Visual pathways in multiple sclerosis

We combine cutting-edge computational methods with clinical expertise to advance our understanding of multiple sclerosis (MS) progression.

We've developed innovative approaches to track and analyse chronic lesion evolution in MS using advanced MRI techniques.

Our work has revealed groundbreaking insights into how MS lesions expand over time and contribute to disease progression.

Using custom-developed software pipelines and artificial intelligence, we’ve demonstrated that chronic lesion expansion follows distinct patterns and plays a crucial role in disability accumulation.

The MAD-MS Study: Advancing our understanding of multiple sclerosis

The Mechanisms of Axonal Degeneration in Multiple Sclerosis (MAD-MS) study represents a landmark research initiative that has transformed our understanding of how MS progresses over time. This comprehensive research program, generously supported by the National Multiple Sclerosis Society (NMSS), has yielded crucial insights into the subtle yet significant ways MS affects the brain, particularly in periods between relapses.

Over the past decade, our team followed 200 people living with relapsing-remitting MS, most for five or more years. This extensive commitment from our participants has enabled us to build one of the most detailed pictures yet of how MS evolves over time. Through annual clinical assessments and advanced brain imaging, we’ve uncovered critical new information about disease progression that occurs independently of relapses – what we call “silent” progression.

Revolutionising our understanding of MS lesions

Perhaps our most significant achievement has been revealing how chronic MS lesions slowly expand over time due to persistent, low-grade inflammation at their edges. We developed new methods to accurately measure this expansion and showed that it significantly contributes to brain tissue loss and disability progression. This work has opened new avenues for developing targeted treatments.

A novel biomarker: the choroid plexus

Our research has uncovered an exciting new frontier in MS research – the role of the choroid plexus. This specialized brain structure, which produces cerebrospinal fluid, shows significant changes in people with MS. We discovered that choroid plexus inflammation and enlargement correlates strongly with disease progression and lesion expansion, particularly in progressive forms of MS. This breakthrough finding suggests the choroid plexus could serve as a valuable biomarker for monitoring disease activity and treatment response.

Understanding chronic demyelination

Using the visual system as a window into MS progression, we provided the first human evidence that chronic demyelination (long-term loss of myelin) directly promotes nerve fiber loss. This finding makes a compelling case for developing new therapies focused on remyelination – helping the brain repair damaged myelin coating around nerve fibers.

Lesion expansion

MS affects people differently as the disease progresses. Recent research has highlighted how chronic active lesions (CALs) in the brain play a role in how MS develops over time. These lesions are crucial in understanding why some people experience worsening symptoms even without relapses.

CALs are characterised by persistent slow-burning inflammation at the lesion edge, causing brain tissue damage, axonal loss, and brain atrophy.

Our lab is leading research into the role of smouldering inflammation at the rim of chronic MS lesions and uncovering the mechanisms behind how lesion expansion correlates with worsening disability and progression in MS patients.

So far, we have developed and refined cutting-edge tools and methodologies to monitor smouldering inflammation and lesion dynamics. Our efforts are laying the foundation for the development of targeted therapies aimed at mitigating smouldering inflammation and slowing down disease progression.

LEAP: Advanced lesion analysis in multiple sclerosis

We developed a robust methodology and designed an automated pipeline to quantitatively measure chronic lesion expansion. This pipeline (LEAP: Lesion Expansion and Analysis Pipeline) allows for precise and reproducible evaluation, enabling more accurate tracking of lesion dynamics in individual patients.

Linking of lesion expansion to disease progression

Our research has established a clear link between chronic lesion expansion and disease progression. By identifying this relationship, we provide crucial insights into how smouldering inflammation drives irreversible damage in multiple sclerosis.

Spatial distribution of lesion expansion in MS

We investigated the spatial distribution of chronic lesion expansion, revealing patterns that highlight the variability and focal nature of smouldering inflammation. This work contributes to understanding the heterogeneity of lesion behaviour and its implications for disease progression.

Biomarker of chronic lesion activity

We identified and validated biomarkers of chronic lesion expansion. These biomarkers provide a novel approach to monitor smouldering inflammation and offer new avenues for targeted treatment strategies.

Disease-modifying therapy trials

Building on the innovative pipeline developed in our laboratory, we have designed a comprehensive protocol for a clinical trial aimed at evaluating the efficacy of drugs targeting smouldering inflammation in multiple sclerosis.

The choroid plexus: a new frontier in MS research

The choroid plexus is a specialised tissue that is a critical interface between blood and cerebrospinal fluid, functioning as both a sophisticated filtration system and an immune gateway. This multifaceted role makes it relevant for understanding neurological conditions like MS.

Research has shown that the choroid plexus plays a more dynamic role in disease progression than previously recognised. Our studies have demonstrated that this structure exhibits significant inflammation and enlargement in people with MS, particularly during the relapsing-remitting phase.

