Publications by authors named "Richard Macdonell"

66 Publications

Acute graft-versus-host disease associated cerebellitis as the cause of pyrexia of unknown origin detected with F-FDG-PET/CT.

Cancer Treat Res Commun 2021 Feb 16;27:100341. Epub 2021 Feb 16.

Department of Clinical Haematology, Austin Health, Heidelberg, Australia; Department of Haematology, Eastern Health and Monash University, Box Hill, Australia.

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http://dx.doi.org/10.1016/j.ctarc.2021.100341DOI Listing
February 2021

Prognostic value of acute cerebrospinal fluid abnormalities in antibody-positive autoimmune encephalitis.

J Neuroimmunol 2021 Apr 30;353:577508. Epub 2021 Jan 30.

Department of Neuroscience, Monash University, Melbourne, Australia; Department of Neurology, Alfred Health, Melbourne, Australia; Department of Neurology, Melbourne Health, Melbourne, Australia; Department of Physiology, The University of Melbourne, Melbourne, Australia. Electronic address:

Objective: To examine the prognostic value of CSF abnormalities in seropositive autoimmune encephalitis (AE).

Methods: We retrospectively studied 57 cases of seropositive AE. Primary outcomes were mortality and modified Rankin Scale, while secondary outcomes were first line treatment failure, ICU admission and relapse. Regression analysis was performed.

Results: CSF white cell count (WCC) was higher in the NMDAR group, while elevated protein was more common amongst other subtypes. We found an association between WCC >5 cells/mm and treatment failure (OR 16.0, p = 0.006)), and between WCC >20 cells/mm and ICU admission (OR 19.3, p = 0.026).

Conclusions: Different subsets of AE have characteristic CSF abnormalities, which may aid recognition during early evaluation. CSF WCC had prognostic significance in our study.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577508DOI Listing
April 2021

Delay from treatment start to full effect of immunotherapies for multiple sclerosis.

Brain 2020 09;143(9):2742-2756

CORe, Department of Medicine, University of Melbourne, Melbourne, 3050, Australia.

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag.
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http://dx.doi.org/10.1093/brain/awaa231DOI Listing
September 2020

Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal Variation.

Front Neurol 2020 16;11:537. Epub 2020 Jun 16.

Menzies Health Institute Queensland, Gold Coast Campus, Griffith University, Southport, QLD, Australia.

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis ( < 0.001) and area postrema relapses ( = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS ( < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January ( = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD.
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http://dx.doi.org/10.3389/fneur.2020.00537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308484PMC
June 2020

Early clinical markers of aggressive multiple sclerosis.

Brain 2020 05;143(5):1400-1413

CORe Unit, Department of Medicine, University of Melbourne, Melbourne, Australia.

Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis.
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http://dx.doi.org/10.1093/brain/awaa081DOI Listing
May 2020

Effects of modified-release fampridine on upper limb impairment in patients with Multiple Sclerosis.

Mult Scler Relat Disord 2020 May 28;40:101971. Epub 2020 Jan 28.

Department of Neurology, Austin Hospital, 145 Studley Road, Heidelberg, VIC 3084, Australia; Melbourne Brain Centre, 245 Burgundy Street, Heidelberg, VIC 3084, Australia. Electronic address:

Background: Modified-release 4-aminopyridine (fampridine-MR) is used in the symptomatic treatment of walking disability in patients with multiple sclerosis (MS).  Its potential for use in other MS symptoms remains unproven and its mode of action in this context is uncertain. Interest is growing in the use of upper limb outcome measures in clinical trials in patients with Multiple Sclerosis, particularly in advanced or progressive disease.  This study tests the following hypotheses: (1) Fampridine-MR improves upper limb function in patients with MS and upper limb impairment.  (2) Treatment with fampridine-MR is associated with measurable alterations in objective electrophysiological parameters (evoked potentials and transcranial magnetic stimulation (TMS)) which may predict response to drug treatment.

Methods: Study population: patients with MS of any disease subtype, duration and severity who have symptomatic impairment of one or both upper limbs.  A healthy control group was included for validation of clinical and electrophysiological measures.  Study design: randomised double blind placebo-controlled trial.  Treatment details: participants allocated to either fampridine-MR 10 mg bd or placebo of identical appearance for 8 weeks.  Primary outcome: performance on 9-hole peg test (9HPT) after 4 weeks.  Secondary outcomes: persistence of effect on 9HPT; grip strength; visual acuity and contrast sensitivity; modified fatigue impact scale score; sensory discrimination capacity; visual, somatosensory and motor evoked potentials; resting motor threshold; paired-pulse TMS; peripheral nerve conduction studies.

