Insights Into Mood and Cognitive Disability in MS: Recognition and Treatment


Depression and cognitive impairment are common in patients with multiple sclerosis (MS) but often are overlooked. These complications affect not only general quality of life but also complicate core symptoms of the disease. Depression in MS is well documented and easily treated while cognitive impairment sometimes needs a sharper eye to detect.

Depression and cognitive impairment are common in patients with multiple sclerosis (MS) but often are overlooked. These complications affect not only general quality of life but also complicate core symptoms of the disease. Depression in MS is well documented and easily treated while cognitive impairment sometimes needs a sharper eye to detect.

A recent survey confirmed what experts in MS have long known: depression in patients with MS is underrecognized and, for the most part, goes untreated. Mohr and colleagues1 found that 67% of patients with MS who met strict criteria for major depression received no antidepressant medication whatsoever.

Depression goes unrecognized and untreated to the same extent in other medical settings and for largely the same reasons: the economics of medical care limit the amount of time that the clinician can devote to both initial and follow-up visits. There is only so much that a physician can accomplish in 15 minutes, and patients with MS require attention to a wide range of symptoms-some more obvious and pressing than depression, points out Joseph Friedman, MD, clinical professor of neurology at Brown Medical School in Providence, Rhode Island.

The prevalence of major depression in patients with MS is extraordinarily high-about 50% of patients will have an episode of depression at some point after an MS diagnosis.2 This prevalence is considerably higher than that seen in both the general population and in patients with other chronic disabling conditions, including those that are neurological.3 Depression also has a profound impact on key features of the illness. It shapes the way patients view their symptoms, particularly cognitive abilities, and it directly contributes to fatigue, the most common symptom of MS. Depression also can affect adherence to disease-modifying medications (DMMs) and thus the course of the illness.

A limited number of studies have evaluated treatment of depression in patients with MS. The findings of these studies, however, are consistent with clinical experience in showing that depressed patients with MS respond to both antidepressants and psychotherapy as well as depressed patients in the general population.

"The nice thing about depression is that it's easy to treat," said Darcy Cox, PsyD, assistant clinical professor of neurology at the University of California, San Francisco. She has spent 7 years at the university's Multiple Sclerosis Center studying the psychological characteristics of MS. Cox believes that neurologists should consider depression as "something to manage along with other symptoms of MS such as spasticity and bladder dysfunction." If the neurologist is comfortable treating the depression, he or she should do so, Cox said. If he is not, the patient should be referred for treatment.

Ellen Lathi, MD, director of the MS Center at Caritas St Elizabeth's Medical Center in Boston, also believes in a vigorous approach to depression recognition and management. "Treat depression early and aggressively," she said, adding that she gets a good response in most patients treated with selective serotonin reuptake inhibitors (SSRIs). If an SSRI doesn't work, she switches to another, and occasionally she turns to bupropion (Wellbutrin).

In Lathi's estimation, about 30% of her patients with MS and depression are referred for additional psychiatric treatment because they have complicated emotional problems, have not responded to several courses of medication, or have additional psychiatric disorders.

Although academic psychiatrists and some professional guidelines about clinical depression advocate the use of formal, validated screening questionnaires, both general neurologists and MS experts tend to steer clear of them. They rely instead on clinical observation and a few pointed questions.

Lathi's approach is typical. If a patient sounds and looks depressed, Lathi asks about his or her mood and ability to carry out usual activities. Research supports this approach. In the general population and among patients with MS, the answers to just 2 questions have been found to detect clinically significant depression with a high degree of sensitivity and specificity: "Have you been consistently depressed or 'down' most of the day, nearly every day for the past 2 weeks?" and "In the past 2 weeks, have you been much less interested in most things or much less able to enjoy the things you used to enjoy most of the time?"4

Like clinical depression in the general population, the basis for depression in patients with MS is unknown. It bears no clear relationship to physical disability, stage or length of illness, or lesion site or extent.2,5 Experts differ on the part played by the symptoms and disabilities that come with MS, the damage to work and social life, and the disease process itself.

Table - Two key questions that can identify clinical depression
Have you been consistently depressed or"down" most of the day, nearly every dayfor the past 2 weeks?

