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3

Characteristics and Management of Major Symptoms

The signs and symptoms of multiple sclerosis (MS) are generally related to the most heavily myelinated parts of the central nervous system (CNS), but they are notoriously variable. Some symptoms such as dizziness, tingling sensations on the skin, or visual tracking disturbances are easily forgotten and are often hard for patients to describe. The majority of fleeting cerebral abnormalities seen on magnetic resonance imaging (MRI) cannot be correlated with any symptoms; even chronically demyelinated areas of the optic nerve and spinal cord can be symptom free.107

In general, MS patients report mental health as more important than physical impairment and bodily pain in determining their quality of life. This is different from neurologists' beliefs about the most important determinants of health-related quality of life for patients with MS or the beliefs of members of the general public about their own quality of life.146 Nine of the most prominent symptoms are described in this chapter. They are presented roughly in order of the importance that MS patients assign to them as determinants of overall quality of life, although it should be noted that this ranking is based on a small survey and that individual variability is a prominent feature of all aspects of MS.146

COGNITIVE IMPAIRMENT

Fear of mental change is one of the greatest concerns of MS patients when they learn they have the disease. Cognitive dysfunction is one of the most disabling features of MS and, even when subtle, can begin to limit a person's ability



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Page 115 3 Characteristics and Management of Major Symptoms The signs and symptoms of multiple sclerosis (MS) are generally related to the most heavily myelinated parts of the central nervous system (CNS), but they are notoriously variable. Some symptoms such as dizziness, tingling sensations on the skin, or visual tracking disturbances are easily forgotten and are often hard for patients to describe. The majority of fleeting cerebral abnormalities seen on magnetic resonance imaging (MRI) cannot be correlated with any symptoms; even chronically demyelinated areas of the optic nerve and spinal cord can be symptom free.107 In general, MS patients report mental health as more important than physical impairment and bodily pain in determining their quality of life. This is different from neurologists' beliefs about the most important determinants of health-related quality of life for patients with MS or the beliefs of members of the general public about their own quality of life.146 Nine of the most prominent symptoms are described in this chapter. They are presented roughly in order of the importance that MS patients assign to them as determinants of overall quality of life, although it should be noted that this ranking is based on a small survey and that individual variability is a prominent feature of all aspects of MS.146 COGNITIVE IMPAIRMENT Fear of mental change is one of the greatest concerns of MS patients when they learn they have the disease. Cognitive dysfunction is one of the most disabling features of MS and, even when subtle, can begin to limit a person's ability

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Page 116to cope, to stay employed, and to carry out family responsibilities and enjoy life.140 Early writers on MS often commented on cognitive and emotional changes, but in the mid-twentieth century, a pattern of denial of these features developed in the medical literature.143 Just as clinicians passed off the frequent symptoms of pain and fatigue as features of the disease, they also ignored the often seen emotional and cognitive changes (Jock Murray, personal communication). Donald Paty (personal communication) noted that there was a negative reaction to his suggestions in the 1970s that cognitive dysfunction should be a focus of study by the National MS Society. At the time, it was estimated that only 5 percent of MS patients might incur cognitive change, and it was argued that cognitive change was relatively unimportant in MS.143 By the 1990s, those views had changed, and in 1992, the MS Society and the International Federation of Multiple Sclerosis Societies jointly held a symposium on “Neurobehavioral Disorders in MS: Diagnosis, Underlying Pathology, Natural History and Therapeutics.” Cognitive changes are now estimated to occur in about 43 percent of MS cases.54 The conviction that cognitive changes must be selectively analyzed and distinguished from other phenomena such as depression and fatigue has emerged only in the last few decades. Standard psychological tests, however, are not very effective in identifying the type of changes that occur in MS. Rao, LaRocca, Fischer, Peyser, and many others have recently made considerable progress in adapting tests that can detect the specific changes seen in this disease,54,57,130 yet much more remains to be done. Paradoxically, as we are learning to separate and more effectively measure the cognitive changes and the affective changes, this separation has made it possible to learn how they are so often linked (Jock Murray, personal communication). Cognitive changes in MS generally are not global, but are most often circumscribed to specific processes. Learning, recall of new information, and speed of information processing are affected most often; deficits in visuospatial abilities and executive functions such as reasoning, problem solving, and planning are also common.54 Performance accuracy is less affected, but it appears affected if timed tests are used.41 Once cognitive impairment is present, it does not often remit (reviewed in 1999 by Fischer54). Poor memory is a common complaint among MS patients.3 Depending on sample selection methods and criteria used to define impairment, approximately 20 to 42 percent of MS patients have some deficit in their free recall of recently learned verbal and visual material (reviewed in 1994 by Fischer et al.56). Although memory deficits are common, certain processes remain intact. For example, the rate of learning, the likelihood of remembering a specific item based on when it was presented, and the ability to detect semantic characteristics of the material to be learned are preserved in all but the most impaired MS patients. Implicit memory, or the ability to learn new information or skills without explicitly attending to it, is also preserved. Recognition of recently learned information

