multiple sclerosis: empirical literature for the clinical health psychologist

Multiple Sclerosis: Empirical Literature forthe Clinical Health Psychologist

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David C. Mohr and Darcy CoxUniversity of California, San Francisco

This article reviews the empirical literature related to clinical health psy-chology in multiple sclerosis (MS). MS is a disease in which the immunesystem attacks the central nervous system. As such, the interactions betweenmedical and psychological variables are complex, and potentially of con-siderable importance to patients. Common neuropsychological and psy-chological problems associated with MS and their etiologies are reviewed.The effects of stress and depression on MS exacerbation are discussed,including clinical, immune, endocrine, and neuroimaging findings. Thetypes of coping common in MS and their effects on adjustment are dis-cussed. The empirical literature on psychological and neuropsychologicalintervention is reviewed. The small literature on caregiving in MS is alsosummarized. © 2001 John Wiley & Sons, Inc. J Clin Psychol 57: 479–499, 2001

Keywords: multiple sclerosis; clinical health psychology; central nervoussystem; stress; depression

Multiple Sclerosis (MS) is a chronic, often disabling disease of the central nervous sys-tem (CNS), affecting approximately 350,000 people in the United States (Anderson, Ellen-berg, Leventhal, Reingold, Rodriguez, & Silberberg, 1992). Prevalence among women isabout twice that found in men. MS is usually diagnosed between the ages of 20 and 40. Itis believed that the immune system attacks the myelin sheath around the axons of theCNS, which results inplaquesor lesions. Thus, virtually all functions innervated by theCNS can potentially be affected. Common symptoms include, but not are limited to, lossof function or feeling in limbs, loss of bowel or bladder control, sexual dysfunction,

Manuscript preparation was supported by research grants RG2719 A1/2 and FG 1376-A-1 from the NationalMultiple Sclerosis Society, and R01 MH59708 from the NIMH.Correspondence concerning this article should be addressed to: David C. Mohr, Ph.D., UCSF Behavioral Med-icine Research Center, Box 1641, San Francisco, CA 94143-1641; e-mail: [email protected].

JOURNAL OF CLINICAL PSYCHOLOGY, Vol. 57(4), 479–499 (2001)© 2001 John Wiley & Sons, Inc.

debilitating fatigue, blindness due to optic neuritis, loss of balance, pain, cognitive dys-function, and emotional changes (Goodkin, 1992; Mohr & Dick, 1998).

There are numerous possible courses (Lublin & Reingold, 1996). Approximately10–15% of all patients have a benign course, with little disease activity. Between 65–70%have a relapsing course (relapsing remitting or secondary progressive) marked by peri-odic disease exacerbations. Exacerbation is a sudden worsening of symptoms, whichremit partially or fully over the course of weeks or months. Approximately 10–15% havea primary progressive course in which there is a steady worsening of symptoms with noexacerbations. A malignant course, characterized by rapid deterioration resulting in death,is rare. The course of the illness can change at any time. MS remains one of the mostdisabling illnesses in the United States, with 81% of all patients out of the workforce(U.S. Bureau of the Census, 1982).

Neuropsychological Symptoms

Cognitive dysfunction is a significant problem for patients with MS. Point-prevalenceestimates of cognitive problems range from 40–60% of patients (Rao, 1986; Rao, Leo,Bernardin, & Unverzagt, 1991a). Because the disease is progressive, lifetime prevalenceis likely considerably higher. Cognitive impairment is related to the effects of MS on thebrain. The degree of cognitive impairment is associated with the total volume of brainmatter damaged by MS-related lesions (Comi et al., 1995; Damian et al., 1994; Hohol,Schilling, Bachmann, Steoppler, & Dorndorf, 1997; Möller, Weidemann, Rohde, Back-mund, & Sonntag, 1994; Patti et al., 1995; Rovaris et al., 1998).

The cognitive impairment symptom profile in MS is heterogeneous, varying greatlyfrom patient to patient (Ryan, Clark, Klonoff, Li, & Paty, 1996). Problems with process-ing speed, attention, and concentration may be among the most common problems withpatients with MS (Brassington & Marsh, 1998; Grant, McDonald, & Trimble, 1989b;Kail, 1998; Kujala, Portin, Revonsuo, & Ruutiainen, 1995). Problems in verbal memoryare also common. Although retrieval of verbal information is the problem that mostcommonly interferes with memory function, impairments can occur across all domains ofmemory functioning, including problems with encoding and storage. Word-finding def-icits and problems with fluency are also seen, particularly with timed generative namingor listing tasks (Basso, Beason-Hazan, Lynn, Rammohan, & Bornstein, 1996; Rovariset al., 1998; Thornton & Raz, 1997). Difficulties with visual–spatial learning and mem-ory, visuoperceptive organization, and visual–spatial construction tasks are also found(DeLuca, Barbieri-Berger, & johnson, 1994). Executive functioning, defined as patients’ability to reason, sequence, problem-solve, and shift sets can also be impacted by MS(Beatty & Monson, 1994; Foong et al., 1997: Zakzanis, 2000 #809).

