Challenging the CNS-only paradigm in Multiple Sclerosis
Dr. Stepheny Zani - 3 March 2026
Dr. Bradley Kerr
Multiple sclerosis (MS) is a debilitating disease leading to movement loss, cognitive impairment and pain. MS affects 1.8 million of people globally and to date there is no cure, however, there are many efforts in place to better understand and treat it.
In MS, the nervous system is deeply affected. This system can be divided into the central nervous system (CNS - brain and spinal cord) and the peripheral nervous system (PNS - nerve fibers extending from the spinal cord to the surface of the skin). They communicate with each other allowing for signals, e.g. pain signals, to travel from the periphery of the body to the brain and vice versa.
Despite no cure, one thing about MS is certain, patients suffer from chronic neuropathic pain, a consequence of damage to nerve fibers. Pain signals transfer from one neuron to another in a fraction of second, more precisely in about 20 milliseconds. This is only possible because the nerve fibers are covered in myelin, a substance made of protein and fat that hugs the fibers and helps with the faster propagation of signals. In MS one’s immune system starts destroying the myelin sheath around neurons, we refer to that as an auto-immune attack. This auto-attack causes chronic inflammation, damaging these neurons and impairing the communication between the brain and the rest of the body.
For a long time, CNS inflammation was the central focus of MS studies; but given the connection between the CNS and the PNS, questions still remained about the impact of the disease on the PNS.
Dr Kerr’s group led by Master’s student, Andrea Klassen, decided to look closer to these peripheral fibers and investigate whether the inflammation would reach them. The authors had previously found sex-differences in the CNS signalling in mice and found that the disease affected the dorsal root ganglia - part of the nervous system that connects the CNS to the PNS. In this new paper published in Neurobiology of Pain, they show that MS is more than a CNS-only disease.
The model used to study MS in research laboratories is called experimental autoimmune encephalomyelitis or EAE. In this model, after the immune system is artificially activated to cause neuroinflammation and destroy the myelin, the mice develop clinical symptoms similar to to MS (neuropathic pain, impaired movement and cognition). Although MS progresses differently in each person, the EAE model develops a known pattern of disease progression, allowing researchers to study MS in a predictable way.
Dr Kerr’s group found that both male and female mice followed a similar pattern of disease progression, developing pain hypersensitivity in their hind paw early in the disease progression (7 days post disease induction in males and 11 days in females). It is worth noting that pain is more complex than just skin sensitivity (nociception) as measured in their paws, it involves higher cognitive functions (e.g. perception). However, the measurement of pain through nociception is well established and allows for non-invasive and easily accessible pain measurements.
But then the story took a turn. When they checked the peripheral nerve fibers using immunohistochemistry, they found the PNS was also affected! This damage also showed differences between males and females. Although mice of both sexes progressed similarly initially, during the chronic phase of the disease male mice had persistent injury in their peripheral nerves, while females started recovering from the damage.
They were demonstrating a word most of us have heard recently, neuroplasticity. It means the nerve fibers are adapting to the changes in the environment around them. The sex differences in neuroplasticity might be driven by the immune cell population causing the inflammation during disease progression. For example, in males these cells favour neurodegeneration, while in females they stimulate nerve regeneration.
The discovery that MS affects the PNS is an important step to facilitate future assessment in MS patients. It allows us to study neuropathic pain on the skin surface and better understand the mechanisms behind it. The study also provides us with some insight into the body’s own healing process and how we might be able to harness it for future treatments. Of course, the first step is to verify whether a similar pattern is observed in humans.
Nevertheless, recognizing the PNS role in MS expands the knowledge about the whole-body impact of the disease and opens our eyes to more than just the CNS. Their work highlights how questioning paradigms bring important discoveries and open pathways to improving the quality of life of people with MS.