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Page 117is generally impaired to a much lesser extent than free recall. Impairment of verbal fluency (the ability to rapidly generate words meeting specific phonological or semantic criteria) and, to a lesser extent, confrontation naming (the ability to retrieve the names of objects) are often associated with memory impairment. Decreases in word fluency are common, whereas decreases in verbal comprehension are less common.4 A study of 44 MS patients found that on tests of cognitive performance designed to measure planning skills tests the MS group performed on average significantly worse than controls.8 However, this was due largely to deficits among chronic progressive, as opposed to relapsing-remitting patients. Another caveat is that this was a timed test, so that in addition to planning skills, information processing speed would have influenced performance, which would likely bias the results since this is often affected in MS patients. Time Course The time course of cognitive changes in MS is highly variable, although they appear to occur very early in the disease, often before the onset of other symptoms. Different types of cognitive change can appear in different sequences in different patients, and few studies have documented changes over time in individual patients. In one study, 50 patients were tested early in the disease (on average, 19 months after clinical onset) and again 4.5 years later.4 Initial tests revealed statistically significant deficits in verbal memory and abstract reasoning relative to controls, with similar results in the follow-up tests. The difference in average scores between patients and controls was about 10 percent. However, the difference in variability was much more striking. The variability in scores for the MS group was consistently greater than for controls, and in 7 out of 15 cases the variance of the MS group was more than twice that of the controls. This suggests that the cognitive performance of many of the MS patients was not measurably affected, whereas others were substantially affected. A simple analysis of group differences is not sufficient to answer this question. This study also illustrates the value of using individual patients as their own controls. Association with Other Symptoms Cognitive and neurological deficits do not appear to develop in parallel, at least not in patients whose disease is still in its early phase.4 Disease duration is not a good predictor of cognitive function in MS, but disease course influences the likelihood of cognitive impairment. Chronic progressive patients tend to do more poorly on neuropsychological tests than relapsing-remitting patients (reviewed in 2001 by Fischer55). Expanded Disability Status Scale (EDSS) scores and specific neurological symptoms are not correlated with cognitive deficits.8,53,134 The EDSS is shown in Appendix D. Despite this, clinicians consis-

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Page 118tently overestimate the correlation between physical disablity and cognitive impairment in MS patients.56 While some studies report that cognitive function is independent of fatigue,63,180 others raise the possibility that they might be caused by a disruption of the same neural circuits (see Fischer 2000 for discussion). Depression is generally not strongly related to overall cognitive function. One study of 20 MS patients found that cognitive deficits (attention, visuomotor search, and verbal fluency) were independent of depressive symptoms.96 Of these, only frontal function impairment was correlated with depression. However, only 4 percent had significant depression scores, and all of these had secondary progressive MS.53 A cross-sectional study of 24 patients found significant association of cognitive impairment (using tests of abstract verbal and nonverbal memory) with depression, but not with the degree of neurological impairment, specific neurological symptoms, disability, or handicap.68 Neuropathological Correlates The traditional view that MS is characterized by discrete lesions does not explain the memory and cognitive changes, which would require a more widespread, bilateral change, especially since the complaints often arise early. Recent evidence from the studies of Ian McDonald in Great Britain and Bruce Trapp in the United States indicates that the effects of demyelination and the destruction of axons occur very early in MS and are widespread. Moreover, the process undoubtedly has been going on for a long time before a person experiences the first symptom. MRI has recently allowed speculation of localization of specific mental changes.139 Although MRI studies of MS patients have reported correlations between cognitive impairment and total lesion burden (the percentage of the brain that shows lesions on MRI scans), neuroimaging techniques have not reached the point where neuropathological changes can be linked to specific aspects of cognitive impairment (reviewed in 2000 by Rovaris and Filippi147). Research on cognitive changes in MS is still in its early stages, and most studies have been relatively small and have not followed changes in individuals. In addition, the application of techniques that allow detection of more specific neuropathological changes, particularly axonal pathology, might provide more useful insights into the causes of cognitive impairment. Pathological Laughing and Crying Pathological laughing and crying is a distinctive type of cognitive change that occurs in a variety of neurological disorders including stroke, amyotropic lateral sclerosis (ALS), Alzheimer's disease, cerebral tumors, and MS. The syndrome is defined as a sudden loss of emotional control—for example, laughing, crying, or both in response to nonspecific, often inconsequential stimuli for no