Results: 40 patients with MS (60% female, median age 52, median disease duration 13.5 years, median EDSS 6.0) were enrolled.  Treatment with fampridine-MR was not associated with any change in upper limb function as measured by the clinical primary or secondary outcomes.  Treatment with fampridine-MR was also not associated with any difference in electrophysiological measures of upper limb function.  This held true after adjustment for hand dominance, disease duration and severity.  Four patients withdrew from the trial because of lack of efficacy or side-effects; all were in the placebo arm.  Three patients were admitted to hospital during the study period; one with MS exacerbation (placebo group), one with syncope (drug group) and one with UTI (drug group); otherwise there were no serious adverse events.

Conclusion: Treatment with fampridine-MR was well-tolerated but did not produce clinical benefit in terms of upper limb function, vision or fatigue, nor was there any measurable effect on objective electrophysiological parameters.
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http://dx.doi.org/10.1016/j.msard.2020.101971DOI Listing
May 2020

Efficacy of alemtuzumab in relapsing-remitting MS patients who received additional courses after the initial two courses: Pooled analysis of the CARE-MS, extension, and TOPAZ studies.

Mult Scler 2020 12 25;26(14):1866-1876. Epub 2019 Nov 25.

Division of Neurology, Department of Medicine, The University of British Columbia, Vancouver, BC, Canada.

Background: Alemtuzumab is given as two annual courses. Patients with continued disease activity may receive as-needed additional courses.

Objective: To evaluate efficacy and safety of additional alemtuzumab courses in the CARE-MS (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis) studies and their extensions.

Methods: Subgroups were based on the number of additional alemtuzumab courses received. Exclusion criteria: other disease-modifying therapy (DMT); <12-month follow-up after last alemtuzumab course.

Results: In the additional-courses groups, Courses 3 and 4 reduced annualized relapse rate (12 months before: 0.73 and 0.74, respectively; 12 months after: 0.07 and 0.08). For 36 months after Courses 3 and 4, 89% and 92% of patients were free of 6-month confirmed disability worsening, respectively, with 20% and 26% achieving 6-month confirmed disability improvement. Freedom from magnetic resonance imaging (MRI) disease activity increased after Courses 3 and 4 (12 months before: 43% and 53%, respectively; 12 months after: 73% and 74%). Safety was similar across groups; serious events occurred irrespective of the number of courses.

Conclusion: Additional alemtuzumab courses significantly improved outcomes, without increased safety risks, in CARE-MS patients with continued disease activity after Course 2. How this compares to outcomes if treatment is switched to another DMT instead remains unknown.
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http://dx.doi.org/10.1177/1352458519888610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720359PMC
December 2020

Efficacy and safety of teriflunomide in Asian patients with relapsing forms of multiple sclerosis: A subgroup analysis of the phase 3 TOWER study.

J Clin Neurosci 2019 Jan 20;59:229-231. Epub 2018 Oct 20.

Multiple Sclerosis Research Unit, Department of Neurology, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada. Electronic address:

In the phase 3 TOWER (NCT00751881) study, teriflunomide 14 mg significantly reduced annualized relapse rate (ARR) and risk of 12-week confirmed disability worsening (12-w CDW) vs placebo in patients with relapsing forms of MS (RMS). The TOWER population included an appreciable proportion of Asian patients. Reductions in ARR and 12-w CDW associated with teriflunomide 14 mg were comparable between the Asian and overall populations, as were the rates for adverse events and serious adverse events, with no new or unexpected safety findings. These observations provide further evidence to support the clinical benefits and safety profile of teriflunomide in a broad range of patients with RMS.
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http://dx.doi.org/10.1016/j.jocn.2018.09.012DOI Listing
January 2019

Bilateral facial nerve palsies secondary to chronic inflammatory demyelinating polyneuropathy following adalimumab treatment.

Clin Neurol Neurosurg 2018 01 22;164:64-66. Epub 2017 Nov 22.

Department of Ophthalmology, Austin Health, Heidelberg, Victoria, Australia; The Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia; Centre for Eye Research Australia, Department of Surgery, University of Melbourne, East Melbourne, Victoria, Australia.

Purpose: Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) presents uncommonly with cranial nerve involvement with ophthalmological implications.

Methods: We report the case of a 37year-old man who developed CIDP which manifested as progressive and relapsing bilateral facial nerve palsy with lagophthalmos and exposure keratopathy, in the setting of treatment of Crohn's disease with the anti-TNF-alpha agent adalimumab.

Results: Symptoms gradually improved over the course of several months following withdrawal of adalimumab and treatment with intravenous immunoglobulin (IVIg) and oral prednisolone.

Conclusion: Bilateral facial nerve involvement occurs uncommonly as a feature of CIDP in its classic form. The prognosis is good for recovery of facial nerve function with discontinuation of anti-TNF-alpha therapy and concurrent use of steroid and intravenous immunoglobulin in this case.
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http://dx.doi.org/10.1016/j.clineuro.2017.11.001DOI Listing
January 2018

The professional practice and training of neurology in the Asian and Oceanian Region: A cross-sectional survey by the Asian and Oceanian Association of Neurology (AOAN).

