Helmut Butzkueven

• MBBS FRACP PhD
• Chair at Monash University (Australia)

Importance Progression independent of relapse activity (PIRA) is a significant contributor to long-term disability accumulation in relapsing-remitting multiple sclerosis (MS). Prior studies have used varying PIRA definitions, hampering the comparability of study results. Objective To compare various definitions of PIRA. Design, Setting, and Parti...

Background Previous studies have indicated that progression independent of relapse activity (PIRA) is uncommon in patients with aquaporin- 4 antibody-positive (AQP4-IgG) neuromyelitis optica spectrum disorder (NMOSD). However, the patterns of disability accumulation in seronegative NMOSD are unknown. This study aimed to evaluate the prevalence of P...

Background Monitoring of cognition in multiple sclerosis (MS) is critical. Traditional cognitive testing is resource intensive and insensitive to subtle changes. Digital tests could address this need; however, their long-term usability remains unexplored. Objectives To determine the long-term acceptability and feasibility of digital cognitive meas...

Background: The choroid plexus (CP) is increasingly recognised as a contributor to chronic inflammation in multiple sclerosis (MS). While CP enlargement is reported in early MS, its role in secondary progressive MS (SPMS) is poorly understood. Objective: We aimed to quantify CP volume in SPMS and compare it to relapsing-remitting MS (RRMS) and clin...

Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system characterised by inflammatory lesions and neurodegeneration. Diagnosis often occurs in women of childbearing age, and therefore pregnancy is frequently encountered in women with MS. However, the effect of pregnancy on the MS brain is not well un...

Background Cognitive impairment is one of the most common and debilitating symptoms of relapsing–remitting multiple sclerosis (RRMS). Digital cognitive biomarkers require less time and resources and are rapidly gaining popularity in clinical settings. We examined the longitudinal trajectory of the iPad‐based Processing Speed Test (PST) and predicto...

In relapsing-remitting multiple sclerosis (RRMS), extended exposure to high-efficacy disease modifying therapy may increase the risk of side effects, compromise treatment adherence, and inflate medical costs. Treatment de-escalation, here defined as a switch to a lower efficacy therapy, is often considered by patients and physicians, but evidence t...

Introduction Multiple sclerosis (MS) is a chronic inflammatory demyelinating and degenerative disease of the central nervous system. There were 33 335 people with MS in Australia in 2021 and 2917 in New Zealand in 2006 and the prevalence and incidence are increasing with time. Although new treatments have substantially improved outcomes in recent d...

Introduction Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system with rapidly evolving treatment options and strategies. An iterative modified Delphi process was used to develop 80 consensus recommendations for the management of MS in Australia and New Zealand. Part 1 of these guidelines inc...

Survival analysis holds a crucial role across diverse disciplines, such as economics, engineering and healthcare. It empowers researchers to analyze both time-invariant and time-varying data, encompassing phenomena like customer churn, material degradation and various medical outcomes. Given the complexity and heterogeneity of such data, recent end...

Background Upper limb dysfunction is a common debilitating feature of relapsing‐remitting multiple sclerosis (RRMS). We aimed to examine the longitudinal trajectory of the iPad®‐based Manual Dexterity Test (MDT) and predictors of change over time. Methods We prospectively enrolled RRMS patients (limited to Expanded Disability Status Scale (EDSS) <...

The development of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS) has been highly successful in recent decades. It is now widely accepted that early initiation of DMTs after disease onset is associated with a better long-term prognosis. However, the question of when and how to de-escalate or discontinue DMTs remains...

Sex and sex hormones are thought to influence multiple sclerosis (MS) through effects on inflammation, myelination and neurodegeneration, and exogenous hormones have been explored for their therapeutic potential. However, our understanding of how sex hormones influence MS disease processes and outcomes remains incomplete. Furthermore, our current k...

Background Effectiveness of disease-modifying treatment (DMT) in people affected by primary progressive multiple sclerosis (PPMS) is limited. Whether specific subgroups may benefit more from DMT in a real-world setting remains unclear. Our aim was to investigate the potential effect of DMT on disability worsening among patients with PPMS stratified...

Objectives: In aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-IgG NMOSD), disability accrual is mostly attributed to relapses. This study aimed to assess the prevalence of progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) in AQP4-IgG NMOSD. Methods: This was a retrospective coho...

Background The relationship between coronavirus disease 2019 (COVID-19) infection and multiple sclerosis (MS) relapse and disease progression remains unclear. Previous studies are limited by small sample sizes and most lack a propensity-matched control cohort. Objective To evaluate the effect of COVID-19 infection on MS disease course with a large...