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Page 119apparent reason. The etiology of pathological laughing and crying is unclear. The cortex and, possibly, prefrontal cortex are thought to be involved. In a study of 152 patients with long-standing disease and significant physical disability (unable to walk without assistance), pathological laughing and crying as distinct from emotional lability affected 10 percent of the patients.49 (Emotional lability refers to abrupt changes in mood.) A preliminary study indicates that such patients had relatively greater difficulty with speed of information processing than their MS control subjects without pathological laughing and crying.51 There have been a number of reviews of euphoria, all suggesting that euphoria is a reflection of organic change. Rabins used pre-MRI studies to show that euphoria was associated with greater brain involvement with MS, particularly in the periventricular areas, but occurred in less than 10 percent of patients.136 Recent MRI studies indicate that the cognitive and emotional changes are likely to have specific neuroanatomical correlates. Management Initial studies have shown some limited gains by methods of cognitive rehabilitation, and more needs to be known about what approaches would be helpful. Memory failures of MS patients sometimes resemble those found in people with histories of closed-head injury. A study of teaching memory strategies to people with MS found that MS subjects were able to learn the strategies quickly and did not appear to require the lengthy training needed by persons with head injury.3 Two studies of the effects of amantadine, a medication often prescribed for fatigue, showed either no effect on cognitive function63 or a modest benefit on processing speed, and that effect was limited to patients who had MS for 7 years or longer.150 It was recently reported that after a 2-year course of interferon-beta (IFN-β-1a) relapsing MS patients had significantly better cognitive functions than placebo-treated controls.58 Although assessment of cognitive changes in MS clinical trials is challenging, further tests will be important to clarify this effect. Until ways of stopping or reducing cognitive change are developed, patients could benefit by any methods that at least help them and provide them with techniques to alleviate the problems. For example, people with memory deficits can use portable tape recorders, daily planners, and computer memory aids to keep track of schedules and review discussions during physician visits or education sessions. Research Needs The revelation of the prevalence of cognitive changes together with the advent of MRI has stimulated a surge of research over the last decade, which has in turn clarified specific needs for further research. Research on the underlying pathophysiological changes leading to cognitive and pathological emotional change is needed, because the relation

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Page 120 ship between pathological changes observed in the disease and the observation of cognitive change is speculative at the present time. Understanding the underlying mechanisms may explain why there isn't a close correlation of cognitive change with disability, disease course, or disease duration. Further research on more representative populations of MS patients is necessary to reveal the extent and degree of involvement, and long-term studies are needed on this group (community-based versus clinic populations). Previous studies are on groups that may not be representative. We need to know more about the impact of early cognitive changes on the quality of life.140 Further research is needed into the MRI, functional MRI, and PET (positron emission tomography) scan correlates of the cognitive change. We need to understand more about why some patients develop severe cognitive change, others mild or moderate change, and others with long-standing disease have no measurable change. Further research is needed into disease-specific neuropsychological tests to better identify early changes in MS, and this should be translated into a standard battery that could be used for the clinic and bedside and as a part of all clinical therapy trials. More data are needed to define the temporal course of cognitive changes and would be invaluable in assessing the impact of new agents used in treating MS. Better measures of the cognitive changes in MS should be developed, although the need for specific neuropsychological tests for the specific changes noted in MS has been recognized, as developed by Stephen Rao.139 DEPRESSION Prevalence and Diagnosis Depression is the most common mood disorder in MS. Alterations in mood and affective state have long been recognized in MS,35 although estimates of their prevalence vary widely. Estimates of the prevalence of major depression among MS clinic patients at any one time range from about 15 to 30 percent and from 40 to 60 percent for lifetime prevalence (reviewed in 1995 by Nyenhuis et al.,126 and in 1997 by Aikens et al.,1,56), which is three times that found in the general population. Depression is more prevalent in MS than other neurological disorders, such as Parkinson's disease, in which it is one-half to one-third less prevalent than in MS.141 However, these estimates might be deceptive because they are typically based on patients attending MS clinics. For example, the estimated prevalence of major depression among stroke patients depends on setting, in-