J Neurol Sci 2017 Nov 20;382:108-115. Epub 2017 Sep 20.

Stroke Consultant, The People 's 115 hospital - Pham Ngoc Thach School of Medicine, 527 Thanh Thai street, Dist. 10, HCM City, Vietnam. Electronic address:

Objective: To survey AOAN member countries regarding their organizational structure, postgraduate neurology training program, and resources for neurological care provision.

Methodology: A cross-sectional survey using a 36-item questionnaire was conducted among country representatives to AOAN from August 2015 to August 2016.

Results: A total of 18/20 AOAN member countries participated in the survey. All the countries have organized association with regular meetings, election of officers and neurology training program. In 9/18 countries, professionals other than neurologists were eligible for affiliation. In 11/18 countries, prior Internal medicine training (or equivalent postgraduate housemanship) is prerequisite to neurology program. Recertification examination is not a practice, but submission of CME is required in 7/18 countries to maintain membership. 12/18 countries publish peer-reviewed journals with at least 1 issue per year. Subspecialty training is offered in 14/18 countries. The ratio of neurologist to population ranges from 1:14,000 to as low as 1:32 million with 9/18 having <1 neurologist per 100,000 population. 6/18 countries have at least 1 specialized center solely for neurological diseases. In government-funded hospitals, the lag time to be seen by a neurologist and/or obtain neuroimaging scan ranges from 1day to 3months. All except one country have several medical- and lay- advocacy or support groups for different neurological conditions.

Implications: The data generated can be used for benchmarking to improve neurological care, training, collaborative work and research in the field of neurosciences among the AOAN member countries. The paper presented several strategies used by the different organizations to increase their number of neurologists and improve the quality of training. Sharing of best practices, academic networking, exchange programs and use of telemedicine have been suggested.
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http://dx.doi.org/10.1016/j.jns.2017.09.022DOI Listing
November 2017

Incidence and prevalence of NMOSD in Australia and New Zealand.

J Neurol Neurosurg Psychiatry 2017 08 26;88(8):632-638. Epub 2017 May 26.

School of Medicine, Griffith University, Gold Coast, Australia.

Objectives: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry.

Background: NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established.

Methods: Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases.

Results: NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD.

Conclusions: NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.
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http://dx.doi.org/10.1136/jnnp-2016-314839DOI Listing
August 2017

Motor neurone disease: progress and challenges.

Med J Aust 2017 May;206(8):357-362

Brain and Mind Centre, University of Sydney, Sydney, NSW.

Major progress has been made over the past decade in the understanding of motor neurone disease (MND), changing the landscape of this complex disease. Through identifying positive prognostic factors, new evidence-based standards of care have been established that improve patient survival, reduce burden of disease for patients and their carers, and enhance quality of life. These factors include early management of respiratory dysfunction with non-invasive ventilation, maintenance of weight and nutritional status, as well as instigation of a multidisciplinary team including neurologists, general practitioners and allied health professionals. Advances in technology have enhanced our understanding of the genetic architecture of MND considerably, with implications for patients, their families and clinicians. Recognition of extra-motor involvement, particularly cognitive dysfunction, has identified a spectrum of disease from MND through to frontotemporal dementia. Although riluzole remains the only disease-modifying medication available in clinical practice in Australia, several new therapies are undergoing clinical trials nationally and globally, representing a shift in treatment paradigms. Successful translation of this clinical research through growth in community funding, awareness and national MND research organisations has laid the foundation for closing the research-practice gap on this debilitating disease. In this review, we highlight these recent developments, which have transformed treatment, augmented novel therapeutic platforms, and established a nexus between research and the MND community. This era of change is of significant relevance to both specialists and general practitioners who remain integral to the care of patients with MND.
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http://dx.doi.org/10.5694/mja16.01063DOI Listing
May 2017

Reply: Transcranial magnetic stimulation as a biomarker for epilepsy.

Brain 2017 03;140(3):e19

Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.

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http://dx.doi.org/10.1093/brain/aww346DOI Listing
March 2017

Improved patient-reported health impact of multiple sclerosis: The ENABLE study of PR-fampridine.

Mult Scler 2016 06 7;22(7):944-54. Epub 2015 Oct 7.

Danish Multiple Sclerosis Center, Copenhagen University Hospital Rigshospitalet, Denmark.

Background: Multiple sclerosis (MS) is a debilitating disease that negatively impacts patients' lives.

Objective: ENABLE assessed the effect of long-term prolonged-release (PR) fampridine (dalfampridine extended release in the United States) treatment on patient-perceived health impact in patients with MS with walking impairment.

Methods: ENABLE was a 48-week, open-label, Phase 4 study of PR-fampridine 10 mg twice daily. Patients who showed any improvement in Timed 25-Foot Walk walking speed at weeks 2 and 4 and any improvement in 12-item MS Walking Scale score at week 4 remained on treatment. The primary endpoint was change from baseline in 36-Item Short-Form Health Survey (SF-36) physical component summary (PCS) score.