Just as the symptom profile is heterogeneous, the severity of deficits can vary also.Some MS patients’ performance is indistinguishable from or only slightly worse than thatof matched controls (Camp et al., 1999; Ryan et al., 1996), while other patients can showprofound impairment. The likelihood of developing cognitive symptoms is also variable.Cognitive functioning may be well preserved for decades after diagnosis in some patients,and decline rapidly in others. In general, patients who experience a large number of cog-nitive deficits early in the disease have a worse cognitive prognosis than patients whosecognitive functioning is initially well preserved (Kujala, Portin, & Ruutiainen, 1996).

Cognitive functioning is adversely impacted both by acute disease exacerbation (Foong,Rozewicz, Quaghebeur, Thompson, & Ron, 1998) and the corticosteriods used to treatdisease exacerbation. However, cognitive functioning may be expected to return to aroundbaseline levels following exacerbation in most cases (Foong et al., 1998).

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Cognitive deficits do not correlate consistently with level of physical impairment(Stenager, Knudsen, & Jensen, 1989). However, cognitive deficits do correlate with patientdisability and handicap, particularly unemployment (Amato, Ponziani, Pracucci, Bracco,Siracusa, & Amaducci, 1995; Beatty, Blanco, Wilbanks, Paul, & Hames, 1995; Franklin,Nelson, Filley, & Heaton, 1989; Rao, Leo, Ellington, Nauertz, Bernardin, & Unverzagtet al., 1991b; Stenager et al., 1989). Patients with high levels of cognitive impairment aremore likely than patients with intact cognitive functioning to be unable to work outsidethe home, to need assistance with daily activities, and to have fewer social supports (Raoet al., 1991b). Thus, cognitive impairment increases needs and decreases resources, leav-ing many patients in situations of considerable hardship.

Assessment of Neuropsychological Functioning

Patients should be educated about the possibility of cognitive difficulties and the need foradequate neuropsychological assessment, conducted by a neuropsychologist with famil-iarity with MS. A neuropsychological assessment of a patient with MS should includean estimate of that patient’s baseline intellectual functioning. The Vocabulary subtest ofthe Wechsler Adult Intelligence Scale, Third Edition (WAIS-III), can be considered avalid single subtest estimate of a patient’s baseline verbal IQ (Wechsler, 1997b). OtherIQ estimates, such as the American National Reading Test (AMNART) or the BaronaEstimates can also be helpful, although the accuracy of these measures can be compro-mised by educational and cultural variables (Barona, Reynolds, & Chastain, 1984; Blair& Spreen, 1989; Wechsler, 1997c). Timed measures should be avoided, as MS patientsare likely to have difficulties with processing speed. Memory and learning should becarefully assessed. An assessment instrument that assesses multiple domains of memory,such as the Wechsler Memory Scale, Third Edition (WMS-III), as well as tests lookingspecifically at verbal memory and learning, such as the California Verbal Learning Test(CVLT), the Rey Auditory Verbal Learning Test (RAVLT), and/or the Buschke SelectiveRecall Test can all be used (Bushke & Fuld, 1974; Rey, 1964; Wechsler, 1997a). Visual–spatial memory and learning can be assessed with the Benton Visual Retention Test or the7/24 Spatial Recall Test, which was developed by Rao (Rao, unpublished manuscript;Sivan, 1992) specifically for use with patients with MS. Attention, concentration, andprocessing speed should also be thoroughly assessed. The Symbol Digit Modalities Test(SDMT) is preferable to the Digit Symbol subtest on the WAIS-III because it is notdependent on intact motor functioning and motor speed (Smith, 1982). Easier tests, suchas Digit Span from the WAIS-III, Corsi Block Tapping, and Trail Making (administeredverbally if the patient has upper limb dysfunction) can be compared to performance onmore demanding tasks such as the Stroop or the Paced Auditory Serial Addition Test(PASAT) (Dodrill, 1978; Gronwall, 1997; Milner, 1971; Spreen & Strauss, 1991). Patientsmay also complain about word-finding problems. These may be apparent on tasks such asthe Controlled Oral Word Association Test (COWAT) or other forms of list naming, suchas Animal Naming (Spreen & Strauss, 1991). However, these tasks can also be adverselyimpacted by slowed processing speed, and scores should be interpreted with this consid-eration in mind. Patients may also exhibit deficits on the Boston Naming Test (BNT),although language impairment of this severity is unusual, and is likely to be apparentduring the clinical interview (Kaplan, Goodglass, & Weintraub, 1983). Patient executivefunctioning should also be assessed. The Wisconsin Card Sorting Task (WCST) may beparticularly effective at identifying patients who have MS-related executive-frontal func-tioning problems (Arnett, Rao, Bernardin, Grafman, Yetkin, & Lobeck, 1994; Beatty &

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Monson, 1996; Grant & Berg, 1948), and may also enable the examiner to make esti-mates of the patient’s likely real world functioning (Kibby, Schmitter-Edgecombe, &Long, 1998).

