Bruce Trapp, PhD––Cleveland Clinic, Lerner Research Institute, Cleveland, Ohio

Background
Multiple sclerosis (MS) is a chronic, disabling neurodegenerative disease. It strikes most often during early adulthood, and it affects about twice as many women as men. Many aspects of MS, including its cause, are not well understood. It is unknown whether MS represents a single disease, or if its symptoms are the result of different diseases that have the same neurodegenerative effects. There is, however, a growing understanding of how the permanent physical and mental disabilities caused by MS arise over time.

MS is characterized by lesions in the central nervous system that interfere with nerve function. These lesions are inflammatory, meaning that immune cells that are normally restricted to the blood have migrated into the brain and the cellular partition between the brain and the blood stream (the blood-brain-barrier) has broken down. Local swelling occurs in the lesion site as cells and water move out of the blood stream into the nervous system tissue. This swelling causes problems with nerve function, because edema and compression of the fibers can block electrical transmission along the nerve fibers. In addition, the immune cells in the lesion make chemicals that attack myelin, a fatty sheath made by support cells that surrounds nerve fibers (called axons). The myelin sheath supports the ability of neurons to transmit signals through the axon, and it provides special chemicals that neurons need to survive. When myelin is attacked and destroyed, the axon can compensate to some extent by rearranging signaling molecules in the denuded area, but the speed and strength of nerve signals traveling through the axon is impaired.

Most of the time, in the early stages of MS, these inflammatory attacks occur over short intervals of acutely heightened disease activity. These episodes are followed by periods of recovery and remission. During the remission period, the local swelling in the nervous system lesion resolves, the immune cells become less active or inactive, and the myelin-producing cells remyelinate the axons. Nerve signaling improves, and the disability caused by the inflammation becomes less severe or goes away entirely. This phase of the disease is called relapsing-remitting MS(RRMS). The lesions do not all heal completely, though. Some remain as “chronic” lesions, which usually have a demyelinated core region which lacks immune cells. Over time, the cells in the center of such lesions mostly die, although inflammation often continues at their edges. People believed for many years that mainly the myelin was destroyed during the acute attacks and the axons were spared. Recent research has shown this is not the case. Even from the very beginning of MS onset, some of the nerve fibers that cross the lesion are
damaged to the point that the axons are severed. This is fatal to the neuron. Broken axons in the brain cannot grow back. The axon eventually degenerates, and the cell body of the neuron may die.

The brain can adapt well to the loss of some neurons, and permanent disability may not occur for many years. However, more than 50% of patients with MS eventually enter a stage of progressive deterioration, called secondary progressive MS (SPMS). In this stage, the disease no longer responds well to disease-modifying drugs, and patients’ disabilities steadily worsen. The destruction of neurons from early in the natural course of MS suggests that the progressive disabilities of SPMS might be the result of an accumulated neuronal loss that eventually overwhelms the brain’s compensatory abilities.

To investigate this further, researchers have been looking into the permanent nervous-system damage caused by MS. They are finding that damage from lesions that are “clinically silent” (that is, those that don’t cause obvious symptoms), from lesions in the gray matter of the brain, and from the cumulative loss of axons (Figure 2) all underlie the permanent disability that most people with MS eventually experience.

Current Research Findings
Damage from clinically silent lesions is significant. Magnetic resonance imaging (MRI) has been extremely useful in extending researchers’ understanding of MS. MRI scans show that there are many more lesions in the nervous system of many people with MS than might be expected from their disabilities. This seems to be because most lesions occur in parts of the nervous system that are not immediately responsible for some sort of behavioral output, like walking or speaking, or for sensory perception. Therefore, even during the “remitting” phases of RRMS, there is generally ongoing damage from MS in these clinically silent lesions. Therefore, damage to the nervous system can be much more extensive than would be guessed by looking at a patient’s symptoms alone.

To explore the extent of damage to axons in MS lesions, Trapp and colleagues (1998) examined brain specimens obtained at autopsy from patients with MS and from people who had had healthy brains. To count the damaged axons, they cut the brain tissue into thin slices, perpendicular to the axons, and looked for swellings in the oval shapes that represent axon cross sections (Figure 1). The swelling indicated severed, degenerating nerve fibers. They found that in new inflammatory lesions there were about 11,000 severed axons per cubic millimeter of brain tissue. In older, chronic lesions, where many cells had already died, there were about 3,000 severed axons per cubic millimeter at the lesion edges (where inflammation was most active), and about 900 in the lesion centers, where little myelin or inflammatory cells remained. In the normal-appearing tissue from the brains of control subjects, there was less than one severed axon per cubic millimeter. These
observations showed that severe damage to axons was the norm in MS lesions, and that the greater the inflammation, the greater the number of severed axons. This meant that inflammation, which characterizes early, active MS, effectively severs axons. The smaller number of severed axons in older lesions indicates that over time the severed axons also continue to degenerate, but at a slower rate.

Lesions in the Gray Matter of the Cerebral Cortex. Traditionally, MS lesions have been thought of as a “white matter” disease. White matter is the axon-rich portions of the brain, where the abundant, fatty myelin makes the tissue look white. The “gray matter” contains neuron cell bodies, and their many thin fibers that handle nerve signals. This includes the dendrites, which are highly branched and detect and pass on signals coming from other neurons to the cell body. Each neuron also has an axon, which is the long thin process that carries information away from the cell body (i.e., to other neurons or to the muscles). Although they are in the “gray” matter, many of these axons are myelinated. They are not as densely packed as in the white matter, though, and therefore the myelin doesn’t affect the color of the tissue as much.