Results: At week 4, 707/901 (78.5%) patients met the criteria to remain on treatment. Patients on treatment demonstrated significant and clinically meaningful improvements in SF-36 PCS scores from baseline (mean change (95% confidence interval)) to week 12 (4.30 (3.83, 4.78); p < 0.0001), week 24 (3.75 (3.23, 4.27); p < 0.0001), week 36 (3.46 (2.95, 3.97); p < 0.0001), and week 48 (3.24 (2.72, 3.77); p < 0.0001). Significant improvements from baseline were also demonstrated in secondary health measures in patients on treatment.

Conclusion: PR-fampridine improved patient-perceived physical and psychological health impact of MS measured in a real-life setting.
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http://dx.doi.org/10.1177/1352458515606809DOI Listing
June 2016

The use of transcranial magnetic stimulation in diagnosis, prognostication and treatment evaluation in multiple sclerosis.

Mult Scler Relat Disord 2015 Sep 23;4(5):430-436. Epub 2015 Jun 23.

Department of Neurology, Austin Health and Faculty of Medicine, The University of Melbourne, Melbourne, Vic, Australia.

Despite advances in brain imaging which have revolutionised the diagnosis and monitoring of patients with Multiple Sclerosis (MS), current imaging techniques have limitations, including poor correlation with clinical disability and prognosis. There is growing evidence that electrophysiological techniques may provide complementary functional information which can aid in diagnosis, prognostication and perhaps even monitoring of treatment response in patients with MS. Transcranial magnetic stimulation (TMS) is an underutilised technique with potential to assist diagnosis, predict prognosis and provide an objective surrogate marker of clinical progress and treatment response. This review explores the existing body of evidence relating to the use of TMS in patients with MS, outlines the practical aspects and scope of TMS testing and reviews the current evidence relating to the use of TMS in diagnosis, disease classification, prognostication and response to symptomatic and disease-modifying therapies.
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http://dx.doi.org/10.1016/j.msard.2015.06.014DOI Listing
September 2015

A new era in the treatment of multiple sclerosis.

Med J Aust 2015 Aug;203(3):139-41, 141e.1

Gold Coast University Hospital, Gold Coast, QLD.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with a multifactorial aetiology and highly variable natural history. A growing understanding of the immunopathogenesis of the condition has led to an expanding array of therapies for this previously untreatable disease. While a cure for MS remains elusive, the potential to reduce inflammatory disease activity by preventing relapses and minimising disease progression is achievable. The importance of early treatment in minimising long-term disability is increasingly recognised. Most of the newer, more effective therapies are associated with risks and practical problems that necessitate an active management strategy and continuous vigilance. While the initiation of these therapies is likely to remain the responsibility of neurologists, other specialist physicians and general practitioners will be involved in the identification and management of adverse effects.
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http://dx.doi.org/10.5694/mja14.01218DOI Listing
August 2015

Randomized comparison trial of density and context of upper limb intensive group versus individualized occupational therapy for children with unilateral cerebral palsy.

Dev Med Child Neurol 2015 Jun 27;57(6):539-47. Epub 2015 Jan 27.

Faculty of Health, Queensland Cerebral Palsy and Rehabilitation Research Centre, School of Medicine, The University of Queensland, Brisbane, Qld, Australia.

Aim: To determine whether short-term intensive group-based therapy combining modified constraint-induced movement therapy and bimanual therapy (hybrid-CIMT) is more effective than an equal total dose of distributed individualized occupational therapy (standard care) on upper limb motor and individualized outcomes.

Method: Fifty-three children with unilateral cerebral palsy (69% males; mean age 7y 10mo, SD 2y 4mo; Manual Ability Classification System level I, n=24; level II, n=23) were randomly allocated, and 44 received either hybrid-CIMT (n=25) or standard care (n=19). Standard care comprised six weekly occupational therapy sessions and a 12-week home programme. Outcomes were assessed at baseline, 13 weeks, and 26 weeks after treatment.

Results: Groups were equivalent at baseline. Standard care achieved greater gains on satisfaction with occupational performance after intervention (estimated mean difference -1.2, 95% CI -2.2 to -0.1; p=0.04) and Assisting Hand Assessment at 26 weeks (estimated mean difference 3.1, 95% CI 0.2-6.0; p=0.04). Both groups demonstrated significant improvements in dexterity of the impaired upper limb, and bimanual and occupational performance over time. The differences between groups were not clinically meaningful.

Interpretation: There were no differences between the two models of therapy delivery. Group-based intensive camps may not be readily available; however, individualized standard care augmented with a home programme may offer an effective alternative but needs to be provided at a sufficient dose.
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http://dx.doi.org/10.1111/dmcn.12702DOI Listing
June 2015

Evolution, current status, and way forward for the Asian Oceanian Association of Neurology.