The results of neuropsychological testing can be used to help patients and their care-givers identify areas of strengths, as well as areas of weakness for which the patient mayneed to adopt compensatory strategies. For example, patients with memory difficultiesmay be helped by using external organizational aids, such as a day planner, keeping itemsin the same place, lists, and other reminders. Their family members may need to helpthem compensate for problems with memory by keeping items such as mail, keys, kitchensupplies, and tools in the same places and by offering memory aids. Patients with diffi-culties in selective attention may need to only work on one task at a time in environmentslow in distractions. Sometimes, family members or caregivers will consider problemswith memory and attention to be willful behavior under the patient’s control, and willinterpret memory failures or distractibility as lack of caring on the patient’s part. Familialeducation about memory problems in MS can help reduce these miscommunications.Open discussion of the particular problems faced by the patient and his or her family andcollaborative development of solutions to these problems can help reduce conflict betweenfamily members. Neuropsychological assessment can be used to help patients determinewhether they are likely to be able to continue their current employment. The neuropsy-chologist can help the patient advocate for accommodations to allow the patient to workdespite cognitive problems, or, if necessary, the results of neuropsychological testing canbe used as part of an application for disability benefits.

Psychological Symptoms

In addition to cognitive problems, patients with MS frequently present with a variety ofpsychological difficulties. Of these, depression may be the most common and mostdebilitating.

Depression

It is widely agreed that depression is one of the more common symptoms in MS (Ander-son & Goodkin, 1996; Schapiro, 1994; Thompson, 1996). Lifetime prevalence of majordepressive disorder (MDD) following MS diagnosis is approximately 50% (Joffe, Lip-pert, Gray, Sawa, & Horvath, 1987; Minden, Orav, & Reich, 1987; Sadovnick, Eisen,Ebers, & Paty, 1991). Point-prevalence data are generally poor, using small samples thatare not necessarily representative, and different assessment measures across studies. Thesemethodological problems have resulted in a wide range of point-prevalence estimates,ranging from 14–57% (Schiffer, Caine, Bamford, & Levy, 1983; Schubert & Foliart,1993; Surridge, 1969; Whitlock & Siskind, 1980). Prevalence relative to other illnesses isalso unclear. Although several studies have found that rates of depression are higher inMS than in other chronic illnesses (Minden et al., 1987; Surridge, 1969) and other neuro-logical disorders (Rabins et al., 1986; Whitlock & Siskind, 1980), these findings are notuniversal (MacLeod & MacLeod, 1998). All of these studies have been too small toproduce reliable results. There is a complete absence of literature examining the naturalhistory of depression in MS. Examination of control conditions in intervention studiessuggests that depression in MS, left untreated, is not self-limiting (Mohr & Goodkin,1999).

The high prevalence of depression may have multiple etiologies. Depression in MSclearly has psychosocial origins. Loss of function in MS is unpredictable, and for many


patients, unrelenting. While absolute level of cognitive of physical impairment is notnecessarily related to adjustment or depression (McIvor, Riklan, & Reznikoff, 1984;Millefiorini et al., 1992; Rabins et al., 1986; Rao et al., 1991a; Whitlock & Siskind,1980), patient’s perceptions of the uncertainty (Wineman, Schwetz, Goodkin, & Rudick,1996), variability in disease (Schiaffino, Shawaryn, & Blum, 1998), and the perceivedintrusiveness of disease on daily activities (Devins et al., 1993a, 1996; Devins, Edwor-thy, Seland, Klein, Paul, & Mandin, 1993b) are all related to depression and adjustment.Loss of social support and social role functioning associated with the disease has alsobeen shown to be associated with depression (Barnwell & Kavanagh, 1997; Gilchrist &Creed, 1994; Gulick, 1997; Pakenham, 1999).

Although the psychological sequelae of MS are associated with depression, this alonewould not account for rates of depression that may be higher than rates found in otherprogressive diseases. We, therefore, speculate that depression may be related to MS-specificdisease processes. For example, depression may result from immune dysregulation asso-ciated with MS. There is evidence that depression is strongly associated with diseaseexacerbation, which is the result of proinflammatory disease activity, measured bothclinically and by magnetic resonance imaging (MRI) (Dalos, Rabins, Brooks, & O’Donnell,1983; Fassbender et al., 1998). Depression has also been associated with specificallylocated brain lesions (Franklin, Heaton, Nelson, Filley, & Seibert, 1988a; Pujol, Bello,Deus, Marti-Vilalta, & Capdevila, 1997). Thus, depression may be a product ofspecificMS-related autoimmune disease processes, as well as the neurological damage caused bythese processes in the form of brain lesions. This would indicate that depression can beboth a complication associated with MS, as well as a symptom of MS.

There has been some speculation that new-onset or increased depression may be aniatrogenic effect associated with some of the medications commonly used to treat MS.There are three disease-modifying medications used to treat MS, two of which are inter-feron drugs. Several uncontrolled studies have shown increases in depression associatedwith the use of interferon drugs (Mohr et al., 1996. 1998; Neilley, Goodin, Goodkin, &Hauser, 1996), although others have found no evidence of such an effect (Borràs, Rio,Porcel, Barrios, Tintoré, & Montalban, 1999; Mohr, Likosky, Dwyer, van der Wende,Boudewyn, & Goodkin, 1999c). Also, MS exacerbations are frequently treated by eitheroral or IV steroids, which are known to produce changes in mood and cognition (MedicalEconomics, 1998).

