Some people who have MS believe that stressful life events were the catalyst for their diagnosis. Many people with MS report that environmental stresses have triggered exacerbations. Almost everyone who has MS believes that having an exacerbation increases the amount of stress they experience. This issue of InforMS will explore what we know about the impact of stress on the disease course in multiple sclerosis, what we know about the impact of stress on general health, and how the two might overlap.

Health and the Stress Response

There was a time when suggestions that stress might affect health were viewed as quackery. “Stress” has long been a medical diagnosis but it was a diagnosis of last resort and one that didn’t get much respect. Stress was often regarded as a problem of personality rather than physiology. Stress resulted from bad choices that could be easily reversed if one so chose. To describe a problem as “stress-related” was to suggest that perhaps you didn’t handle your life very well.

In the past 30 years, though, our thinking about the importance of stress has changed dramatically. Today it is hard to open a newspaper without stumbling across some article on stress. Why? Because in the past few decades scientific studies have determined that chronic stress plays a role in our susceptibility to diseases and is a risk factor for all kinds of health complications. What we know today is that stress is a very complex interaction of personality, environment, and physiology, and much of it functions beyond our conscious control.

The human body is a complex, intricate and interactive system that is both very stable and very adaptive. Our body strives to be in a well-regulated equilibrium known as homeostasis. We maintain this stability by constantly changing. Our regulating systems actively adjust to both predictable and unpredictable internal and external events with the goal, always, of returning the body to homeostasis.

The autonomic nervous system is the control center for homeostasis and regulates functions such as heart rate, digestion, respiration and immune functioning. Most of the actions of the autonomic nervous system are involuntary but some, such as breathing, work in tandem with the conscious mind. These systems keep the body on track and maintain our physiologic infrastructure. They keep the heart pumping, the hair growing, the immune system working, and they do it automatically. We don’t have to think about them.

The body also has an automatic procedure for dealing with threatening intrusions that disrupt homeostasis. It is called the stress response and it is also under the control of the autonomic nervous system. The stress response is the human body’s emergency system. Triggering the stress response, which is automatic in the face of a severe threat, is the physiological equivalent to dialing 911. It activates a cavalcade of emergency responders whose function is to respond to the crisis, subdue the threat and return the body to homeostasis. The stress response reallocates the body’s energy resources. Energy is rushed to the heart, lungs and muscles—all the systems necessary for survival—and diverted from non-essential functions such as digestion and growth.

The stress response is non-specific, which means that it responds to all threats in pretty much the same way. It is primarily mediated by two hormones, adrenaline and cortisol, that circulate in our blood all the time, but at increased levels during times of stress. These hormones alter metabolism. Adrenalin provides the body with a rush of available energy so that it has increased resources to deal with whatever the threat. Cortisol helps get that energy to the organs that most need it by turning off all nonessential metabolic activities. Until the stress response is shut down these hormones—especially cortisol—continue to circulate in the blood at elevated levels.

The importance of shutting down the stress response after the crisis is over cannot be overstated. It is important to our general health to have normally low levels of the stress hormones, especially cortisol. Chronically elevated levels of cortisol are implicated in many common diseases—from altered thyroid functioning to heart disease—and have long been known to depress the production of good HDL cholesterol.

The stress response comes from an older part of the brain, the limbic system, that developed in simpler times, when the threats that faced humans were huge and terrifying but fairly unambiguous. The phrase “fight or flight response” describes the limited choices available to man in those early conflicts—you fought or you fled. The possible outcomes to these conflicts were equally straightforward: you escaped or you were victorious in battle, or you were lunch. End of story. The stresses were huge, but they didn’t last long, and the body, if there still was a body, would return to homeostasis and turn off the stress response. With the stress response it is true that “all’s well that ends” in homeostasis.

Acute, life-threatening assaults are exactly the kinds of problems the stress response manages best but those aren’t the problems it usually gets today. The threats we face now, in industrialized societies, are different from those faced by our ancestors. We aren’t often killed by predators, and we don’t usually die in epidemics or from the infectious diseases that used to be certain killers. What threatens our safety today is much less quantifiable and immediate. The threats that we face are more psychological—fears of terrorism, global warming, crashing stock markets, poisonous peanut butter and chronic slow-moving diseases, like multiple sclerosis.

Humans are different from other animals because our stress response can be turned on by thoughts and emotions. We turn it on to manage psychological threats even though this isn’t what it was designed to do. It does it anyway, because automatic activation of the stress response is our default setting. The net result is an elevated level of stress hormone that affects the functioning of our metabolism just as it would if we were fighting off a predator, but with a critical difference. A physical threat and the accompanying stress response will usually resolve fairly soon. A psychological threat can go on endlessly and so can the stress response.