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Page 121creasingly linearly from community samples (2 to 4 percent) to primary care settings (5 to 10 percent) to inpatient medical settings (6 to 14 percent).25 The prevalence of depression among the MS population at large has not been well studied and is probably lower than that among patients attending specialized clinics. Many studies of depression among MS patients have been plagued by methodological difficulties.141 Varying diagnostic criteria have been used, including unstandardized tests. Most importantly, factors that affect mood or its assessment are frequently not taken into account. For example, mood can be affected by exacerbations, psychoactive prescription drugs (for example, corticosteroids), and fatigue. Research on depression in MS is complicated by the fact that validated depression rating scales rely, in part, on evaluations of fatigue and other bodily symptoms that are common in MS, and can occur independently of depression.126 The Beck Depression Inventory (BDI), which is one of the most widely used depression scales, evaluates depression based on responses to 21 questions, including many that ask about symptoms that overlap with those of MS. For example, subjects are asked whether they get tired more easily than they used to or whether they worry a lot about health problems. Positive answers to such questions from people with MS might have little to do with depressed mood and might simply reflect a realistic appraisal of their condition. Thus, it seems likely that scales such as the BDI would tend to overestimate depression in people with medical conditions that produce certain symptoms. One study that used different scales to measure depression among MS patients found that the apparent prevalence of depression among MS patients varied, depending on the scale used. When only the mood scale was used for the Multiple Depression Inventory (MDI), a self-report depression scale, 18 percent of patients were rated as depressed, in contrast to 31 percent rated with the BDI and 27 percent when the total MDI scale was used.126 Another study found little difference between the scores of MS patients and healthy controls, except for questions about sexual disinterest for which MS patients exceeded healthy controls.2 This potential tendency for spurious increase in depression has been noted for other medical conditions and should be carefully evaluated.23,26 Although much of the research on depression and MS has focused on the existence of major depressive syndromes, many MS patients suffer from mood alterations that are consistent with depression but do not qualify as major depressive disorder.76,126 Association with Other Symptoms Depression is not clearly related to the severity or type of disability, type of MS, or duration of symptoms.52,134 Measures of depression are not related to EDSS values. However, depressive symptoms interfere with daily functioning in

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Page 122medically well individuals as well as in those with chronic disease. Depressed patients tend to function worse in their work, physical, and social roles compared to patients with a variety of medical conditions, including advanced coronary artery disease, arthritis, diabetes, and lung problems.189 Depression also appears to increase the burden of disability. Smith and Young162 found that MS patients who met criteria for depression on either the Hospital Anxiety and Depression Scale (HADS) or the Beck Depression Inventory were three times more likely than nondepressed patients to perceive their disability as being greater than their physician did. Depression is often associated with other neurological symptoms of MS, particularly cognitive impairment, fatigue, and pain, although, as discussed earlier in the section on cognitive impairment, the data on the link between depression and cognitive impairment are inconsistent. These other symptoms can be worsened by depression or can themselves increase depression. For example, depressed MS patients have reduced working memory capacity (reading span),7 and it is important to establish which causes which or if both are independently caused by the same factors. Both mental fatigue and total fatigue are correlated with depression.61,93 Depression and disability are significant predictors of fatigue,93 although as noted above, fatigue is used as an indicator of depression and thus the correlation might be overestimated. Depression has been linked to cognitive impairment in numerous studies, but these have generally been cross-sectional studies in which comparisons are made between different groups of patients tested at a single point in time. Interestingly, the only study that compared depression and cognitive function in individual patients who were tested at times when they were not depressed and during bouts of major depression found no significant correlation between depression and cognitive performance.154 While the causes of depression in MS are likely multifactorial, several pathophysiological correlates have been reported. Depression is far less common in patients with lesions that are restricted largely to the spinal cord as opposed to the brain.136 Measures of brain atrophy, such as enlargement of subarachnoid spaces (sulci, fissures, cisterns) and enlargement of ventricles, are associated with depression in MS patients (reviewed in 2000 by Bakshi et al.).10 Recent MRI studies have reported that white matter lesions in the frontal and parietal areas of the brain are correlated with depression, suggesting that those lesions might lead to depression by disconnecting the cortical areas in the brain that regulate mood.10 Suicide As with depression, suicide rates in MS patients are high. The rate of suicide attempts among a group of MS patients who used hospital services in Nova Scotia was three times that of the general population.59 The suicide rates among Danish women and men with MS are, respectively, 50 and 70 percent greater than those of the general Danish population.169 It is sobering to note that about one in