Neurology 2014 Nov;83(20):1853-5

From the Department of Neurology (M.M.M.), Janakpuri Super Speciality Hospital (N.S.G.), Janakpuri, New Delhi, India; the University of Virginia (P.M.), Charlottesville; the Neurological Institute at Taipei Veterans General Hospital and National Yang-Ming University (C.-P.T.), Taiwan; the Department of Neurology (R.K.), Institute of Health-Bioscience, Tokushima University, Kuramoto-cho, Tokushima, Japan; Aga Khan University (M.W.), Karachi, Pakistan; and Austin Health (R.M.), Heidelberg, Australia.

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http://dx.doi.org/10.1212/WNL.0000000000000975DOI Listing
November 2014

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 3 treatment practicalities and recommendations. MS Neurology Group of the Australian and New Zealand Association of Neurologists.

J Clin Neurosci 2014 Nov 30;21(11):1857-65. Epub 2014 Jun 30.

Department of Neurology, Auckland City Hospital, Auckland, New Zealand.

In this third and final part of our review of multiple sclerosis (MS) treatment we look at the practical day-to-day management issues that are likely to influence individual treatment decisions. Whilst efficacy is clearly of considerable importance, tolerability and the potential for adverse effects often play a significant role in informing individual patient decisions. Here we review the issues surrounding switching between therapies, and the evidence to assist guiding the choice of therapy to change to and when to change. We review the current level of evidence with regards to the management of women in their child-bearing years with regards to recommendations about treatment during pregnancy and whilst breast feeding. We provide a summary of recommended pre- and post-treatment monitoring for the available therapies and review the evidence with regards to the value of testing for antibodies which are known to be neutralising for some therapies. We review the occurrence of adverse events, both the more common and troublesome effects and those that are less common but have potentially much more serious outcomes. Ways of mitigating these risks and managing the more troublesome adverse effects are also reviewed. Finally, we make specific recommendations with regards to the treatment of MS. It is an exciting time in the world of MS neurology and the prospects for further advances in coming years are high.
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http://dx.doi.org/10.1016/j.jocn.2014.01.017DOI Listing
November 2014

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 1 historical and established therapies. MS Neurology Group of the Australian and New Zealand Association of Neurologists.

J Clin Neurosci 2014 Nov 30;21(11):1835-46. Epub 2014 Jun 30.

Department of Neurology, Auckland City Hospital, Auckland, New Zealand.

Multiple sclerosis (MS) is a potentially life-changing immune mediated disease of the central nervous system. Until recently, treatment has been largely confined to acute treatment of relapses, symptomatic therapies and rehabilitation. Through persistent efforts of dedicated physicians and scientists around the globe for 160 years, a number of therapies that have an impact on the long term outcome of the disease have emerged over the past 20 years. In this three part series we review the practicalities, benefits and potential hazards of each of the currently available and emerging treatment options for MS. We pay particular attention to ways of abrogating the risks of these therapies and provide advice on the most appropriate indications for using individual therapies. In Part 1 we review the history of the development of MS therapies and its connection with the underlying immunobiology of the disease. The established therapies for MS are reviewed in detail and their current availability and indications in Australia and New Zealand are summarised. We examine the evidence to support their use in the treatment of MS.
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http://dx.doi.org/10.1016/j.jocn.2014.01.016DOI Listing
November 2014

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 2 new and emerging therapies and their efficacy. MS Neurology Group of the Australian and New Zealand Association of Neurologists.

J Clin Neurosci 2014 Nov 28;21(11):1847-56. Epub 2014 Jun 28.

Department of Neurology, Auckland City Hospital, Auckland, New Zealand.

In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of β-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes.
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http://dx.doi.org/10.1016/j.jocn.2014.01.018DOI Listing
November 2014

Teriflunomide reduces relapses with sequelae and relapses leading to hospitalizations: results from the TOWER study.

J Neurol 2014 Sep 28;261(9):1781-8. Epub 2014 Jun 28.

Icahn School of Medicine at Mount Sinai, 5 East 98th Street, Box 1138, New York, NY, 10028, USA,

Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. This post hoc analysis of the Phase III TOWER study evaluated the effects of teriflunomide treatment on five severe relapse outcomes: relapses with sequelae defined by an increase in Expanded Disability Status Scale (EDSS)/functional system (FS) score (sequelae-EDSS/FS) 30 days post relapse; relapses with sequelae defined by the investigator (sequelae-investigator); relapses leading to hospitalization; relapses treated with intravenous corticosteroids; and intense relapses using the definition of Panitch et al. from the EVIDENCE study based on specified increases in EDSS for severe relapses. Adjusted annualized rates for the five severe relapse outcomes were derived using a Poisson model with robust error variance, with treatment, baseline EDSS strata and region as covariates. Compared with placebo, teriflunomide significantly reduced annualized rates of relapses with sequelae-EDSS/FS [14 mg, 36.6 % (p = 0.0021); 7 mg, 31.3 % (p = 0.0104)] and sequelae-investigator [14 mg only, 53.5 % (p = 0.0004)], relapses leading to hospitalization [14 mg only, 33.6 % (p = 0.0155)], relapses requiring intravenous corticosteroids [14 mg, 35.7 % (p = 0.0002); 7 mg, 21.5 % (p = 0.0337)], and intense relapses [14 mg only, 52.5 % (p = 0.0015)]. Patients treated with teriflunomide 14 mg spent significantly fewer nights in hospital for relapse (p = 0.009) and had lower annualized rates of all hospitalizations (p = 0.030). Taken together, the positive effects of teriflunomide on severe relapses indicate that teriflunomide may reduce relapse-related healthcare costs.
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http://dx.doi.org/10.1007/s00415-014-7395-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155167PMC
September 2014

