinics.ResultsThe overall mean time spent on treatment with cladribine tablets, fingolimod, and alemtuzumab extrapolated over 4 years was 25±3, 62±6, and 189±18 hours (p<0.0001, 1-way ANOVA, repeated measures). Neurologists’ overall time spent also favoured cladribine tablets (2.3±0.7 hours) over alemtuzumab (9.5±1.8 hours) and fingolimod (2.9±0.7 hours), (overall p=0.001). Similar results were found for nurses and patients, with the largest difference between therapies (favouring cladribine tablets) recorded for patients.ConclusionCladribine tablets were associated with a significantly lower overall time taken to treat RRMS compared to fingolimod and alemtuzumab. This warrants further research to determine if cladribine tablets could (a) increase productivity for doctors and nurses, and (b) improve patient quality of life by reducing the burden of managing their disease.
070 Baseline characteristics and safety profile of patients with relapsing-remitting multiple sclerosis (RRMS) in the first interim analysis of the peginterferon BETA-1A treatment in the phase 4 plegridy observational program (POP)
Authors: Salvetti Marco , Yun Jang , Appiah-Badu David , Sabatella Guido , Naylor Maria L 
Published: May 2018

IntroductionThe 5 year, observational, phase 4 POP study explores the long-term safety and effectiveness of peginterferon beta-1a 125 mcg every 2 weeks in RRMS patients treated in real-world settings. This analysis presents interim data from POP on baseline characteristics, adverse events (AEs), and clinical effectiveness.MethodsPOP is ongoing in >150 sites in 14 countries. Patients who initiated peginterferon beta-1a treatment either ≤31 days pre-enrolment (naive subgroup, ‘PegNaive’) or >31 days pre-enrolment (experienced subgroup, ‘PegExperienced’) will be followed for ≤5 years.ResultsAt the time of this analysis, 467 patients were included, 411 (88%) of whom were followed for ≥12 months. A total of 153 patients (33%) discontinued treatment, primarily due to AEs (55%) or lack of efficacy (13%). At baseline, mean age was 44.9 years, 76% of patients were female, and mean Expanded Disability Status Scale score was 1.9. Of the 371 patients (79%) with prior disease-modifying therapy use, 217 (58%) had been treated with intramuscular interferon beta-1a. More patients were PegNaive than PegExperienced (60% vs 40%). AEs were more common in PegNaive patients than in PegExperienced patients (35% vs 20%), as were AEs leading to treatment discontinuation (29% vs 15%). The most commonly reported AEs leading to treatment discontinuation in both groups were injection-site erythema and influenza-like illness. Serious AEs were reported in 5% of PegNaive and 9% of PegExperienced patients. A high proportion of patients in both groups were relapse free (PegNaive, 84.4%; PegExperienced, 81.5%).ConclusionIn this first interim analysis of the POP study, the safety profile was consistent with that observed in the phase 3 trial of peginterferon beta-1a. No new safety signals were observed. PegNaive patients were more likely than PegExperienced patients to experience AEs and discontinue treatment due to injection-site reactions and flu-like symptoms, highlighting a need for prophylactic mitigation strategies.Study supportBiogen
073 Alemtuzumab induced allergic inflammatory syndrome (ALIAS) with eosinophilic acalculous cholecystitis: a report of two cases
Authors: Fontes-Villalba Ariadna , Parratt John DE 
Published: May 2018

IntroductionAlemtuzumab, a humanised monoclonal antibody directed at CD52, is a highly active treatment for multiple sclerosis (MS) that induces rapid depetion of circulating lymphocytes. Infusion-associated reactions and autoimmune disorders are established adverse effects. We describe two cases of alemtuzumab associated allergic inflammatory syndrome involving the lungs and gallbladder in two young patients after their first course of Alemtuzumab.Case 1 A 26 year old female with relapsing-remitting MS (RRMS) received her first course of alemtuzumab. On the fourth day of treatment, she developed bronchospasm, chest pain and an interstitial infiltrate in the right lower lobe on chest X-ray. She had right upper quadrant pain and a positive Murphy’s sign and ‘gallbladder sludge’ on ultrasound. Blood tests showed lymphopenia and eosinophilia. The patient was diagnosed with acalculous cholecystitis. Antibiotic therapy was initiated but laparoscopic cholecystectomy was required. The pathology demonstrated eosinophilic cholecystitis.Case 2 A 29 year old man with RRMS was switched to alemtuzumab due to positive JCV antibody status. He had an episode of hemoptysis on the fifth day of the infusion. Two days later, haemoptysis was accompanied by chest tightness. Physical examination revealed a palpable liver and positive Murphy sign. Blood tests were remarkable for abnormal liver enzymes. Signs of interstitial changes in the right lower lobe were observed on a chest X-ray. The patient was diagnosed with acalculous cholecystitis and antibiotic therapy was initiated. The infiltrate resolved and the clinical signs quickly improved.ConclusionThe characteristics of this condition are acute onset (within days of alemtuzumab) and non-infective inflammation of the lung (right lower lobe in these cases) and gallbladder. The pathology in one case indicates this is likely to be a drug related, allergic phenomenon with extensive eosinophilic infiltration of the gallbladder.
082 Real world experience of treating multiple sclerosis with alemtuzumab
Authors: Khalili Ellie , Venning Brent , Boggild Mike , Broadley Simon A 
Published: May 2018