The brain has another automatic feature that further complicates our ability to manage stress—the frontal lobes. This is a wonderful part of the brain that allows us to create, organize, anticipate and problem solve. And, because it allows us to create and anticipate, it is also the part of the brain that keeps us awake at night fretting about what might happen in the future. Like the stress response, this worry response is automatic. To quote psychologist Daniel Gilbert from his book, Stumbling on Happiness:

“The greatest achievement of the human brain is its ability to imagine objects and episodes that do not exist in the realm of the real. It is this ability that allows us to think about the future. Not thinking about the future requires that we convince our frontal lobe not to do what it was designed to do, and like a heart that is told not to beat, it naturally resists this suggestion.”

Environmental Variables

The stress response is also mediated by variables in our environment. Psychological factors can make a stress response bigger or smaller. According to neurobiologist Robert Sapolsky, there are some specific attributes of psychological stressors that increase the likelihood of an activated stress response.

Lack of Control: Not surprisingly, the perception that we have some control over what’s happening to us can diminish the stress response. This can be actual control or just the perception of control. Imagine that you are in a bumper car at the amusement park. Bumper car steering wheels don’t work very well and don’t really help you steer the car, but imagine how much more stressful the ride it would if there were no steering wheel to clutch.

In fact, research studies have confirmed the stress-reducing properties of both real and imaginary control. For example, a laboratory rat can be trained to push a lever to decrease the frequency of electric shock. This rat will develop fewer ulcers than a rat that doesn’t have a lever. If the lever is removed entirely, the rat will have as many ulcers as the control rat. If the lever is merely disabled—it is present but no longer prevents shock— the rat who has been trained will still use it, and will still have fewer ulcers than the control rat, even though both experience the same strength and number of electric shock. Similarly, human subjects who have a button to push to control the noise level around them have a lower level of perceived stress compared to the control group without the button—even if they never push the button. Perception of control can also work in the other direction—if you think you have control over things that are in fact beyond your control, this misperception can increase stress.

No Predictive Information: Information that allows us to anticipate what’s coming next can decrease the impact of a psychological stressor. Knowing when a stressor is coming, or having some information about how long it will last allows us to prepare and pace ourselves. The stress of common medical procedures can be decreased by the doctor merely saying—“this will sting.” In the absence of any stressor, the lack of predictability alone can trigger a stress response.

Social Isolation: Social isolation increases the likelihood of a stress response. In human studies, people exposed to mild stressors had a smaller cardiovascular stress response if they had a friend present. People who are socially isolated are more likely to have heart disease. Even transient social support appears to be protective in humans.

No Outlet for Frustration: Chronic stress is less likely if an animal has an outlet for frustration. Exercise is a classic stress reliever because it provides both a distraction and a mechanism for discharging all the energy generated by the stress response. Hobbies that engage your interest and energy can also provide positive outlets. Fighting with coworkers, kicking the dog, or drinking too much are also outlets for frustration, but probably not as effective in the long run.

Perception That Things Are Worsening: The stress response is more likely to be triggered when we perceive that a situation is getting worse. For example, two people are offered the same $50,000 a year job. For the person who was previous paid $30,000, this is probably a joyous and stress-reducing event. For the second person, who last earned $70,000, it may have just the opposite effect. The event is neutral. Stress comes from the meaning we attach to it.

Stress and MS Exacerbations

We now understand that stress is a very complex process that incorporates personality, environment and physiology, and many of our responses to it are automatic. We have a good idea of what it does to the human body. What does it do the body of a person with multiple sclerosis? Do exacerbations cause stress? Does stress cause exacerbations?

Do Exacerbations Cause Stress?

We can anticipate the answer to this question by reminding ourselves of the stressor variables—no control, no predictive information, social isolation–that intensify the stress response. If you wanted to create a set of psychological stressors that would guarantee a full-blown stress response, you could find no better template than MS.

The perception of having no control is a classic MS problem. “I feel like I have no control over what is happening to me” has probably been said by 99% of people with MS. That we don’t know the cause of MS and have not yet found a cure fuels this uncertainty.

Social isolation is a problem for many people with MS, and not necessarily because they are homebound or have no support system. MS is difficult to explain to people who don’t have it. What a person with MS experiences internally is often quite different from how they appear externally—they might look just fine even though they are experiencing intense but invisible symptoms. People report feeling frustrated and exhausted by trying to explain the symptoms they feel but other people can’t see, such as fatigue or brain fog. They can become incensed when they complain of fatigue, only to have someone reply, “Well, I’m tired, too.” To explain that these two types of tiredness are very different and that MS tiredness never really goes away can feel like too big a task. If other people chronically do not understand what we are experiencing, we begin to feel isolated and estranged from them.

The perception that things are getting worse is built into MS because it’s a chronic, progressive illness. Even though it usually progresses slowly and sometimes progresses very little, the worsening of symptoms, especially during an exacerbation, can certainly make it feel like things are getting much worse.

MS is an erratic disease. We cannot say if or how much MS might progress. We cannot say if symptoms will get better or worse. There simply is no predictive information with MS—about how you will be doing in ten years or how you will be doing tomorrow. The absence of predictive information is probably one of the most frustrating and stressful aspects of MS.

Clearly, just living with MS, whether it is exacerbating or not, can be a stressful experience. Common sense tells us that exacerbations cause stress and the research bears this out.