Internal jugular and vertebral vein volume flow in patients with clinically isolated syndrome or mild multiple sclerosis and healthy controls: results from a prospective sonographer-blinded study.

Phlebology 2014 Sep 24;29(8):528-35. Epub 2013 Sep 24.

Department of Neurology, Austin Health, Melbourne, Australia The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia Department of Medicine, University of Melbourne, Victoria, Australia.

Objectives & Methods: We evaluated internal jugular vein and vertebral vein volume flow using ultrasound, in patients with clinically isolated syndrome or mild multiple sclerosis and controls, to determine whether volume flow was different between the two groups.

Results: In patients and controls, internal jugular vein volume flow increased from superior to inferior segments, consistent with recruitment from collateral veins. Internal jugular vein and vertebral vein volume flow were greater on the right in supine and sitting positions. Internal jugular vein volume flow was higher in the supine posture. Vertebral vein volume flow was higher in the sitting posture. Regression analyses of cube root transformed volume flow data, adjusted for supine/sitting, right/left and internal jugular vein/vertebral vein, revealed no significant difference in volume flow in patients compared to controls.

Conclusions: Our findings further refute the concept of venous obstruction as a causal factor in the pathogenesis of multiple sclerosis. Control volume flow data may provide useful normative reference values.
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http://dx.doi.org/10.1177/0268355513505505DOI Listing
September 2014

COMBIT: protocol of a randomised comparison trial of COMbined modified constraint induced movement therapy and bimanual intensive training with distributed model of standard upper limb rehabilitation in children with congenital hemiplegia.

BMC Neurol 2013 Jun 28;13:68. Epub 2013 Jun 28.

Queensland Cerebral Palsy and Rehabilitation Research Centre, School of Medicine, Faculty of Health Sciences, The University of Queensland, Brisbane, Australia.

Introduction: Children with congenital hemiplegia often present with limitations in using their impaired upper limb which impacts on independence in activities of daily living, societal participation and quality of life. Traditional therapy has adopted a bimanual training approach (BIM) and more recently, modified constraint induced movement therapy (mCIMT) has emerged as a promising unimanual approach. Evidence of enhanced neuroplasticity following mCIMT suggests that the sequential application of mCIMT followed by bimanual training may optimise outcomes (Hybrid CIMT). It remains unclear whether more intensely delivered group based interventions (hCIMT) are superior to distributed models of individualised therapy. This study aims to determine the optimal density of upper limb training for children with congenital hemiplegia.

Methods And Analyses: A total of 50 children (25 in each group) with congenital hemiplegia will be recruited to participate in this randomized comparison trial. Children will be matched in pairs at baseline and randomly allocated to receive an intensive block group hybrid model of combined mCIMT followed by intensive bimanual training delivered in a day camp model (COMBiT; total dose 45 hours direct, 10 hours of indirect therapy), or a distributed model of standard occupational therapy and physiotherapy care (SC) over 12 weeks (total 45 hours direct and indirect therapy). Outcomes will be assessed at 13 weeks after commencement, and retention of effects tested at 26 weeks. The primary outcomes will be bimanual coordination and unimanual upper-limb capacity. Secondary outcomes will be participation and quality of life. Advanced brain imaging will assess neurovascular changes in response to treatment. Analysis will follow standard principles for RCTs, using two-group comparisons on all participants on an intention-to-treat basis. Comparisons will be between treatment groups using generalized linear models.

Trial Registration: ACTRN12613000181707.
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http://dx.doi.org/10.1186/1471-2377-13-68DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750247PMC
June 2013

In vivo TSPO imaging in patients with multiple sclerosis: a brain PET study with [18F]FEDAA1106.

EJNMMI Res 2013 Apr 24;3(1):30. Epub 2013 Apr 24.

Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm SE-171 77, Sweden.