Another possible reason for the high rates of depression is that many of the symp-toms of depression are confounded with MS, including fatigue, psychomotor agitation orretardation, changes in sleep, and diminished ability to concentrate.

Anxiety and Anger

Compared to depression, little has been written on anxiety in MS. Given the degree ofuncertainty and the perceived potential threat of the disease (Wineman, 1990; Wineman,Durand, & McCulloch, 1994; Wineman et al., 1996), it is not surprising that the rates ofanxiety appear to be higher in MS than those found in the normal population (Maurelliet al., 1992). Like much of the empirical literature on the prevalence of depression in MS,the literature on anxiety prevalence is poor, with small sample sizes and a lack of con-sistency in methods of assessment across studies. Existing work suggests that the point-prevalence of problems with anxiety ranges from 19% to 34% (Minden & Schiffer, 1991;Pepper, Krupp, Friedberg, Doscher, & Coyle, 1993; Stenager, Knudsen, & Jensen, 1994),with one study finding anxiety to be more common than depression (Feinstein, O’Connor,Gray, & Feinstein, 1999).


Anxiety can have several sequelae. Anxiety can aggravate depression in MS and isassociated with increased rates of suicidal ideation, compared to depressed MS patientswith little or no anxiety (Feinstein et al., 1999). Anxiety is also related to decreasedadherence to disease-modifying medications, which are all administered by injection.Anticipatory injection anxiety is related whether or not the patient is able to self-inject,and self-injection is associated with adherence (Mohr, Boudewyn, Likosky, Levine, &Goodkin, in press). Experienced injection anxiety is also directly related to decreasedadherence to disease modifying medications.

Anger in MS patients has been frequently noted by clinicians (Minden, 1992; Mohr& Dick, 1998; Pollin, 1995). However, there is little empirical literature in this area.Anger can be an appropriate response to the frustrations of having a chronic illness and toencountering new physical limitations. It may become problematic when the intensity ofthe anger causes distress, and/or when the anger is displaced onto others in the environ-ment. This is an important area that deserves greater research efforts.

Pathological Laughing and Crying, and Euphoria

Pathological laughing and crying (PLC) has been used synonymously with pseudobulbaraffect. PLC is defined as bouts of uncontrollable laughing, crying, or both, in response tononspecific stimuli in the absence of a matching mood state (Poeck, 1969). It is estimatedthat PLC occurs in approximately 5–10% of MS patients (Feinstein et al., 1997; Surridge,1969). It is generally associated with greater physical and cognitive disability. PLC isgenerally responsive to fluoxetine (Seliger, Hornstein, Flax, Herbert, & Schroeder, 1992)and fluvoxamine (Iannaccone & Ferini-Strambi, 1996). Euphoria is a similar condition inwhich the patient’s mood is consistently cheerful, and he or she is seemingly unaware orunconcerned with his/her condition. Estimates of the prevalence of euphoria vary from5–48%, although in our experience the lower number is likely more accurate. Euphoria isa symptom of MS, as it is associated with greater lesion load in the brain (Kahana,Leibowitz, & Alter, 1971; Rabins et al., 1986; Surridge, 1969). Extreme caution shouldbe used in ascribing symptoms such as PLC or euphoria to psychological causes such asrepression or denial, particularly in patients with substantial cognitive impairment.

Effects of Psychological Variables on MS

The Effects of Stress on MS

Many patients report that stress results in disease exacerbation. This notion was firstconsidered by Charcot, one of the earliest investigators of MS, who speculated that grief,vexation, and adverse changes in social circumstance were related to the onset of MS(Charcot, 1877). While early case–control studies failed to detect a significant relation-ship between stressful life events, psychological distress, and first symptom or clinicalexacerbations of MS (Antonovsky, Leibowitz, Medalie, Smith, Halpern, & Alter, 1968;Pratt, 1951), more recent studies have supported such a relationship. Patients with MSare more likely to report stressful life events prior to the first identified symptom com-pared to patients experiencing the first symptom of other neurological disorders or rheu-matoid arthritis (Warren, Greenhill, & Warren, 1982), or healthy controls (Grant, Brown,Harris, McDonald, Patterson, & Trimble, 1989a). Both case–control and longitudinalstudies have shown that stress increases the risk of experiencing a disease exacerbation(Ackerman, Rabin, Heyman, Frank, Anderson, & Baum, 2000; Franklin, Nelson, Heaton,Burks, & Thompson, 1988b; Sibley, 1997; Warren, Warren, & Cockerill, 1991).


Data also suggest that different types of stress may have differential effects. AlthoughSibley (Sibley, 1997) found marital and job-related stress was followed by clinical exac-erbation, major negative life events, such as a death in the family, were not. MS patientsin a clinical trial in Israel showed a decreased exacerbation rate while under actual orthreatened missile attack during the Persian Gulf War and for the two-month periodthereafter (Nisipeanu & Korczyn, 1993). This suggests that it may be important to dif-ferentiate between relatively severe stressors and moderate, but more chronic, stressorswhen examining the relationship between stress and disease activity.