Through advanced imaging techniques and comprehensive analysis, we’ve shown that changes in the choroid plexus correlate with MS activity. The choroid plexus appears to be chronically activated in MS, potentially serving as an alternative route for immune cell entry into the brain.

These findings imply that the choroid plexus may represent both a valuable indicator of disease activity and a promising target for treatment.

Choroid plexus volume in multiple sclerosis predicts expansion of chronic lesions and brain atrophy

We established a significant link between choroid plexus volume and the expansion of chronic MS lesions. This discovery reveals how inflammation in the choroid plexus may contribute to the gradual growth of existing brain lesions, particularly those in proximity to the brain’s ventricles.

Longitudinal enlargement of choroid plexus is associated with chronic lesion expansion and neurodegeneration in RRMS patients

Through comprehensive longitudinal monitoring of people with relapsing-remitting MS, we mapped the temporal changes in choroid plexus volume and its relationship with both inflammatory activity and brain tissue loss. This research provides valuable insights into how the choroid plexus influences different aspects of MS progression.

Choroid plexus volume is enlarged in clinically isolated syndrome patients with optic neuritis

In early MS presentations (clinically isolated syndrome), we investigated the relationship between choroid plexus changes and early signs of inflammation and nerve damage in the visual system. This study offers crucial understanding of how choroid plexus inflammation may influence MS from its earliest stages.

The visual system: a window into multiple sclerosis

The visual system offers a unique window into how MS affects nerve fibres and their protective myelin coating. When MS affects the optic nerve through optic neuritis – inflammation of the nerve connecting the eye and brain – it creates a natural setting to compare affected and unaffected pathways within the same person.

The visual system’s architecture allows us to understand how nerve fibres lose their myelin coating (demyelination) and how they degenerate over time. When optic neuritis occurs, we observe how nerve fibre damage causes deterioration—mirroring what happens in the brain during MS, but the visual system allows precise measurements.

We use two techniques to study these processes:

Multifocal Visual Evoked Potentials (mfVEP): measures the speed and strength of visual signals traveling between the eye and brain, reflecting myelin health
Optical Coherence Tomography (OCT): provides high-resolution retinal images to precisely track nerve fibre loss

We provided the first human evidence that chronic demyelination directly leads to nerve fiber loss, demonstrating this through long-term studies of people who experienced optic neuritis. This finding has important implications for developing treatments that could protect nerve fibers by promoting myelin repair.
We pioneered the use of mfVEP as a precise tool for measuring demyelination and remyelination in MS. This technique has since been adopted in clinical trials worldwide to test new treatments aimed at protecting and repairing myelin.
Our research revealed that the pattern of nerve damage follows specific pathways in the visual system, providing crucial insights into how MS affects neural networks throughout the brain. These findings help explain why protecting nerve fibers early in the disease course is so important for preventing long-term disability.

Disease-modifying therapy trials

Current disease-modifying therapies (DMTs) have limited effectiveness against chronic active lesions (CALs), a key driver of MS progression. CALs present unique challenges due to sustained microglial activation, iron-mediated tissue damage, and compartmentalized inflammation.

High-efficacy anti-inflammatory treatments have shown inconsistent results in targeting CALs. Traditional DMTs struggle to address compartmentalized inflammation within CALs, as the intact blood-brain barrier limits drug penetration and effectiveness.

Though some newer therapies and traditional agents show promise, measuring their treatment effects has been challenging due to limitations in quantifying lesion changes.

The Lesion Expansion and Analysis Pipeline (LEAP) enables the precise quantification of lesion expansion and reliable assessment of treatment effects through a standardised protocol suitable for clinical trial implementation. The methodology allows for more accurate evaluation of treatment efficacy and shorter trial durations, streamlining CAL drug development and validation.

COMPASS-MS (Comparing Outcomes of Multiple Pharmacotherapies on Active Smouldering Sites in MS)

A groundbreaking international clinical trial proposal built upon the measurement tools and insights we developed through MAD-MS. This world-first investigation will compare how different MS treatments affect smouldering inflammation in chronic lesions – a critical factor in disease progression we identified through MAD-MS.
By leveraging patient data from multiple international centres, COMPASS-MS has been designed to deliver crucial insights within 18 months that could transform treatment selection for people with MS.

Design of clinical trial to test effectiveness of individual drugs in reducing smouldering inflammation

We developed a novel approach to clinical trials focusing on smouldering inflammation, showing how chronic lesion expansion can serve as a powerful and efficient endpoint. Our research demonstrates that meaningful treatment effects can be detected with smaller patient groups, creating new opportunities for evaluating targeted therapies while maintaining robust scientific standards.

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South Block, Sydney Eye Hospital
8 Macquarie Street
Sydney, NSW 2000