Early Axonal Loss and Neurodegeneration in Multiple Sclerosis

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• Early Axonal Loss and Disability
• MRI and Brain Volume Measurement
• Constant Neurodegeneration Rate
• Predicting Disability Progression
• Implications for Early Treatment
• Full Transcript

Early Axonal Loss and Disability

Dr. Paul Matthews, MD, states that the primary goal of multiple sclerosis treatment must be reducing permanent disability. He emphasizes that this permanent disability results directly from cumulative axon loss. Critically, this axonal damage occurs very early in the disease process. Dr. Paul Matthews, MD, explains that treatment decisions should not be based solely on the severity of a patient's clinical symptoms at a given moment. Instead, therapy must focus on preventing the cumulative assaults that lead to irreversible neurological damage.

MRI and Brain Volume Measurement

Advanced MRI techniques provide powerful tools to assess neurodegeneration in multiple sclerosis. Dr. Paul Matthews, MD, notes that these diagnostic tests can identify neuron and axon loss even at the earliest stages of the disease. This includes the clinically isolated syndrome (CIS) phase, which is often a precursor to a formal MS diagnosis. A key biomarker is brain volume loss, which serves as an indirect measure of injury to nerve cells and their axons. Seminal work by Professor Nicola De Stefano demonstrated the utility of this approach in monitoring disease activity.

Constant Neurodegeneration Rate

A crucial finding in multiple sclerosis research is the consistent rate of neurodegeneration. Dr. Paul Matthews, MD, highlights that the rate of brain volume loss progresses approximately equally throughout the entire MS disease course. This means nerve cells and axons continue to die from the first symptoms of clinically isolated syndrome through to the late secondary progressive phase. Landmark research from Dr. Elizabeth Fisher and Dr. Rick Rudick at the Cleveland Clinic supported this. They studied MS patient cohorts for over a decade, showing that rates of brain volume loss remained approximately constant over that extended time.

Predicting Disability Progression

The measurement of brain volume loss is not just a diagnostic tool; it is also a powerful prognostic indicator. Dr. Paul Matthews, MD, explains that the rate of brain volume loss over time is a good predictor of disability progression in multiple sclerosis. This correlation underscores the direct link between underlying neurodegeneration and the clinical worsening that patients experience. This finding has been confirmed by multiple research groups, including the work of Dr. Matthews and his colleagues. It provides a quantifiable target for therapies aimed at slowing disease progression.

Implications for Early Treatment

These discoveries have profound implications for treatment strategy in multiple sclerosis. Dr. Paul Matthews, MD, argues that the timing of therapeutic intervention must reflect the timing of axonal damage, which begins early. Therefore, effective treatment should be initiated as soon as possible to prevent cumulative damage. The interview with Dr. Anton Titov, MD, explores how these insights should directly influence a neurologist's choice of treatment strategy. The goal is to protect the nervous system from the relentless assault that leads to permanent disability, making early and effective intervention paramount.

Full Transcript

Dr. Anton Titov, MD: You are one of several leading neurologists who discovered and studied neurodegeneration in multiple sclerosis. You worked with Dr. Douglas Arnold at McGill University in Montreal. You worked with Dr. Margaret Esiri, a neuropathologist in Oxford. You studied axonal loss in multiple sclerosis.

Let me quote from one of your research articles on multiple sclerosis: "The main focus for treatment in multiple sclerosis must be the reduction of permanent disability. It is accepted that permanent disability results from cumulative axon loss. This axon loss occurs very early in multiple sclerosis."

Effective treatment may be available. Then the timing of therapeutic intervention should reflect the timing at the start of axonal damage. That would mean treating multiple sclerosis early. Treatment decisions should not be based on the severity of the clinical state of multiple sclerosis. Therapy must focus on preventing the cumulative assaults. Cumulative damage results, eventually, in permanent disability.

This has profound implications for treatment strategy in multiple sclerosis. Can you assess by MRI the neuronal and axonal loss in a patient with a recent diagnosis of multiple sclerosis? How would that affect the treatment strategy choices in multiple sclerosis patients?

Dr. Paul Matthews, MD: I think we have learned that we can use a variety of diagnostic tests based on different imaging techniques. We can identify neuron and axon loss. We can do that even at the earliest stages of multiple sclerosis in the clinically isolated syndrome.

Seminal work was done by Professor Nicola De Stefano, now at the University of Siena. It showed that the rate of brain volume loss progresses approximately equally through the entire course of multiple sclerosis disease. Brain volume loss is an indirect measure of the injury to nerve cells and axons.

It means that nerve cells continue to die from the first symptoms of multiple sclerosis with the clinically isolated syndrome through to the late secondary progressive phase of multiple sclerosis. The rate of death of axons and nerve cells remains approximately similar.

Further data has come to demonstrate it even more directly. Dr. Elizabeth Fisher, during the time that she was at the Cleveland Clinic, discovered this important finding in multiple sclerosis. Together with Dr. Rick Rudick and their colleagues, she studied cohort patients from the initial treatment groups with interferon beta over an extended period of time.

They studied multiple sclerosis patients well over a decade. They demonstrated that the rates of brain volume loss over that time were approximately constant. Moreover, in other work, she and a variety of other workers, including ourselves, show that the rate of brain volume loss in multiple sclerosis over time is a good predictor of the progression of disability.