We had an opportunity to follow 36 patients who received gadolinium enhancedMRI scans every four weeks for 28–100 weeks (gadolinium is a dye that permits visual-ization of the breakdown in the blood–brain barrier). We assessed mood and stress at eachMRI scan. We found that increased stress due to increased conflict and disruption inroutine predicted the risk of developing a new brain lesion eight weeks later (Mohr et al.,2000a). There was a similar marginal effect in which daily hassles were suggested topredict new brain lesions eight weeks later. As predicted, there was no effect for severelife stressors. This study supported the notion that different types of stressors have dif-ferent effects. Furthermore, this is the first study to suggest that one way stress may affectMS is by increasing permeability of the blood–brain barrier.

Although it appears that stress does have some effect on MS disease processes, thisprocess is not well understood. The immune and endocrine pathways that might mediatethe effects of stress remain unexplored. MS does not appear to alter the immune andendocrine stress response to acute stressors (Ackerman, Martino, Heyman, Moyna, &Rabin, 1996; Ackerman, Martino, Heyman, Moyna, & Rabin, 1998); however, there areno data to date examining the immune and endocrine stress response to chronic stressorsin MS. It is also unclear if there are patient variables which might leave people morevulnerable to the effects of stress. Such moderators are suggested by the inconsistenteffects of stress across patients and the relatively weak effects seen in the population as awhole (Mohr et al., 2000a).

Finally, it should be remembered that having MS and experiencing disease exacer-bations may be stressful events in themselves. Thus, rather than thinking of stress anddisease activity as simple, one-way causal effects, dynamic reciprocal models of stressand MS must be developed. Such models would serve to guide future research in thisarea.

Effects of Depression on MS

There are at least two potential pathways by which depression might affect MS disease:indirectly, by affecting behaviors that affect MS exacerbation or progression, or directly,via effects on the immune system. There is some support for the indirect hypothesis. Alongitudinal study of patients initiating an interferon medication found that depressionwas associated with decreased adherence to medications used to treat MS (Mohr et al.,1996). But if the depression is treated with either psychotherapy or antidepressant med-ications, the risk of discontinuation is no greater than patients reporting no depression(Mohr et al., 2000b).

We have also examined whether depression might have a direct effect on MS diseaseactivity by examining immune dysregulation over the course of treatment for depression.Our marker of immune dysregulation was T cell production of interferon gamma (IFN-g).IFN-g is a cytokine, or protein, produced by T cells that has been shown both to precedeand to cause MS exacerbation (Lu, Jensen, & Arnason, 1993; Panitch, Hirsch, Schindler,


& Johnson, 1987). We found that IFN-g production dropped significantly over the courseof treatment for depression, and that changes in the Beck Depression Inventory (BDI)(Beck, Ward, Medelson, Mock, & Erbaugh, 1961) were strongly correlated with changesin IFN-g production (Mohr, under review; Mohr, Boudewyn, & Genain, 1999a). Wefurther examined the hypothesis that this relationship was due to changes in vegetativesigns by dividing the BDI into its affective, cognitive, and vegetative factors (Louks,Hayne, & Smith, 1989; Startup, Rees, & Barkham, 1992). We found a significant corre-lation between change in depressive cognition and change in IFN-g production, but nosignificant correlations for affective or vegetative symptoms. This finding is consistentwith emerging literature that changes in immunity previously ascribed to mood may infact be due to attitudes (Bower, Kemeny, Taylor, & Fahey, 1998; Taylor, Kemeny, Reed,Bower, & Gruenewald, 2000).

Coping

Impairment, strictly defined as problems in body function or structure that affect one’sability to function and participate in life (World Health Organization, 1999), is not asso-ciated with decreased adaptation (Provinciali, Ceravolo, Bartolini, Logullo, & Danni,1999). On the other hand, limitations in a person’s ability to engage in normal activitiesor societal roles are associated with decreased well-being and psychological adaptation.For example, not being able to walk does not affect well-being in and of itself. However,loss of ambulation can reduce well-being when it prevents completion of a desired task orincreases the effort required to participate in activities. A person who is able to minimizethe effects of impairment on their ability to perform activities and engage in life willexperience the impairments as less stressful. This suggests that coping plays a substantialrole in adaptation.

The vast majority of coping research in MS has utilized Lazarus and Folkman’smodel, which defines coping as “constantly changing cognitive and behavioral efforts tomanage specific external and/or internal demands that are appraised as taxing or exceed-ing the resources of the person” (Lazarus & Folkman, 1984) (p. 141). Much of the workin MS has relied on assessment instruments developed by Folkman (Folkman & Lazarus,1986; Folkman & Lazarus, 1988), which broadly classify coping strategies into problem-focused and emotion-focused strategies, based upon the targets of the coping behaviors.