Background and Objectives Women with multiple sclerosis (MS) are at risk of disease reactivation in the early postpartum period. Ocrelizumab (OCR) is an anti-CD20 therapy highly effective at reducing MS disease activity. Data remain limited regarding use of disease-modifying therapies (DMTs), including OCR, and disease activity during peripregnancy...

Purpose Understanding the long-term safety of disease-modifying therapies for multiple sclerosis (MS) in routine clinical practice can be undertaken through registry-based studies. However, variability of data quality across such sources poses the challenge of data fit for regulatory decision-making. CLARION, a non-interventional cohort safety stud...

Background and objectives: Exposure to natalizumab, an efficacious treatment for relapsing-remitting multiple sclerosis (RRMS), is associated with increased risk of progressive multifocal leukoencephalopathy (PML). Compared with every-4-week (Q4W) dosing, extended-interval dosing of natalizumab is associated with decreased risk of PML. Clinical ef...

Healthcare breakthroughs are extending the lives of multiple sclerosis (MS) patients and cancer survivors, creating a growing cohort of individuals navigating a dual diagnosis. Determining the relationship between MS and cancer risk remains challenging, with inconclusive findings confounded by age, risk exposures, comorbidities, genetics and the on...

Survival analysis holds a crucial role across diverse disciplines, such as economics, engineering and healthcare. It empowers researchers to analyze both time-invariant and time-varying data, encompassing phenomena like customer churn, material degradation and various medical outcomes. Given the complexity and heterogeneity of such data, recent end...

Spinal cord lesions in multiple sclerosis (MS) have considerable impact on disability. High-efficacy disease-modifying treatments (hDMTs) are associated with greater reduction of relapses and new brain lesions compared to low-efficacy treatments (lDMTs). Knowledge on the impact of DMTs on cord lesion formation is limited as these outcome measures w...

Objectives To characterize the use of ofatumumab (OFA), a fully human self-administered anti-CD20 monoclonal antibody, in a real-world setting in Australia by assessing the profile of relapsing multiple sclerosis (RMS) patients initiating OFA through an evaluation of patient demographics, background MS disease characteristics and prior therapy hist...

Introduction Autoimmune encephalitis (AE) is an acute neuroinflammatory disease that has high prevalence of chronic (>3 months post-acute illness) morbidity characterized by cognitive and functional impairment. It remains unclear if this morbidity is residual injury from the acute event or driven by ongoing neurodegeneration. Objective Evaluate Nf...

Background/Objectives The COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapy (DMT), particularly anti-CD20 monoclonal antibodies (mAB) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic. Methods A multi-centre long...

Background Ofatumumab is a self-administered disease modifying therapy (DMT) approved in Australia for relapsing multiple sclerosis (RMS). We have previously described a novel, high efficacy therapy (HET) classification system¹ which includes ofatumumab and other monoclonal antibody therapies, ocrelizumab, natalizumab and alemtuzumab. Given the rei...

Background/Objectives Cladribine reduces the frequency of relapses by 57% and disability worsening by 33% compared to placebo in relapsing-remitting multiple sclerosis (RRMS). No head-to-head comparisons of cladribine to other potent immunotherapies are available. Methods Patients with RRMS who were treated with cladribine, fingolimod, natalizumab...

Introduction Autoimmune encephalitis (AE) is an acute neuroinflammatory disease that can be difficult to diagnose and treat. Access to medical services is often poor for patients in rural and regional settings and may impact the outcomes for a rare disease such as AE. Objective To explore treatment access for patients with AE in a rural or regiona...

Background Upper limb dysfunction is a common debilitating feature of relapsing remitting multiple sclerosis (RRMS). We aimed to examine the longitudinal trajectory of the iPad-based Manual Dexterity Test (MDT) and predictors of change over time. Methods We prospectively enrolled relapsing-remitting multiple sclerosis (RRMS) patients with an EDSS...

Background Cognitive impairment is one of the most common and debilitating symptoms of relapsing remitting multiple sclerosis (RRMS). Digital cognitive biomarkers require less time and resources and are rapidly gaining popularity in clinical settings. We examined the longitudinal trajectory of the iPad-based Processing Speed Test (PST) and predicto...

Background/Objectives Failure of natalizumab to control disease activity in multiple sclerosis (MS) is an uncommon event. It is currently unknown whether switching to an alternative high-efficacy disease-modifying therapy offers any benefits over persevering with natalizumab. Methods Patients from the MSBase cohort suffering failure of natalizumab...