The symptoms of MS, particularly the fatigue and pain, may contribute significantly to the depression that accompanies this illness, according to Syed Rizvi, MD, clinical assistant professor of neurosciences at Brown University and director of Rhode Island Hospital's Multiple Sclerosis Center in Providence. He also theorizes that the high prevalence of depression in MS may be related in part to the fact that women are more predisposed to MS and to depression than men, so that in a select patient population in which women predominate, depression rates will be higher than in a mixed population or a population in which men predominate.

Lathi doesn't know why these patients become depressed, but she is not convinced that the depression is "disease-specific." Like Rizvi, she thinks that the high prevalence of depression may in part be an "artifact of the predominance of women in the MS population."

Cox, on the other hand, is struck by the high prevalence of depression in MS in comparison with other disabling conditions. She said that although social isolation and symptoms of MS such as pain play roles, the disease process itself contributes to depression. Inflammatory lesions and frontal lobe dysfunction could be at play, she said. She also pointed to the relatively high prevalence of depression in other autoimmune conditions such as lupus and rheumatoid arthritis. Cox would like to see more research into disease-specific factors related to depression.

Although some early studies suggested that treatment with interferon (IFN)-ß might precipitate depression, subsequent controlled research, clinical experience over the past decade, and a recent review of the existing data indicate that IFN-ß does not pose a significant risk of depression.6

Cox suggests that the inconsistencies on this matter in the early literature could have arisen from the observation that IFN-ß treatment may precipitate depression in a small subset of vulnerable patients. Lathi, a strong advocate of disease-modifying therapy, said that depression is not a reason to discontinue the therapy. If depression develops in a patient receiving a DMM, the patient should continue to take the DMM and be treated for depression, according to Lathi.

Although depression in MS has been well documented, the subtle cognitive impairment that afflicts about half of patients with MS has come to light in only the past 20 years. Recognition of this impairment has obliged both researchers in MS and clinicians to think differently about the effect of the disease process on cognition, the disability that the disease brings, and the type of rehabilitation that patients with MS require.

According to Cox, the old idea about cognition in MS was that "patients are either fine from a cognitive standpoint or horribly demented." She believes that this notion came to some extent from Jean-Martin Charcot (1825-1893) and the neurologists of his era whose patients had severe forms of MS that were sometimes accompanied by dementia. In fact, dementia is uncommon in MS; when it occurs, it tends to do so late in the disease.4 But research has shown that about 50% of patients with MS have cognitive deficits that-although more subtle than dementia-produce significant disability.4,7

Cognitive impairment can occur early in the course of illness, even before the second relapse, pointed out Christopher Christodoulou, PhD, assistant professor at the State University of New York at Stonybrook. He has been studying cognitive function in MS for much of the past decade. Rates of cognitive impairment may be slightly higher in the progressive than in the relapse-remitting forms of the disease but they occur in all forms and stages of the illness, he said. Most frequent are deficits in memory, information processing, concentration, and attention.

Slowed information processing is particularly problematic, said Cox. Deficits in information processing make it difficult for patients to learn new things, to keep up at meetings, and to do jobs that require multitasking. For example, it might take a cognitively impaired patient with MS 8 hours to learn a new computer system that ordinarily takes a person 1 hour to learn, said Cox.

Cognitive impairment may be the most serious consequence of the disease, said Christodoulou. It is a better predictor of overall function than physical disability, he said. Patients with MS who suffer from cognitive impairment have higher rates of divorce and unemployment compared with patients who have MS without cognitive impairment, he said. In fact, although most cognitively impaired persons continue to work, cognitively impaired persons with MS find that they cannot. Indeed, cognitive impairment is the main reason why these persons stop working.

Unless the clinician is explicitly on the lookout for cognitive impairment, it is often missed, said Christodoulou. The usual assessment of mental status and familiar instruments such as the Mini-Mental State Examination are fine for detecting dementia but do not pick up the more subtle cognitive deficits seen in MS. Formal rating scales that screen for cognitive impairments are available-the Multiple Sclerosis Neuropsychological Screening Questionnaire8 and the Brief Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis9 are among them-but they are not yet widely applied outside research settings. MS experts, such as Lathi, rely on clinical impression or "eyeballing the patient" to identify significant impairment.