Background: The activation of microglia, in general, and the upregulation of the translocator protein (18 kDa) (TSPO) system, in particular, are key features of neuroinflammation, of which the in vivo visualization and quantitative assessment are still challenging due to the lack of appropriate molecular imaging biomarkers. Recent positron emission tomography (PET) studies using TSPO radioligands such as [11C]PK11195 and [11C]PBR28 have indicated the usefulness of these PET biomarkers in patients with neuroinflammatory diseases, including multiple sclerosis (MS). [18F]FEDAA1106 is a recently developed PET radioligand for the in vivo quantification of TSPO. In the present study, we aimed at investigating the diagnostic usefulness of [18F]FEDAA1106 in patients with MS.

Methods: Nine patients (three on the interferon beta therapy and six without immunomodulatory therapy; seven females/two males; age 34.2 ± 9.1 years old) with relapsing-remitting MS in acute relapse and with gadolinium (Gd)-enhancing lesion(s) in the magnetic resonance imaging (MRI) scans and five healthy controls (four females/one male, age 38.0 ± 9.7 years old) were investigated in this study. Genetic information about the TSPO binding could not be obtained because knowledge about the importance of genetic background for TSPO binding was not available at the time the study was performed. Dynamic PET measurements were performed using an ECAT EXACT HR system (CTI/Siemens, Knoxville, TN, USA) for a total of 150 min, with a 30-min break after the injection of 153.4 ± 10.2 MBq of [18F]FEDAA1106. Metabolite-corrected arterial plasma samples were used to calculate the input function. PET data were analyzed in the following ways: (1) region-of-interest analysis for cortical and subcortical regions was performed using a two-tissue compartment kinetic model in order to estimate binding potentials (BPND) and distribution volume (VT), (2) the feasibility of the estimation of BPND and VT was investigated for MS lesions, and (3) VT parametric images by a Logan plot and standard uptake value (SUV) images were visually compared with the corresponding MRI, focusing on MRI-identified MS lesions.

Results: There were no significant differences in the BPND or VT values between patients with MS and healthy controls. Robust BPND and VT values could not be obtained for most MS lesions due to noisy time-activity curves. Visual inspection of VT and SUV images in all nine patients did not reveal high uptake of the radioligand inside and beyond MRI-identified active MS lesions with the exception of one Gd-enhanced MS lesion in the whole patient population.

Conclusions: In our study, [18F]FEDAA1106 as a PET radioligand could neither differentiate patients with MS from healthy controls nor detect active plaques in the brain of MS patients. Stratification with respect to genetics and binder status might help to uncover the differences between the groups, which could not be detected here.

Trial Registration: ClinicalTrials.gov, NCT01031199.
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http://dx.doi.org/10.1186/2191-219X-3-30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640965PMC
April 2013

Cortical excitability and neurology: insights into the pathophysiology.

Funct Neurol 2012 Jul-Sep;27(3):131-45

Department of Clinical Neurosciences, St Vincent's Hospital, Fitzroy, Victoria, Australia.

Transcranial magnetic stimulation (TMS) is a technique developed to non-invasively investigate the integrity of human motor corticospinal tracts. Over the last three decades, the use of stimulation paradigms including single-pulse TMS, paired-pulse TMS, repetitive TMS, and integration with EEG and functional imaging have been developed to facilitate measurement of cortical excitability.Through the use of these protocols, TMS has evolved in-to an excellent tool for measuring cortical excitability.TMS has high sensitivity in detecting subtle changes in cortical excitability, and therefore it is also a good measure of disturbances associated with brain disorders. In this review, we appraise the current literature on cortical excitability studies using TMS in neurological disorders.We begin with a brief overview of current TMS measures and then show how these have added to our understand-ing of the underlying mechanisms of brain disorders.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812767PMC
May 2013

Cortical excitability and refractory epilepsy: a three-year longitudinal transcranial magnetic stimulation study.

Int J Neural Syst 2013 Feb 3;23(1):1250030. Epub 2012 Dec 3.

Department of Neurology, Austin Health, Heidelberg, Epilepsy Research Centre, Australia.

Transcranial magnetic stimulation was used to study the effect of recurrent seizures on cortical excitability over time in epilepsy. 77 patients with firm diagnoses of idiopathic generalized epilepsy (IGE) or focal epilepsy were repeatedly evaluated over three years. At onset, all groups had increased cortical excitability. At the end of follow-up the refractory group was associated with a broad increase in cortical excitability. Conversely, cortical excitability decreased in all seizure free groups after introduction of an effective medication.
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http://dx.doi.org/10.1142/S012906571250030XDOI Listing
February 2013

Guillain-Barré syndrome following pandemic (H1N1) 2009 influenza A immunisation in Victoria: a self-controlled case series.

Med J Aust 2012 Nov;197(10):574-8

Royal Children's Hospital, Melbourne, VIC, Australia.

Objectives: To determine the relative incidence (RI) of Guillain-Barré syndrome (GBS) in a single Australian state following pandemic (H1N1) 2009 influenza A immunisation (monovalent vaccine or seasonal trivalent influenza vaccine [TIV]) in 2009-2010.

Design, Setting And Participants: Active GBS surveillance (cases assessed by two neurologists according to the Brighton criteria) from 30 September 2009 to 30 September 2010, conducted at 10 hospitals in Victoria, Australia.