Background Comparisons between cladribine and other potent immunotherapies for multiple sclerosis (MS) are lacking. Objectives To compare the effectiveness of cladribine against fingolimod, natalizumab, ocrelizumab and alemtuzumab in relapsing-remitting MS. Methods Patients with relapsing-remitting MS treated with cladribine, fingolimod, natalizu...

Following NOVA (part 1) and the approval of the subcutaneous (SC) route of administration of natalizumab by the European Medicines Agency, an extension phase of the NOVA phase IIIb study (part 2) was initiated to collect patient preference data for SC versus intravenous (IV) dosing in patients receiving every-6-week (Q6W) dosing of natalizumab. Thi...

Background The COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapies (DMT), particularly anti-CD20 monoclonal antibodies (mAb) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic onset. Methods A multi-centre longitu...

Background and objective Autoimmune encephalitis (AE) is often associated with clinically significant memory impairment. This study aimed to evaluate memory in a cross-sectional prospective AE cohort using multiple memory paradigms. Methods 52 patients (50% seropositive) meeting Graus criteria for possible AE were prospectively recruited between O...

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system affecting predominantly adults. It is a complex disease associated with both environmental and genetic risk factors. Although over 230 risk single-nucleotide polymorphisms have been associated with MS, all are common human variants. The mechanisms by which they increase...

Background The use of non-specific immunosuppressants (NSIS) to treat multiple sclerosis (MS) remains prevalent in certain geographies despite safety concerns, likely due to resource limitations. Objective To use MSBase registry data to compare real-world outcomes in adults with relapsing-remitting MS (RRMS) treated with dimethyl fumarate (DMF) or...

Background We sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid exposure. Methods In a retrospective multicentre cohort study, Cox proportional hazards models examined t...

Background In Australia, tixagevimab/cilgavimab 150 mg/150 mg was a government-funded pre-exposure prophylaxis for COVID-19 people with multiple sclerosis (pwMS) and other neuroimmunological conditions (pwNIc) treated with anti-CD20 antibodies or sphingosine-1-phosphate receptor modulators were eligible. Objective To analyse the roll-out, uptake a...

Cognitive symptoms are reported commonly throughout all phases of a migraine; however, there is a paucity of objective cognitive profiling. Previous studies have been limited by practice effect, and variable populations. Participants completed 1 month of daily testing with a computerised cognitive battery involving a simple reaction (SRT), choice r...

Background: It remains unclear whether routine cerebrospinal fluid (CSF) parameters can serve as predictors of multiple sclerosis (MS) disease course. Methods: This large-scale cohort study included persons with MS with CSF data documented in the MSBase registry. CSF parameters to predict time to reach confirmed Expanded Disability Status Scale...

Background The Big Multiple Sclerosis Data (BMSD) network ( https://bigmsdata.org ) was initiated in 2014 and includes the national multiple sclerosis (MS) registries of the Czech Republic, Denmark, France, Italy, and Sweden as well as the international MSBase registry. BMSD has addressed the ethical, legal, technical, and governance-related challe...

Background Evidence from network meta-analyses (NMAs) and real-world propensity score (PS) analyses suggest monoclonal antibodies (mAbs) offer a therapeutic advantage over currently available oral therapies and, therefore, warrant consideration as a distinct group of high-efficacy disease-modifying therapies (DMTs) for patients with relapsing multi...

Background The International Multiple Sclerosis Genetics Consortium and MultipleMS Consortium recently reported a genetic variant associated with multiple sclerosis (MS) severity. However, it remains unclear if these variants remain associated with more robust, longitudinal measures of disease severity. Methods We examined the top variant, rs10191...

Background Ongoing controversy exists regarding optimal management of disease modifying therapy (DMT) in older people with multiple sclerosis (pwMS). There is concern that the lower relapse rate, combined with a higher risk of DMT-related infections and side effects, may alter the risk-benefit balance in older pwMS. Given the lack of pwMS above age...

Background and objectives: Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses, and though patients with POMS usually recover from relapses better than adults, patients with POMS reach irreversible disability at a younger age than adult-onset patients. There have be...

Background Aggressive disease control soon after multiple sclerosis (MS) diagnosis may prevent irreversible neurological damage, and therefore early initiation of a high-efficacy disease-modifying therapy (DMT) is of clinical relevance. Objectives Evaluate long-term clinical outcomes in patients with MS who initiated treatment with either natalizu...

Background and objective Autoimmune encephalitis (AE) is a rare neuroinflammatory disease affecting the central nervous system. To examine language functions in patients with different subsets of AE consisting of seropositive and seronegative groups. Methods Fifty-two patients were recruited from neurology departments in Melbourne, Australia, who...