Listening carefully to what patients say about their mental abilities is a key first step in identifying cognitive dysfunction, but the impression of a patient's spouse, other family members, or caregivers is essential for accurate assessment, said Cox. Patients, particularly when they are depressed, tend to see themselves as worse than they are. Research shows that an informant's impression of the patient's cognitive performance correlates more closely than does the patient's report with neuropsychological test performance.8 Noteworthy for clinicians is the finding from recent research that although patients are not particularly accurate when they appraise their cognitive performance at a single point, they are quite accurate in detecting changes in their cognitive performance over time.10

Formal neuropsychological testing is the most trustworthy way to detect cognitive impairment and offers the most comprehensive picture of a patient's cognitive status, but such testing is time consuming, expensive, and not always readily available. Neuropsychologists and clinicians specializing in MS care agree that such testing is clinically useful only in select situations.

Christodoulou suggests that neuropsychological testing should be considered when patients are distressed by cognitive changes, when they report problems at work, when their cognitive function changes significantly over time, or when spouses complain about the patient's cognitive function. The results of neuropsychological tests document deficits and can inform treatment and rehabilitation.

One of the reasons why cognitive impairment in MS creates such disability is because there are no good solutions for it. "If someone has trouble walking, they can get around in a wheelchair or with a cane, but cognitive impairment can't be so readily managed," said Lathi.

Some uncontrolled studies and a few small controlled ones suggest that the cholinesterase inhibitors, such as donepezil (Aricept), provide some improvement.7 More controlled studies are under way.

Although the DMMs do not appear to appreciably improve cognitive functioning, they do seem to preserve it and slow the rate at which it worsens.4 This beneficial effect should not come as a surprise, said Lathi. Brain imaging data indicate that cognitive impairment is correlated both with lesion lode and cerebral atrophy.4,11 Furthermore, the DMMs help resolve lesions that lead to atrophy. For Lathi, the effects of DMMs on cognition is another argument for their use and for encouraging patients to adhere to treatment with them.

Christodoulou emphasizes that all patients with MS and cognitive impairment benefit from learning the tactics that can help them compensate for cognitive deficits. This approach, he said, is far more effective for these patients than cognitive remediation, which is the other approach to cognitive rehabilitation that seeks to alleviate deficits through various forms of practice.

Patients need a toolbox of techniques that use their intact skills to compensate for deficits, said Christodoulou. For example, patients can counter memory problems by always leaving items such as keys in the same place, keeping notes regarding meetings and conversations, and visualizing the things they need to remember if verbal memory is poor. External aids such as handheld computers, electronic calendars, and schedules can help as can modifications to the home and work environments.

Patients should be encouraged to avoid multitasking and to hold conversations in quiet places to enhance information processing and concentration. These and other compensation strategies need to be tailored to the individual patient. Neuropsychologists, occupational therapists, social workers, and physical therapists familiar with MS are the health professionals who can provide help.


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2. Siegert RJ, Abernethy DA. Depression in multiple sclerosis: a review. J Neurol Neurosurg Psychiatry. 2005;76:469-475.
3. Minden SL, Schiffer RB. Affective disorders in multiple sclerosis: review and recommendations for clinical research. Arch Neurol. 1990;47:98-104.
4. Mohr DC, Cox D. Neuropsychiatric disorders in multiple sclerosis. In: Jeste DV, Friedman JH, eds. Current Clinical Neurology: Psychiatry for Neurologists. Totowa, NJ: Humana Press Inc; 2006:177-189.
5. Feinstein A. The neuropsychiatry of multiple sclerosis. Can J Psychiatry. 2003;49:157-163.
6. Goeb JL, Even C, Nicolas G, et al. Psychiatric side effects of interferon-beta in multiple sclerosis. Eur Psychiatry. 2006;21:186-193.
7. Krupp LB, Christodoulou C, Melville P, et al. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology. 2004;63:1579-1585.
8. Benedict RH, Cox D, Thompson LL, et al. Reliable screening for neuropsychological impairment in multiple sclerosis. Mult Scler. 2004;10:675-678.
9. Rao SM; Cognitive Function Study Group of the National Multiple Sclerosis Society. A manual for the brief, repeatable battery of neuropsychological tests in multiple sclerosis. Milwaukee: Section of Neuropsychology, Medical College of Wisconsin; 1990.
10. Christodoulou C, Melville P, Scherl WF, et al. Perceived cognitive dysfunction and observed neuropsychological performance: longitudinal relation in persons with multiple sclerosis. J Int Neuropsychol Soc. 2005;11:614-619.
11. Christodoulou C, Krupp LB, Liang Z, et al. Cognitive performance and MR markers of cerebral injury in cognitively impaired MS patients. Neurology. 2003;60:1793-1798.

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