Problem-Focused Coping

Problem-focused coping, such as confrontive coping or problem solving, tends to beassociated with well-being in people without chronic physical illness (Folkman & Laz-arus, 1986; Lazarus & Folkman, 1984; Zeidner & Saklofske, 1996). This relationship isless clear in MS, with some studies finding a positive relationship between adaptationand problem-focused coping (Aikens, Fischer, Namey, & Rudick, 1997; Mohr, Goodkin,Gatto, & Van Der Wende, 1997a; O’Brien, 1993b; Pakenham, Stewart, & Rogers, 1997)and others finding no relationship (Beatty, Hames, Blanco, Williamson, Wilbanks, &Olson, 1998; Hickey & Greene, 1989; Jean, Beatty, Paul, & Mullins, 1997; Jean, Paul, &Beatty, 1999). However, such main-effects analyses may miss important relationships.For example, different aspects of the disease may require different coping strategies. Wehave found that problem solving is related to lower levels of psychological distress inpatients with high levels of physical impairment, but is unrelated to distress in patientswith less impairment (Mohr et al., 1997a). Thus, the utility of some problem-focusedstrategies may be moderated by impairment, and possibly other disease related variables.


Specific forms of problem-focused coping my also be more helpful than others. Forexample, behavioral coping strategies that are focused on achievable health maintenancegoals (e.g., moderate levels of exercise tailored to the person’s physical capacities, main-taining a healthy diet and appropriate weight, adherence to medical regimens) or behav-ioral compensation (e.g., compensating for fatigue by building rest periods into one’sdaily schedule, proper use of ambulation aids or other adaptive devices, shopping atnonpeak hours) are associated with higher quality of life (QOL) in MS in cross-sectionalstudies (Gulick, 1997; Stuifbergen, 1995). Mediational analyses suggest that health behav-iors mediate the effects of disability on QOL (Stuifbergen & Roberts, 1997). However,when behavioral strategies are focused on alleviating problems that cannot be resolved(e.g., attempts to return physical functioning to a pre-MS baseline despite progresseddisability), coping efforts are likely to result in frustration (Maes, Leventhal, & DeRid-der, 1996). Although there is little empirical data on this, our clinical experience suggeststhat such fruitless coping strategies are commonly employed by MS patients who arehaving difficulty accepting their disease and/or impairments.

Cognitive coping strategies such as cognitive reframing, information gathering, plan-ning, and goal setting have generally been associated with better adaptation to MS (Aikenset al., 1997; Baker, 1998; Mohr et al., 1997a). Cognitive reframing is a way of reconcep-tualizing a problem from something considered impossible to solve into something forwhich other coping strategies may be helpful. For example, if an untreatable memorydisorder can be reframed as an organizational problem, this can allow the patient toutilize other strategies such as information gathering, planning, and goal setting (e.g.,develop systems of reminders, use an organizer, keep “to do” lists) that can reduce theimpact of the impairment on role performance (Allen, Goldstein, Heyman, & Rondinelli,1998; Canellopoulou & Richardson, 1998).

Positive reframing, a specific form of cognitive coping, is related to better adaptationin MS (Aikens et al., 1997; Mohr, Goodkin, Likosky, Gatto, Baumann, & Rudick, 1999b;Mohr et al., 1997a). Positive reframing can be a complex and profound coping strategy.In a recent study, in which we asked patients how MS had affected their lives, we foundthat patients not only reported a variety of demoralizing consequences, but the majorityalso reported a variety of benefits they had derived from the disease (Mohr et al., 1999b).The benefits included such things as improved relations with family, increased compas-sion, enhanced appreciation of life, as well as other benefits. Benefit-finding was asso-ciated with positive reappraisal. These findings are consistent with findings from otherpopulations with medical illnesses (Affleck & Tennen, 1996; Folkman, 1997; Taylor,1983).

Emotion-Focused Coping

Consistent with research from other chronic illnesses, both cross-sectional and longitu-dinal studies in MS have found that passive, avoidant, emotion-focused coping strategies(e.g., wishful thinking, self-blame, avoidance) are related to poorer adjustment and lowerlevels of QOL (Aikens et al., 1997; Buelow, 1991; Mohr et al., 1997a; O’Brien, 1993b;Pakenham, 1999; Pakenham et al., 1997).

There has been little focus on emotion-focused coping, compared to problem-focused coping. This may be due in part to the widespread belief that emotion-focusedcoping is associated with poor outcomes. However, in a progressive disease with fewoptions for affecting changes in symptoms, emotion-focused coping strategies may accountfor a substantial portion of a patient’s coping efforts. Furthermore, not all emotion-


focused coping is necessarily deleterious. Clinicians have touted the salutary effects ofacceptance (Minden, 1992; Pollin, 1995). One of the longest longitudinal studies exam-ining psychosocial functioning in MS found that acceptance was related to adaptation inMS up to seven years later (Brooks & Matson, 1982; Matson & Brooks, 1977). Interpre-tation of these results is complicated by the finding that “fighting” MS was also related tosubsequent adaptation, and that the use of religion or family as major coping strategieswas associated with decreases in adjustment. Although this study is important, it did nothave the benefits of improvements in assessment methodologies that have occurred overthe past 25 years, particularly in coping. The adaptive use of emotion-focussed copingstrategies, such as acceptance, is a significant hole in the MS coping literature.