Background and objectives: The impact of immunomodulatory therapies on the risk of cervical pre-cancer and invasive cancer development is important for the health and safety of women with multiple sclerosis (wwMS). We investigate the risk of cervical abnormalities in wwMS treated with disease-modifying therapies (DMTs). Methods: This is a multic...

Objectives Some disease-modifying therapies (DMTs) have been associated with COVID-19 severity in people with MS. Comprehensive exploration of these relationships in large international samples is needed. Methods Clinician-reported demographic/clinical data from 27 countries were aggregated into a dataset of 5,648 patients with suspected/confirmed...

Autoimmune encephalitis (AE) encompasses a number of neuroinflammatory conditions. Optimal biomarkers to guide therapeutic decision making and prognostication remain to be identified. Objective To identify biomarkers of disease severity and predictors of patient outcome. Methods Clinical, radiological, serological, CSF, EEG and neuropsychological...

Objectives Despite the rapid increase in research examining outcomes in Autoimmune Encephalitis (AE) patients, there are few cohort studies examining cognitive outcomes in this population. Here, we conducted a retrospective observational study to characterise the neuropsychological outcomes of these patients. We then examined demographic data, clin...

Background COVID-19 vaccination induces protective spike antibodies. Some responses are attenuated in people living with multiple sclerosis (MS) on high efficacy disease modifying therapies (DMT). It is unknown whether antibodies afford immunity against emerging SARS-CoV-2 variants such as Delta and Omicron. Objective We aimed to determine the lon...

Objectives This study aimed to investigate the association between latitude of residence, ultraviolet B radiation exposure (UVB) and MS severity. Methods This observational study used MSBase registry data. Included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry. The latitude of...

Objective To investigate the association between early relapses shortly after relapsing remitting multiple sclerosis (RRMS) onset and disability progression during secondary progressive MS (SPMS). Methods In this observational cohort study, 4,988 patients from the MSBase registry who reached SPMS, defined by the Lorscheider criteria, were identifi...

Objectives To develop and implement the first international observational database for patients with Myasthenia Gravis (MG) to advance collaborative outcome-based MG research and improve the quality of care for patients with MG. Methods The MGBase was developed based on the highly successful Multiple Sclerosis registry, MSBase. This approach lever...

Introduction Cladribine (Mavenclad®) is an oral treatment for relapsing remitting MS (RRMS). In RRMS clinical trials, Cladribine has been shown to reduce brain atrophy, relapse rates, and new lesions on MRI. Cladribine is thought to produce its beneficial effects through its lymphocytic actions. Objective To investigate the mechanism of action of...

Objective To compare the effectiveness of ocrelizumab with interferon-β, fingolimod and natalizumab in relapsing-remitting multiple sclerosis (MS). Method Using the MSBase registry, we identified patients with relapsing-remitting MS treated for >=6 months with ocrelizumab, interferons (interferon β-1a, interferon β-1b subcutaneous or interferon β-...

Background Ageing-related processes contribute to neurodegeneration and disability in multiple sclerosis (MS). Biomarkers of senescence such as leukocyte telomere length (LTL) could help personalise prognosis and treatment. A history of pregnancy has been shown to be protective against disability accumulation in women with MS¹: it is unclear if thi...

Objectives While cognitive dysfunction after autoimmune encephalitis (AE) is subjectively noted by patients and caretakers alike; objective neuropsychological assessments in chronic AE cohorts, are rarely reported. Methods Standardised neuropsychological assessments were performed prospectively in a series of 50 patients with AE. Patients were rec...

Background To mimic as closely as possible a randomised controlled trial (RCT) and calibrate the real-world evidence (RWE) studies against a known treatment effect would be helpful to understand if RWE can support causal conclusions in selected circumstances. The aim was to emulate the TRANSFORMS trial comparing Fingolimod (FTY) versus intramuscula...

Vitamin D deficiency is a risk factor for developing multiple sclerosis (MS). However, the immune effects of vitamin D in people with MS are not well understood. We analyzed transcriptomic datasets generated by RNA sequencing of immune cell subsets (CD4⁺, CD8⁺ T cells, B cells, monocytes) from 33 healthy controls and 33 untreated MS cases. We utili...

Introduction Atypical parkinsonian syndromes (APS) are rare neurodegenerative syndromes for which parkinsonism is one significant feature. APS includes progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS). The diagnosis of APS remains reliant on clinical features with no available diagnostic or prognos...