IntroductionAlemtuzumab is a highly effective therapy for multiple sclerosis that has a significant, but well-defined adverse event profile. We report cases treated since the commercial release of alemtuzumab at two centres in Queensland with the aim of comparing real-world experience with trial data.MethodsThis was a retrospective case note review of patients treated with alemtuzumab for multiple sclerosis since becoming commercially available in Australia. The two sites were the Gold Coast University Hospital and the Townsville Hospital. Demographic, clinical and MRI data were systematically collected from the available records at each site. De-identified aggregated data were analysed using descriptive statistics (mean (±SD), median (range)) and compared with phase III clinical trial data.Results104 cases treated with alemtuzumab were identified at the two sites. The median age at first treatment was 3817–55 years, slightly older than the trial populations (33 and 35 years) and two-thirds were female. The mean disease duration was 8.4 (±7.0) years, which is longer that seen in the trials (2.1 and 4.5 years). The median number of prior relapses was 31–12 with 1 (0–3) in the prior 2 years. The median number of prior treatments for MS was 1.5. The median follow up was 201–35 months. The median EDSS at time of first treatment was 2 (0–7) and at last follow up was 1.5 (0–7). At last follow up, 24/104 (23%) had improved, 61/104 (58%) were stable and 9/104 (9%) had worsened. Autoimmune adverse events were seen in 18/104 (17%) with autoimmune thyroid disease being the most common (13/104 (13%).ConclusionAlemtuzumab is an effective therapy for MS. Clinical outcomes in a real world setting were similar to those seen in phase III clinical trials. Autoimmune diseases occurred in a similar proportion to those seen in clinical trials.References. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet2012;380(9856):1819–28.. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet2012;380(9856):1829–39.
084 Treating yourself: a glucocorticoid secreting tumour suppressing myasthenia gravis
Authors: Swayne Andrew , Lane Michael , Brown Helen , Prain Kerri , Wong Richard , Gillis David , Blum Stefan 
Published: May 2018

IntroductionWe aimed to report a single patient seen at a tertiary neurology centre with a rarely described phenomenon of interaction between myasthenia gravis and a glucocorticoid secreting tumour.CaseA 70 year old, otherwise healthy male underwent a CT imaging of his chest after being trampled by a cow. Apart from several rib fractures, this revealed a slightly lobulated but well-defined right adrenal mass. Further studies revealed elevated morning cortisol levels of 847 nmol/L (reference range 140–640 nmol/L). The mass was excised and was found to be a 60 mm by 30 mm by 25 mm lesion, which was well circumscribed. It comprised of clear cells with foamy cytoplasm and a lesser component of eosinophilic cells, consistent with a functional adrenal adenoma producing glucocorticoid. Within days of the resection the patient described becoming weaker with fatigable proximal weakness of both upper and lower limbs. Acetylcholine receptor antibodies were positive and a diagnosis of myasthenia gravis was made. Upon commencement of pyridostigmine at 60 mg TDS and prednisolone 10 mg OD the symptoms improved and the patient was able to resume his previous active lifestyle.ConclusionThe phenomenon of myasthenia gravis being suppressed by a functional adrenal adenoma has only previously been reported twice.1 2 This case report adds to the literature and can be distinguished from the other two cases by the rapidity of onset of symptoms of myasthenia over days after tumour resection. It tells a cautionary tale of medical therapy disrupting the brittle balance of nature.References. Petramala L, Marinelli C, Giallonardo AT, Concistre A, Lucia P, Venuta F, … Letizia C. A case report of subclinical hypercortisolism due to adrenal incidentaloma complicated by myasthenia gravis after adrenalectomy. Tumori2016;102(Suppl.2).. Topham L, Chapman A, Gibbs C, Saha M. A patient with pemphigus foliaceus and myasthenia gravis treated by a cortisol-secreting adrenal adenoma. Br J Dermatol2015;172(1):280–282.
095 Increased incidence of moyamoya angiopathy in northern queensland
Authors: Harrison Emma L , Devlin Michael J , Stoodley Marcus A , White Richard P 
Published: May 2018

IntroductionInitially described in Japan in 1957, moyamoya angiopathy is recognised in other populations, particularly within Europe and North America. Moyamoya disease (MMD) is a rare chronic progressive cerebrovascular disorder of unknown aetiology characterised by concentric stenosis of large intracranial vessels with collateralisation from moyamoya vessels and the leptomeningeal vessels. Affected individuals may present with transient ischaemic attacks or ischaemic stroke, however presentations with intracerebral haemorrhage, epilepsy or cognitive impairment in both children and adults also occur. Those with moyamoya syndrome (MMS), MMD in the setting of an associated disease such as neurofibromatosis, type one diabetes mellitus and trisomy 21, appear to follow a similar clinical course.MethodsWe conducted a retrospective review of patients with Moyamoya angiopathy who presented to the Townsville or Mackay Hospital Health Service between January 2012 and January 2018.ResultsWe identified eleven cases of moyamoya angiopathy between 2012 and 2018. The cumulative incidence in our study population was 0.436 per 1 00 000 persons per year. The most common presentation was ischaemic stroke. We will present additional morphologic data, functional cerebral blood flow studies and outcomes following revascularisation (including ECIC bypass).ConclusionThe findings from our small case series suggests the incidence of moyamoya angiopathy within Northern Queensland is higher than anticipated in European and Northern American populations. Additional research is required to ascertain whether this is primarily due to an increased awareness of the condition and extended diagnostic workup within our centre, specific patient characteristics which predispose to the disease or due to increasing prevalence of moyamoya angiopathy in the general population.