Main Outcome Measures: The RI of GBS in the risk window of 0-42 days after vaccination.

Results: Sixty-six potential GBS cases were identified, with complete data on 50 confirmed cases. The Victorian annual incidence of GBS was 1.7 per 100 000 population. Three cases had received monovalent vaccine and one case had received seasonal TIV within 42 days of symptom onset. The RI of GBS following monovalent vaccination was 3.4 (95% CI, 0.8-15.0). For TIV, there was one case in the risk period (RI, 0.69; 95% CI, 0.08-5.64).

Conclusions: This is the first published study reviewing GBS after a trivalent and/or monovalent influenza vaccine containing the pandemic (H1N1) 2009 strain, with only a small proportion of GBS cases occurring after influenza immunisation. H1N1-containing vaccines were not statistically associated with GBS, but this study could not exclude smaller increases in the RI. Active surveillance of adverse events following immunisation is required to maintain public and health care professional confidence in mass vaccine implementation programs.
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http://dx.doi.org/10.5694/mja12.10534DOI Listing
November 2012

Baseline smoking status and the long-term risk of death or nonfatal vascular event in people with stroke: a 10-year survival analysis.

Stroke 2012 Dec 25;43(12):3173-8. Epub 2012 Oct 25.

Department of Medicine, Monash Medical Centre, Southern Clinical School, Clayton, Victoria, Australia.

Background And Purpose: Smoking may exacerbate the risk of death or further vascular events in those with stroke, but data are limited.

Methods: 1589 cases of first-ever and recurrent stroke were recruited between 1996 and 1999 from a defined geographical region in North East Melbourne. Both hospital and nonhospital cases were included. Over a 10-year period, all deaths, recurrent stroke events, and acute myocardial infarctions that were reported at follow-up interviews were validated using medical records. Cox proportional hazards regression was used to assess the association between baseline smoking status (never, ex, and current) and outcome (death, acute myocardial infarction, or recurrent stroke).

Results: Patients who were current smokers (Hazard Ratio [HR], 1.30; 95% Confidence Interval [CI], 1.06-1.60; P=0.012) at the time of their stroke had poorer outcome when compared with those who had never smoked. Among those who survived the first 28 days of stroke, current smokers (HR, 1.42; 95% CI, 1.13-1.78; P<0.003) and ex-smokers (HR, 1.18; 95% CI, 1.01-1.39; P=0.039) at baseline had poorer outcome than those who had never smoked. Current smokers also had a greater risk of recurrent events than past smokers (HR, 1.23; 95% CI, 1.00-1.50; P=0.050).

Conclusions: Patients who smoked at the time of their stroke or had smoked before their stroke had greater risk of death or recurrent vascular events when compared with patients who were never smokers. There are benefits of smoking cessation, with ex-smokers appearing to have a lesser risk of recurrent vascular events than current smokers.
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http://dx.doi.org/10.1161/STROKEAHA.112.668905DOI Listing
December 2012

Chronic cerebrospinal venous insufficiency is not more prevalent in patients with mild multiple sclerosis: a sonographer-blinded, case-control ultrasound study.

Mult Scler 2013 May 7;19(6):749-56. Epub 2012 Sep 7.

Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.

Objectives: We designed a prospective case-control study of patients with clinically isolated syndrome (CIS) and Relapsing-Remitting Multiple Sclerosis (RRMS) with an Expanded Disability Status Score (EDSS) of ≤2, compared with age-and-sex-matched healthy controls, to test the hypothesis that chronic cerebrospinal venous insufficiency (CCSVI) is more prevalent in patients with CIS or mild MS.

Methods: All subjects were examined using a Siemens Antares duplex ultrasound machine. The internal jugular, vertebral and intracranial veins were studied in subjects in both supine and sitting postures. The sonographer was blind to the subject's clinical status. Measures included the criteria proposed by Zamboni and volume flow. Presence of CCSVI was defined as ≥2 Zamboni criteria.

Results: Seventy patient-control pairs were recruited, with 11 males and 59 females in each group. Only one subject, a control, satisfied the Zamboni definition of CCSVI; however, 19 patients and 13 controls had abnormalities as defined by Zamboni, the difference largely caused by a higher prevalence in patients of internal jugular vein (IJV) stenosis, defined as a cross-sectional area ≤0.3cm(2). This difference disappeared with a more rigorous stenosis definition. Further analysis revealed there was IJV valve variation in seven patients and one control.

Conclusions: Our findings indicate that CCSVI, as defined by the Zamboni ultrasound criteria, is not present in CIS and mild RRMS (EDSS ≤2), providing further evidence that CCSVI does not have a causal role in MS; however, we found an apparent increase in IJV variation in patients with CIS or mild MS that would warrant further investigation.
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http://dx.doi.org/10.1177/1352458512459986DOI Listing
May 2013