Floodlight Open was a global, open-access, digital-only study designed to understand the drivers and barriers in deployment and use of a smartphone app in a naturalistic setting and broad study population of people with and without multiple sclerosis (MS). The study utilised the Floodlight Open app: a ‘bring-your-own-device’ solution that remotely...

Aim To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS). Methods Real-world data from the MSBase Registry were obtained for patients with RES-RRMS wh...

Background Treatment switching is a common challenge and opportunity in real-world clinical practice. Increasing diversity in disease-modifying treatments (DMTs) has generated interest in the identification of reliable and robust predictors of treatment switching across different countries, DMTs, and time periods. Objective The objective of this r...

Low serum levels of 25-hydroxyvitamin D (25(OH)D), and low sunlight exposure, are known risk factors for the development of multiple sclerosis. Add-on vitamin D supplementation trials in established multiple sclerosis have been inconclusive. The effects of vitamin D supplementation to prevent multiple sclerosis is unknown. We aimed to test the hypo...

INTRODUCTION Smart devices are widely available and capable of quickly recording and uploading speech segments for health-related analysis. The switch from laboratory recordings with professional-grade microphone set ups to remote, smart device-based recordings offers immense potential for the scalability of voice assessment. Yet, a growing body of...

Modern management of MS targets No Evidence of Disease Activity (NEDA): no clinical relapses, no magnetic resonance imaging (MRI) disease activity and no disability worsening. While MRI is the principal tool available to neurologists for monitoring clinically silent MS disease activity and, where appropriate, escalating treatment, standard radiolog...

INTRODUCTION: Smart devices are widely available and capable of quickly recording and uploading speech segments for health-related analysis. The switch from laboratory recordings with professional-grade microphone set ups to remote, smart device-based recordings offers immense potential for the scalability of voice assessment. Yet, a growing body o...

It is unknown whether the currently known risk factors of multiple sclerosis reflect the etiology of progressive-onset multiple sclerosis (POMS) as observational studies rarely included analysis by type of onset. We designed a case–control study to examine associations between environmental factors and POMS and compared effect sizes to relapse-onse...

Introduction: Prescribing guidance for disease-modifying treatment (DMT) in multiple sclerosis (MS) is centred on a clinical diagnosis of relapsing-remitting MS (RRMS). DMT prescription guidelines and monitoring vary across countries. Standardising the approach to diagnosis of disease course, for example, assigning RRMS or secondary progressive MS...

Importance Multiple sclerosis (MS) severity may be informed by premorbid sociodemographic factors. Objective To determine whether premorbid education, income, and marital status are associated with future MS disability and symptom severity, independent of treatment, in a universal health care context. Design, Setting, and Participants This nation...

Objective This study uses the Wechsler intelligence and memory scales to characterize the cognitive function of patients with autoimmune encephalitis (AE) in the chronic stage of the disease. AE is a group of neuroinflammatory disorders, and cognitive impairment is a significant source of chronic morbidity in these patients. Methods Fifty patients...

Objectives: As part of the CLARION study: (1) characterize the incidence of severe infections, herpes zoster, and malignancies in patients newly initiating cladribine or fingolimod for relapsing multiple sclerosis (MS); (2) estimate the incidence of severe lymphopenia among cladribine users; and (3) describe prior/subsequent disease-modifying ther...

Background and purpose The validity, reliability, and longitudinal performance of the Patient‐Determined Disease Steps (PDDS) scale is unknown in people with multiple sclerosis (MS) with mild to moderate disability. We aimed to examine the psychometric properties and longitudinal performance of the PDDS. Methods We included relapsing–remitting MS...

Modern management of MS targets No Evidence of Disease Activity (NEDA): no clinical relapses, no magnetic resonance imaging (MRI) disease activity and no disability worsening. While MRI is the principal tool available to neurologists for monitoring clinically silent MS disease activity and, where appropriate, escalating treatment, standard radiolog...

Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we e...

Background In multiple sclerosis (MS), accelerated aging of the immune system (immunosenescence) may be associated with disease onset or drive progression. DNA methylation (DNAm) is an epigenetic factor that varies among lymphocyte subtypes, and cell specific DNAm is associated with MS. DNAm varies across the lifespan and can be used to accurately...

Background COVID-19 vaccination-induced Spike antibodies are attenuated in people living with multiple sclerosis (pwMS) on high-efficacy disease-modifying therapies (DMTs). It is currently unknown whether vaccine boosters will elicit a greater protective antibody cross-reactivity against emerging variants of concern, such as XBB.1 and BQ.1.1. Obje...