Psychological Intervention

Psychotherapy

The prevalence of psychological distress among MS patients has long been recognized,and led to several early reports of group psychotherapies lasting from six months totwo-and-a-half years (Barnes, Busse, & Dinken, 1954; Bolding, 1960; Day, Day, & Her-rmann, 1953).Althogh objective outcomes are lacking in this early reports, authors reporteddecreased depression, increased self-reliance, and decreased utilization of overly usedmedical services.

The empirical literature has examined cognitive-behavioral therapies (CBT), relax-ation, supportive group psychotherapy, and antidepressant medications (see Mohr & Good-kin, 1999, for a review). Larcombe and Wilson (1984) described the first controlled,randomly assigned treatment study employing a six-week group-administered CBT. Thestudy was small, with 9 active patients and 10 controls, but, nevertheless, showed a largereduction in depression for CBT, compared to an increase in depression for the controlgroup. Subsequently Foley et al. (1987) compared 18 patients who received a six-weekindividually-administered “stress-inoculation” based on CBT principles to 18 patientsreceiving a Treatment as Usual (TAU) control that included some supportive therapy forsome patients. Foley reported significant reductions in depression and anxiety for theactive treatment group and no change for the control group. These changes were main-tained at six-month follow-up. Crawford and McIver (1987) compared a 13-session groupCBT stress management program administered to 23 patients to 21 control patients. Thegroup CBT treatment was effective at reducing depression and anxiety. Similar to Lar-combe and Wilson’s findings, the control group worsened.

Many patients with MS have mobility impairments or experience fluctuations insymptoms that prevent them from attending a clinic on a regular basis. Others may livefar from specialized treatment. Alternative treatment delivery methods via telephone orthe Internet might increase access to mental health treatment for these patients. We haverecently completed a small trial in which 16 patients received an eight-week manualizedform of CBT delivered over the telephone while another group of 16 patients received aTAU control (Mohr et al., 2000b). The active treatment group showed significant improve-ments in depressive symptoms at post treatment compared with the TAU. Moreover,adherence to disease modifying medications was better for the active treatment groupthan the control condition.

Several other forms of therapy have also been evaluated. A 50-week insight-orientedgroup psychotherapy was compared to a current events group and a no-treatment controlgroup (Crawford & McIvor, 1985). The insight-oriented group showed significant reduc-tions in depression compared to the other two groups. However, this effect size was


significantly smaller than the effect sizes seen in briefer CBT interventions (Mohr &Goodkin, 1999). One report of a group psychotherapy employing relaxation, visualiza-tion, and art therapy reported declines in depression and improvements in verbal learningand abstraction; however, inadequate statistical analyses made it impossible to determineif these changes were significantly different from the wait list control group (Maguire,1996).

Antidepressant medication is likely the most widely administered treatment (Mohret al., 1997b) because it can be easily administered by neurologists. Both desipramine(Schiffer & Wineman, 1990) and sertraline (Mohr, Goodkin, Islar, Hauser, & Germain,under review) have been shown to be effective in reducing depression in clinical trials.Retrospective chart review has shown a wide variety of antidepressant medications to beeffective (Scott, Allen, Price, McConnell, & Lang, 1996). However, because many phy-sicians may not adequately monitor antidepressant use and effectiveness after prescrib-ing, patients treated with antidepressants in general medicine or neurology clinics arelikely underdosed, and have high rates of nonadherence. Properly taken in sufficientdoses, antidepressant medication is a useful tool that should be considered by patientsand the mental health professionals treating them.

Many MS patients are reluctant to take antidepressant medications. Many feel theyare already taking too many medications, while others see taking mood-modifying med-ication as a personal failure. Patients may also be sensitive to being labeled a somatisizerby health care providers, and may perceive a prescription for antidepressants as an indi-cation their physician is not taking their disease seriously. Medications may be useful forpatients, and should be carefully considered by both patients and therapists. However,medication is not a substitute for individual psychotherapy to help patients develop skillsto cope with emotions, thoughts, adjustment, and MS symptoms.

Most of the clinical literature and the efficacy studies to date focus on three differentforms of treatment: coping and skills training, emotional expression and enhancement ofsocial support, and medication. We have recently completed the first comparative trialexamining individual CBT, supportive-expressive group psychotherapy (Spiegel & Clas-sen, 2000), and the antidepressant sertraline for the treatment of major depressive disor-der in MS (Mohr et al., under review). Using the Beck Depression Inventory (BDI)(Beck et al., 1961) as the primary outcome measure, a significant difference was foundbetween the treatments, with supportive-expressive group therapy being less effectivethan CBT or sertraline. These data revealed that depression in MS is more difficult totreat than previously thought. Only half the patients who received CBT showed clinicallysignificant improvement, while more than 75% of patients receiving sertraline or groupremained refractory to treatment. Clearly, more aggressive strategies for the treatment ofdepression in MS must be developed. Obvious possibilities include increasing the dose oftreatments (e.g., the frequency or length of treatment) or combining treatment modalities.A better understanding of the indicators for specific treatments would allow us to explic-itly target problems with effective treatments, thereby increasing the effectiveness of ourservices.

