Behavioral Interventions in Multiple Sclerosis

A Biopsychosocial Perspective

C Heesen; S Köpke; J Kasper; J Poettgen; A Tallner; DC Mohr; SM Gold


Expert Rev Neurother. 2012;12(9):1089-1100. 

In This Article


Clinical & Epidemiological Evidence for the Impact of Psychosocial Factors on MS Manifestation & Disease Activity

Numerous studies have investigated genetic and environmental risk factors in MS and recent evidence suggests that in particular the combination of such factors, for example smoking and certain HLA haplotypes, can substantially affect the risk developing MS. However, very few studies have addressed the relevance of psychosocial factors. One of the first large-scale studies conducted in this area has shown that severe trauma during adulthood (loss of a child) is a relevant risk factor for developing MS.[7] Bereaved parents in this study had an approximately 50% increase in MS risk, which increased to over twofold if the follow-up after the exposure was 7–15 years. An unexpected loss increased the risk to an odds ratio of 2.13.

A growing body of evidence from animal models and human studies has demonstrated that stress throughout a lifetime, starting with intrauterine or early postnatal stress, can dramatically alter neurobiological 'set points' as well as the major stress response systems.[8] While this work provides a biological framework for long-term health consequences of early life stress, only two studies so far have addressed the link between childhood trauma and MS pathogenesis. An analysis of a large prospective cohort study in the USA did not show higher rates of childhood sexual abuse or violence in women who later developed MS.[9] However, a smaller case–control study conducted in Germany, which employed a detailed childhood trauma questionnaire that included assessment of emotional traumatization such as neglect, reported a significantly higher rate of childhood trauma in MS patients compared with healthy subjects. In this study, MS patients had a more than threefold increased risk of emotional abuse and emotional neglect was twice as common in patients as in the control subjects.[10]

While the evidence for a link between psychological stress and the risk to develop MS is still scarce, numerous prospective studies have demonstrated an association between stress and MS relapses in established disease. Such a link had been hypothesized since the first description of MS by Charcot in the 19th century[11] and is now supported by more than two dozen prospective clinical studies.[12] In a meta-analysis of this literature, Mohr and colleagues reported an effect size of 0.53 for association between stressful life events and the occurrence of MS relapses.[13] Intriguingly, this effect is comparable to effect sizes of first-generation immunomodulators (IFN-β and glatiramer acetate), however in the opposite direction, indicating that it likely to be clinically relevant. The most dramatic evidence supporting an association between stress and relapses was provided by two recent studies on war stress by Golan et al.[14] and Yamout et al.,[15] which showed an at least threefold increase in relapse risk during a 6-week period of hostilities in the Middle East. While this strongly suggests a link between stress and disease activity in MS, observational studies are prone to selection bias and reverse causation effects, which precludes any conclusions regarding the causal role of stress in MS.

Relevance of Psychological Factors in Current Health Status

The so-called hidden symptoms of MS, namely depression, fatigue and cognitive dysfunction, are frequent in this population, often co-occur, partially overlap and may be directly linked to disease-associated factors such as inflammatory markers or neurodegenerative processes. Undoubtedly, this triad is of major health relevance. The 12-month prevalence for major depression in MS patients (aged 18–45 years) has been estimated to be around 25%[16] and lifetime prevalence rates may be as high as 50% compared with 15% of the normal population.[17] Fatigue is among the most frequent complaints in MS and even a stronger predictor for retirement than mobility issues.[18] Cognitive problems are of major importance in MS and subtle impairments in domains such as processing speed, attention and learning can be detected at the earliest stages of MS with sophisticated batteries.[19] The fact that neuropsychological dysfunction can occur in the absence of any mobility impairments suggests that the so-called benign variants of MS require careful examination of hidden symptoms. Indeed, cognition might be the most sensitive marker of overall brain damage.[20]

Recent studies indicate that, in addition to neuropsychological difficulties such as learning, memory and executive functioning, social cognition is also affected.[21] As social support might be a major buffer for stress effects in MS[22] and psychological adjustment, these findings indicate a major relevance for coping with MS. In fact, coping research has shown that cognitive dysfunction is associated with less active coping patterns.[23] However, very few studies have addressed the link between neuropsychological test performance and everyday functioning of patients.

Drug Treatment Reality in MS

Undoubtedly, the licensing of IFN-β preparations to treat MS in 1993 was a breakthrough. However, more than 15 years later, very little is still know about the long-term efficacy of disease-modifying therapies.[24] There are now even more effective anti-inflammatory treatments, such as natalizumab, that carry significant risk rates, as high as 1:100, of developing disabling and possibly life-threatening side effects.[25] In addition, treatments are highly effective in reducing MRI marker signals in inflammatory cases, but show weak or no effects in late-stage 'degenerative' MS.[3] Although all the new drugs claim neuroprotective effects, only the pivotal IFN-β1a trial[26] has thoroughly investigated drug effects on cognitive dysfunction showing some positive effects. Any symptomatic drug treatments have failed so far in the area of cognition.[27] Moreover, there is still no effective drug for treatment of fatigue, and drug treatment of depression in MS has only been poorly studied.[28]

Against this background, a critical review on the available evidence for nonpharmacological interventions to enhance activity, participation and autonomy in individuals with MS is warranted. The authors prefer the term BI as it is not defined through the absence of a drug treatment but emphasizes a person's ability to change their cognition and behavior. This does not mean to manipulate people to show expected behaviors as for example encompassed in the term compliance, but to enhance reflections on options as well as on personal preferences and values. These interventions may also be called self-management[29] or empowerment approaches.[30] This approach also includes interventions focusing on patient information about what is scientifically known about the disease and its treatment, and what is unknown. These interventions will be referred to as evidence-based patient information.[31] The critical appraisal through this approach is a prerequisite for shared decision-making, opening areas to decide and act, and is therefore strongly tied to behavior. By this definition, BI in our understanding cover an area from exercise training to patient information programs and cognitive-behavioral therapy, but also include relaxation and mindfulness interventions. Most of these are complex interventions with many active factors that are difficult to disentangle[32] and nearly impossible to investigate in a double-blinded manner. However, especially with the aim of acceptance and integration into routine care including reimbursement, we authors strongly emphasize the framework for the evaluation of complex interventions[33] to rigorously evaluate BI.