Retrograde Trans-Synaptic Degeneration in MS and its Impact on Visual Function

Omar Al-Louzi, MD

Retrograde trans-synaptic degeneration (RTSD) is a phenomenon where a patient who experiences injury to one neuroaxonal unit propagates through synapses, which then leads to further neuronal loss. According to previous research, up to 70% of patients with multiple sclerosis (MS) experience visual symptoms of the condition that can negatively affect their quality of life.¹ Additionally, other prior studies show lesions on posterior visual pathway with topographically corresponding retinal injury through RTSD^.2

At the annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, February 23-25, 2023, in San Diego, Omar Al-Louzi, MD, and colleagues presented an abstract study that investigated the association between RTSD measures, visual function and clinical disability. The research was conducted as a cross-sectional single-center study where 98 people with MS and 38 non-MS control patients were included. Findings showed that RTSD in the visual pathway occurs in approximately 20% of patients with MS. In addition, it was associated with longer disease duration, subclinical visual field deficits, and low contrast visual dysfunction.³

Al-Louzi, director of the Visual Outcomes Laboratory at Cedars Sinai, sat down in a recent interview with NeurologyLive® to provide an overview of the few presentations from the forum and the motivations behind the research. Additionally, he talked about the risks that still remain with disease modifying therapies, and as well as the combination crossover with infections.

NeurologyLive®: What was the focus of the presentations that were given at ACTRIMS and how do disease modifying therapies affect viral infections in MS patients?

Omar Al-Louzi, MD: Our lab had two presentations during the ACTRIMS Forum. The first one was on the role of imaging and viral infections. The second was studying trans-synaptic degeneration, which is the death of nerve cells or neurons related to MS lesions, that passes across synapses like a domino effect. The first presentation covered aspects of certain viral infections that can emerge or reactivate after patients with MS start on some disease modifying therapies. Some of those therapies can modulate or suppress the immune system in very unique ways. As a result of that, immune suppression that occurs can lend itself to those viruses to cause infections. When those infections affect the brain, we can not only detect and diagnose using imaging, but more importantly, follow over time. We can then make sure that the patients receive the right treatment in terms of altering the management so that the infection doesn't get worse, while treating their MS at the same time.

The main infection that I focus on in my presentation is called progressive multifocal leukoencephalopathy (PML). That infection really is caused by a virus called the JC virus. This JC virus is prevalent throughout the population, it's present in approximately 50% to 70% of patients depending on the study. We've been working on novel machine learning applications and tools that can be used to detect this at a very early stage with imaging. We've studied those artificial intelligence applications in terms of being able to quantify the volume of lesions caused by the JC virus and track it over time. Therefore, if we stop certain disease modifying therapies, or introduce a new management approach to patients, we can follow their response and the alteration in the burden of this infection that occurs in the brain.

We've used this technology in a pilot study that involved administering immunotherapy. We’ve mostly studied it for patients who've had this infection in a different context, in the context of hematological malignancies and immune suppression from either primary immune suppressive disorders. Our hope is that this would be available for our MS community, for us to be able to better monitor them and constitute the pharmacovigilance programs when they start their treatments.

What are some of the current treatments used to treat MS, and the risks associated with those certain types of medications?

With the number of disease modifying therapies that have come to market, it is such an exciting and revolutionary time and in treating our patients with MS. Year by year, we're seeing that we can not only provide treatments that are effective, but we can balance the safety profile of those treatments, putting our patients with MS at minimum risk. Of course, that risk still exists. A lot of the risks depend on the type or category of medication that we use. Broadly speaking, there are many different mechanisms of action for MS modifying treatments.

Certain medications, for example, do suppress the immune system. Those belong to certain categories of medications. Some of them are oral medications that the patient takes. One particular group is called S1P receptor modulators. Those medications specifically trap the lymphocytes and the lymph nodes, reducing the number of circulating lymphocytes. They’re like the policemen, trying to look at viruses that are around and try to guard them. If you're reducing the number of lymphocytes that are out there, reducing cells that are doing important surveillance work, that oftentimes results in opportunistic infections or viruses taking advantage of that situation and causing these infections.

But more commonly, it occurs with one of the infusion medications known as natalizumab. Natalizumab is a treatment that is very effective for the control of inflammatory activity in MS. It works through a unique mechanism, blocking the lymphocytes from crossing the blood brain barrier—that barrier that really interfaces with the brain and the spinal cord tissue. It acts as a bouncer, where the lymphocytes are not able to enter the brain. As a result, you get a very high effectiveness for controlling MS lesions if you're preventing the immune cells from going to the areas where we think other immune inflammation develops. But of course, the correlate to that is if there's any latent viruses within the brain, the most common being the JC virus, there is a risk of those viruses reactivating and causing the progressive multifocal leukoencephalopathy condition.

Transcript edited for clarity.

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REFERENCES
1. Al-Louzi OA, Bhargava P, Newsome SD, et al. Outer retinal changes following acute optic neuritis. Mult Scler. 2016;22(3):362-372. doi:10.1177/1352458515590646
2. Al-Louzi O, Button J, Newsome SD, Calabresi PA, Saidha S. Retrograde trans-synaptic visual pathway degeneration in multiple sclerosis: A case series. Mult Scler. 2017;23(7):1035-1039. doi:10.1177/1352458516679035
3. Manukyan S, Zabala G, Locke Laura, et al. Quantifying Retrograde Trans-Synaptic Degeneration of the Visual Pathway in Multiple Sclerosis. Presented at ACTRIMS Forum 2023; February 23-25; San Diego, California. Abstract P341.