Cognitive Rehabilitation

There has been little research in the area of cognitive rehabilitation for patients withMS-related cognitive difficulties. One study found that patients in a research setting wereable to learn new and more effective mnemonics from examiners, and thus to improvetheir scores on measures of memory. However, patients were not able to independently


develop these mnemonics effectively. As this is a laboratory study, it is not known whetherpatients were able to successfully generalize these strategies to real world tasks (Canel-lopoulou & Richardson, 1998). Plohmann and colleagues (Plohmann et al., 1998) foundthat use of a computer-based attention cognitive rehabilitation program significantlyimproved mildly attention-impaired MS patients’ alertness, divided attention, and selec-tive attention. Self-report measures obtained from these patients suggested that theseimprovements were generalized to their daily lives. Another study (Jønsson, Korfitzen,Heltberg, Ravnborg, & Byskov-Ottosen, 1993) does not find convincing results of improve-ment in cognitive functioning, but does find improvement in depression as a result ofcognitive skills training. Further research into possible rehabilitative strategies for cog-nitive deficits in MS is clearly needed.

Caregiving

The loved ones who care for MS patients with disabilities are an understudied and under-served group. Unlike the caregivers of Alzheimer’s Disease or stroke patients, MS care-givers are more likely to be young or middle aged adults, to have children at home, to bein the early part of career development, and/or to be finishing his/her education (O’Brien,1993a).

Two reported emotional consequences of MS caregiving have been discussed: chronicsorrow, and caregiver burden. Chronic sorrow is a pervasive sadness that is permanent,periodic, and progressive (Hainsworth, 1996). It is distinct from acute grief resultingfrom loss or from depression. Chronic sorrow is a chronic state of grief in which theillness serves as a constant reminder of loss (Burke, Hainsworth, Eakes, & Lindgren,1992; Hainsworth, 1996).

Caregiver burden has received considerable attention in other neurological disorderssuch as Alzheimer’s Disease (Horowitz, 1985). Although this topic has not received asmuch attention in MS, the emerging findings are similar. The vast majority of caregiversreport that the demands of caregiving disrupt their other obligations to friends, family,and career (O’Brien, 1993a). Caregivers feel confined because they feel unable to leaveto leave the care-recipient alone. Higher levels of caregiver burden are associated withnumerous patient variables, including higher levels of unstable disease course, higherlevel of physical disability, depression and mood changes, incontinence, and pain (Aron-son, 1997; Knight, Devereux, & Hamish, 1997; Schwartz & Kraft, 1999). Caregiverburden accounts for a large portion of the variance in caregiver health, mood, and lifesatisfaction (O’Brien, Weinman, & Nealon, 1995). Frequently perceptions of caregiverburden differ such that MS patients believe their caregivers experience less burden thanthe levels reported by the caregivers (Aronson, Cleghorn, & Goldenberg, 1996; O’Brien,Weinman, & Nealon, 1995). This discrepancy suggests that the care receiver may notsupport the needs of the caregiver emotionally or instrumentally (e.g., allowing a break).Thus, the cycle of burden continues to the point where the caregiver experiences chronicsorrow or depression (Mohr & Dick, 1998).

Some studies have suggested that that caregivers utilize problem focused copingstrategies (O’Brien, 1993a). However, the interaction of coping styles between thecaregiver and care-recipient may be more important than the coping strategies of eitherperson alone. Pakenham (1998) has found that larger differences between partners inproblem-focused coping is related to better adjustment for both the caregiver and thecare-recipient. In fact, there was no independent effect of individual coping on adjust-ment for the caregiver or care-recipient beyond the differential in problem-focused cop-ing. These findings point to the limitations of research and interventions conducted with


the patient or caregiver alone. Both live within the context of a relationship that clearlyhas a strong effect on well-being and adjustment. This speaks to the need to develop andevaluate dyadic or family interventions that treat not only the individuals, but also therelationships that form the primary context for their lives.

Summary

Research into psychological and neuropsychological functioning in MS reinforces thebiopsychosocial model of medicine (Engle, 1977). Comorbidity of psychological andmedical illness are complex, and interact on a variety of levels. Within the MS patient,depression can both result from and cause MS disease activity. Within the context ofmedical treatment, some commonly used medications can affect psychological and neuro-psychological functioning. However, the relationship between medical and psychologicalvariables is likely reciprocal. Patients’ psychological states may affect their adherence tomedical regimens, thereby exerting an indirect effect on MS disease processes. Psycho-logical states may also directly influence MS. Stress arising from interpersonal conflictand disruption in routine can increase the odds of developing new brain lesions, anddepression may increase MS-related autoimmune activity. Interactions between patientsand their social supports are poorly understood, are likely quite complex, and may affectwell-being. Thus, the interactions affecting disease can occur at a variety of levels: withinthe patient, in the treatment setting, interactions between the patient and their socialenvironment. Psychological interventions can be effective in many instances; however,not enough is known about the interactions between patient variables, treatment modal-ities, and outcomes. Increasing our understanding of the specific effects and indicationsfor psychological and neuropsychological intervention may increase our ability to effec-tively improve the quality of life for patients with MS.

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multiple sclerosis: empirical literature for the clinical health psychologist

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