Does Stress Cause Exacerbations?

Studies have been done for many years to see if there is a relationship between stressful life events and MS exacerbations. For many reasons, researching this connection is very complicated. Early studies relied on retrospective data, which depend on patient memory, and memory is often unreliable. It is difficult to define and measure stress because what is experienced as stressful varies from person to person, and from culture to culture. It is also hard to identify and measure environmental variables that might modify stress. It is difficult to find sensitive, reliable and affordable measures of disease activity because exacerbations are sometimes silent— they may be evident on an MRI but not during a clinical exam. These are but a few of the challenging methodological problems to manage when studying stress and MS.

Nevertheless, many studies have been done and most of them have found some interesting associations between stress and MS although none of them has been conclusive.

All of the studies have supported what we would suspect—that not all stressors are created equal. For example, people exposed to a severe, life-threatening stressor—the threat of missile attack during the 1991 Gulf War—had a decreased rate of relapse. Less traumatic stress appears to have a different impact. One researcher performed a meta-analysis of the all the studies on this topic from 1965 to 2003. He concluded that there is a significantly increased risk of MS exacerbation after non-traumatic stressful life events. Nevertheless, he found it impossible to link specific stressors to exacerbation.

Studies have also evaluated other variables that might be associated with exacerbations. Depression has been identified by some as a potential risk factor. Coping style and degree of social support were two variables associated with exacerbations but their importance was not consistent. Interestingly, a coping style that used distraction was associated with fewer enhancing MRI lesions. A good support network was found by many studies to facilitate the ability to manage stress.

What about physical stressors? Epidemiological studies have suggested that physical traumas, including motor vehicle accidents and surgery, do not have an impact on MS. However, infections of either viral or bacterial origin, regardless of body site, are often associated with an increased risk of relapse within the following two to six weeks.

Can we conclude anything from these studies? These data suggest that severe stressors have a weaker association to MS exacerbations than moderate stressors that are more frequent. Other variables, such as coping style, may modify the impact of stressors. In short, stress is often seen hanging around at the scene of the crime, and while there is enough evidence to press charges, there isn’t enough evidence to convict.

Future Research Directions

One of the puzzling questions about the relationship between stress and MS centers on the role played by cortisol. MS exacerbations are inflammatory processes. Cortisol is the principal hormone our metabolism releases (from our internal drug store) to control any inflammation in the body. The stress response increases the level of circulating cortisol in the blood. If stress raises cortisol levels, wouldn’t stress be good for MS exacerbations?

Perhaps severe, traumatic stress is—the previously mentioned soldiers threatened with missile attack did have decreased frequency of exacerbations. It is the chronic, moderate stressors that seem to cause the trouble. Why might chronic stress have a different effect?

This is a research focus of David Mohr at Northwestern University. Immune cells have receptors that bind cortisol, and when that happens, the immune cells take direction from the cortisol. Dr. Mohr’s hypothesis is that the increased blood level of cortisol, secondary to chronic stress, has reduced the number of these receptor sites on the immune cells. This might cause the immune cells to be less responsive to regulation by cortisol—an immune cell rebellion, if you will.

Dr. Mohr is also exploring how variables such as coping response and social support might affect this whole process. For example, if a person does not have sufficient coping or support resources to neutralize a troublesome stressor, this might result in the activation of the stress response system, which might then trigger an MS flare.

What does it all mean?

Does stress cause MS exacerbations? Who knows? It certainly seems likely that stress has at least a significant supporting role in a complex drama that has too many characters and a really confusing plot. We do know that chronic stress causes lots of other problems, and for that reason alone, it deserves some attention from us.

We can’t avoid stress, and even if we could, we wouldn’t want to. If everything were predictable, things would be quite dull. The point isn’t to avoid stress—it’s to learn to manage it.

If you are reading this, you already have some stress management skills. If you didn’t, you would have died long ago. Most of us, though, could benefit from paying more attention to stress–both how we create it and how we manage it. Stress management seems to be one of those activities that never quite makes it to the top of the list. Like drinking eight glasses of water each day, actively managing our stress is something we know we ought to do, but most of us don’t.

Often the shortest part of any article on the topic of stress is “Some Stress Management Techniques.” It ends up as a small side bar at the end of the page. This suggests that managing stress is the simple part of this whole problem. It isn’t. So many of the processes that cause us to respond poorly to stress are processes outside of our conscious control.

To have a stress response, to worry—this is the default setting, this is what our brains were designed to do. To override these ingrained patterns takes thought, planning, good information and lots of practice.

We have a society that cranks out plenty of threats to our sense of safety and security. We have frontal lobes that soak up this information and from it invent a future that scares us to death. This fear and uncertainty then fuels our stress response. If, on top of all that, you have MS, your plate is really full.

We don’t choose to worry. We don’t choose to be stressed. We don’t make a choice to turn on the stress response. The choice we can make is whether we learn how to turn it off. The next issue of InforMS will focus on a host of different strategies for evaluating and managing stress.

By Pat Daily, LCSW. Originally published in InforMS Winter 2009