Although researchers have thought of MS lesions as primarily affecting the white matter, recent studies of the cerebral cortex from deceased patients with MS have contradicted this idea (see Trapp, 2007). The cerebral cortex is the thin sheet of gray matter at the surface of the brain that is responsible for most higher-order processes, like reasoning. What became clear from these studies was that the gray-matter lesions can be extensive in MS, although less obvious in the microscope because the lesions show many fewer signs of inflammation. They have been classified into three types. The first, type I, describes lesions located at the boundary between the gray and white matter that affect both kinds of nerve tissue. The second, type II, occurs in the gray matter close to blood vessels, and may not be specifically caused by MS, because similar lesions can also be found in brain tissue frompeople who did not have MS. The third, type III, can be extensive, spreading out over large areas of the cerebral cortex, and usually, though not always, affecting only the upper portion of the cortical gray matter.

In one study, researchers examined the characteristics of gray-matter lesions in brain specimens from 20 people with MS and 7 without (Bo, Vedeler, Nyland, Trapp, & Mork, 2003). They found that within the lesions, axons and dendrites were severed and there was extensive neuron cell death. Furthermore, the total brain area taken up by the lesions in the gray matter of the 20 brains studied was much greater than the lesions in the white matter (26% vs. 6.5%). This finding shows that damage to the gray matter of the cerebral cortex may contribute significantly to the development of permanent physical disabilities and difficulties with higher, cognitive, functions such as memory and thinking seen in SPMS, and indeed may be the dominant location for lesions in MS.

Unfortunately, there is no good noninvasive system for viewing cortical lesions. The inflammation and the contrast with nearby tissues that makes white-matter lesions relatively easy to see by MRI are lacking in the gray matter lesions, which is partly why these lesions were largely overlooked in the past. New imaging techniques that allow cortical lesions to be monitored in patients with MS are urgently needed.

Future Research
To understand how to stop the damage inflicted on the nervous system by inflammation, we need a better understanding of exactly how the damage occurs. At the moment, it is not completely clear how the axons in MS lesions are severed. It is likely that when the myelin has been stripped away by the immune attack, the axons are more vulnerable to chemicals made by the immune cells (e.g., enzymes that attack cellular components, like proteins). In addition, neurons rely on myelin-producing cells for factors that are essential for their survival. When the myelin has been repeatedly stripped from axons in chronic lesions, myelinproducing cells are lost and the neurons may die because they lack sufficient amounts of these survival molecules. Finally, many studies have shown that when neurons are significantly damaged, they are programmed to self-destruct. Therefore, it is possible that repeated or long-term damage could trigger neuronal suicide. A deeper understanding of the mechanisms underlying the damage may help in identifying specific targets for new therapies.

One issue that remains mysterious is why patients experience the progressive disability that defines the SPMS phase of the disease. It makes sense that when enough axons are severed in inflammatory lesions, permanent damage to brain function would eventually result. By the time patients enter the SPMS phase, however, inflammation tends to be much less prominent, and, in fact, the disease responds poorly or not at all to anti-inflammatory medications. One study(Confavreux, Vukusic, Moreau, & Adeleine, 2000), showed that it took extremely variable lengths of time for a patient’s disability to reach a score of 4 on the Extended Disability Status Scale. However, the time required thereafter to reach a score of 7 was very similar from patient to patient. This is consistent with the idea that after some threshold of neural damaged is reached, the damage progresses regardless of continuing or abating inflammation.

Why and how this progressive degeneration occurs needs to be understood, so that therapies can be developed to prevent it. Furthermore, if subsequent research proves that progressive neurodegeneration is set in motion when a threshold amount of neuron loss is crossed, it will be important to seek new therapies that can be taken over the long-term and can halt inflammation early in the disease, long before this critical threshold is reached.

Finally, to follow the effectiveness of such therapies, new imaging techniques that permit physicians to follow the amount and rate of axon loss in individual patients will be invaluable. The development of such techniques is an important goal for the near future.

Clinical Implications
The studies described here support the idea that anti-inflammatory treatment of MS should begin as early in the course of the disease as possible. By extension, suspected MS should be verified as quickly as possible, because many patients have silent lesions for years before their first acute neurological episode, and it is important to minimize this early damage. Likewise, treatment should be continued between relapses, to prevent or minimize damage from clinically silent lesions.

Further Reading
Bo, L., Vedeler, C. A., Nyland, H. I., Trapp, B. D., & Mork, S. J. (2003). Subpial demyelination in the cerebral cortex of multiple sclerosis patients. Journal of Neuropathology and Experimental Neurology, 62, 723-732.

Confavreux, C., Vukusic, S., Moreau, T., & Adeleine, P. (2000). Relapses and progression of disability in multiple sclerosis. The New England Journal of Medicine, 343, 1430-1438.

Trapp, B. D. (2007). Pathogenesis of neurological disability in multiple sclerosis. International Journal of MS Care, Supplement, pp. 4-7.

Trapp, B. D., Peterson, J., Ranshohoff, R. M., Rudick, R., Mork, S., & Lars, B. (1998). Axonal transection in the lesions of multiple sclerosis. The New England Journal of Medicine, 338, 278-285.

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