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Page 123five patients who ended their lives with Dr. Kevorkian had MS. (He is the assistedsuicide advocate who presided over 47 deaths in the United States from 1990 to 1997.)43 Risk factors of suicide for men with MS include mental disorders (which includes depression), recent exacerbations, and moderate disability; risk factors for women with MS are not distinct.168 That study did not include social factors in the analysis of risk factors, but another study reported that people with MS who experience physical decline but have supportive relationships are less likely to commit suicide than those without such relationships.102 Depression is generally associated with an increased risk of suicide; about 15 percent of all people with major depression commit suicide.141 Recognition and treatment of depression thus is an important tool in suicide prevention.168 Treatment Depression and anxiety among MS patients are often unrecognized and untreated.50 Although there is a general consensus that depression in MS can often be effectively treated (treatments are listed in Table 3.1), there are few controlled clinical trials of antidepressant treatment in MS. A small double-blind study indicated that desipramine was effective in the treatment of depressive symptoms, although anticholinergic side effects limited the dose that could be given.155 However, the study did not examine the effect of antidepressant treatment on the functional abilities or perception of disability in these patients. Another study reported that response to pharmacological treatment for depressive symptoms among MS patients was “extremely high,” as was the relapse rate after discontinuation of the medication.156 In that study, conducted in 1996, 51 out of 228 patients (22 percent) received pharmacological treatment for depression. In addition, treatment of depression improves adherence to beta-interferon (IFN-β) therapy (reviewed in 1999 by Walther and Holfeld185). Even an eight-week treatment of cognitive behavior therapy administered by telephone has been reported to improve adherence.117 Studies conducted in the 1980s reported that as many as 40 percent of MS patients with depression did not receive appropriate treatment (reviewed in 1994 by Fischer et al.56). Paradoxically, a survey of MS practitioners suggested that they tend to overestimate the prevalence of major depression in MS.56 The median estimate made by MS practitioners was that 30 percent of MS patients are depressed at any one time, which is higher than estimates of most studies based on validated depression rating scales.126 Depression as a Side Effect of Interferon Therapy Based on early clinical trial results, depression is listed as a possible side effect of beta-interferon therapy in MS. However, the data are contradictory (Table 3.2).185 Patients in the first large, controlled North American clinical trial

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Page 124 TABLE 3.1 Medications Used to Treat Depression Trade Name Generic Name Mechanism Elavil153 Amitriptyline A tricyclic antidepressant. Amitriptyline is metabolized to nortriptyline, which is an active metabolite. Has significant anticholinergic and sedative effects, with moderate orthostatic hypotension. Has very high ability to block serotonin uptake and moderate activity with respect to norepinephrine uptake. Pamelor69 Nortriptyline A tricyclic antidepressant. Studies suggest that nortriptyline interferes with the transport, release, and storage of catecholamines. Operant conditioning techniques in rats and pigeons suggest that nortriptyline has a combination of stimulant and depressant properties. (SSRI), meaning that it blocks serotonin from Paxil123,153 Paroxetine Paxil is a selective serotonin reuptake inhibitor being reabsorbed into the sender nerve cell. This process increases the amount of serotonin available to be absorbed by the next cell and may help message transmission. Prozac115,123,153 Fluoxetine hydrochloride An SSRI that increases serotonin levels in the midbrain. Tofranil153 Imipramine A tricyclic antidepressant. In MS it is used to treat bladder symptoms, including urinary frequency and incontinence, and also for the management of neurologic pain. Wellbutrin153 Bupropion hydrochloride Mechanism of the antidepressant effect of bupropion is not known. It is a weak blocker of the neuronal uptake of serotonin and norepinephrine; it also inhibits the neuronal reuptake of dopamine to some extent. Zoloft115,123,153,157 Sertraline Zoloft is an SSRI that blocks serotonin from being reabsorbed into the sender nerve cell. This process increases the amount of serotonin available to be absorbed by the next cell and may help transmission of nerve cells.

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Page 125 Potential Side Effects Dryness of mouth, constipation, increased appetite and weight gain, dizziness, drowsiness, decreased sexual ability, headache, nausea, unusual tiredness or weakness, unpleasant taste, diarrhea, heartburn, increased sweating, vomiting Dizziness, drowsiness, headache, decreased sexual ability, increased appetite, nausea, unusual tiredness or weakness, unpleasant taste, diarrhea, heartburn, increased sweating, vomiting Decrease in sexual drive or ability, headache, nausea, problems urinating, decreased or increased appetite, unusual tiredness or weakness, tremor, trouble sleeping, anxiety, agitation, nervousness or restlessness, changes in vision including blurred vision, fast or irregular heartbeat, tingling, burning, or prickly sensations, vomiting Anxiety, nervousness, insomnia, fatigue, tremor, sweating, gastrointestinal distress, anorexia, diarrhea, dizziness, decreased libido Dizziness, drowsiness, headache, decreased sexual ability, increased appetite, nausea, unusual tiredness or weakness, unpleasant taste, diarrhea, heartburn, increased sweating, vomiting Restlessness, agitation, anxiety, insomnia, delusions, hallucinations, psychotic episodes, confusion, paranoia, weight loss Nausea, diarrhea or loose stools, tremor, trouble sleeping, drowsiness, dry mouth, decreased appetite, weight loss, sweating, anxiety, or decreased sexual drive

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Page 166 Multicenter clinical trials are essential to evaluate currently available treatments, especially for the constant dysesthetic pain that is currently the most refractory of the multiple pain syndromes accompanying MS. Cannabinoids might be particularly promising for patients with spasticity but should also be evaluated for other nonparoxysmal pain complaints. To establish whether acute disease activity is associated with pain, an effort should be made to correlate new-onset clinical signs, MRI with gadolinium, and pain location, quality, and time course. Response to anti-inflammatory agents could be studied as well. Continued efforts should be made to understand the pathophysiology of a neuropathic pain, including the continuous dysesthetic pain that occurs in patients with demyelinating diseases such as MS. Efforts to understand abnormal expression of ion channels in demyelinated neurons appear promising. The extensive literature on spinal cord injury and pain offers a number of models that could be extended to this type of study so that it can address demyelinating lesions (for example, Brewer and Yezierski, 199821). In addition, although it is difficult to assess continuous pain in animals, the mouse models for inflammatory demyelination offer an area where parallel human and animal work could progress. Lesion Location A specific attempt should be made to identify patients with new-onset continuous dysesthetic pain for functional imaging in a concerted effort to locate the relevant pathology. In these patients, quantitative sensory testing should be carried out, especially to assess spinothalamic tract function (heat, heat pain, cold, cold pain). In addition, examination should look for signs of a hyperpathic state (summation, sensory radiation, pain with light mechanical stimulation [allodynia]). With these data in hand, it might be possible to move closer to determining whether the animal model mirrors the human pain problem. Studies on Nervous System Inflammation and Pain It appears likely that inflammation per se can lead to abnormal hyperexcitability of pain-signaling neurons. By understanding the underlying molecular mechanisms, it may become possible to devise better interventions. REFERENCES 1. Aikens JE, Fischer JS, Namey M, Rudick RA. 1997. A replicated prospective investigation of life stress, coping, and depressive symptoms in multiple sclerosis. J Behav Med.; 20: 433-45.

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