Invisible Symptoms of MS

11
Invisible Symptoms of MS: Fatigue, Depression, and Cognition

Leigh E. Charvet¹, Benzi Kluzer², and Lauren B. Krupp¹

¹ Department of Neurology, Stony Brook Medicine, Stony Brook, NY, USA

² Department of Neurology, University of Colorado, Denver, CO, USA

Introduction

Fatigue, cognitive dysfunction, and depression are often referred to as the invisible symptoms of multiple sclerosis (MS). These symptoms each have the potential to be the most disabling symptoms of the disease but can be missed on routine physical examination. Further, patients may not mention these symptoms unless specifically questioned. Therefore, it is critical for the clinician to directly address each of these symptoms in the MS patient and manage them appropriately. This chapter will review the prevalence, impact, physiology, recognition, and management of each of these symptoms.

Fatigue

Fatigue is the most common symptom reported by MS patients, affecting approximately three-fourths of all patients, and is a leading contributor to decrements in quality of life. Fatigue is also reported by 40% of patients to be their most disabling symptom, more so than any other symptom including weakness or ataxia, and can contribute to unemployment as well as early retirement. It has been associated with feelings of loss of control over one’s environment. Fatigue in MS occurs among all MS subtypes, can persist over years, but can also be seen acutely during relapses. Like other MS symptoms, it can be exacerbated by heat.

Assessment

Fatigue is typically viewed as a subjective feeling of exhaustion that cannot be fully explained by limb weakness or mood. It is associated with the sense that increased effort is required to perform activities. Fatigability, a closely related concept, refers to objective measurable declines in motor or cognitive function during continuous performance of a task. It is important to distinguish fatigue from related symptoms such as depression and sleepiness as the management is different. Studies have shown that MS subjects have both increased subjective fatigue complaints and objective fatigability of motor and cognitive performance. However, subjective fatigue is not adequately explained by reduced motor or cognitive performance. Clinically significant fatigue and fatigability in MS differ from the normal fatigue seen in healthy individuals in that they may have several of the following features: (1) provoked by minimal or no exertion, (2) unpredictably related to activity, (3) poorly responsive to rest or require disproportionate amount of rest, (4) interfere with daily function, and (5) are chronic.

While fatigue may be intrinsic to the disease process itself, it is essential to rule out potential secondary causes. When taking a history from MS patients complaining of fatigue, it is important to determine whether fatigue onset correlates with changes in medications, mood, pain, or sleep. Antispasticity medications may occasionally be associated with fatigue. Disease-modifying treatments are less clearly linked to fatigue, and some have been associated with reductions in fatigue. Depressed mood often occurs with fatigue, and fatigue can be a symptom of clinical depression. In these cases, there is severe fatigue upon awakening versus the more common pattern of worsening fatigue as the day progresses. While less studied, anxiety and pain may also be related to fatigue. Sleep disorders commonly seen in MS include insomnia, sleep apnea, nocturia, rapid eye movement sleep behavior disorder, periodic leg movements of sleep, and restless legs syndrome. Sleep studies can help elucidate the cause of daytime fatigue and are probably underutilized in MS. Patients experiencing severe fatigue have twice the frequency of sleep disorders as those without fatigue. Finally, routine laboratory tests should be performed to rule out other common causes of fatigue in the general population including thyroid studies, complete blood count (for anemia), a metabolic panel, and infections.

In clinical practice, fatigue is best detected through a thorough history and a directed interview. Fatigue specific scales, such as the Fatigue Severity Scale or Modified Fatigue Impact Scale, may be used to detect and track fatigue but are typically not needed. Fatigability may also provide an explanation for apparent discrepancies in patients who report difficulties with cognitive or motor function in daily activities but perform well on objective (but brief) bedside testing.

Pathogenesis

The pathogenesis of fatigue in MS is likely multifactorial. Several lines of research have provided insight. Neuropsychological studies have shown some correlations between psychomotor slowing and subjective fatigue complains, suggesting that cognitive effort may partially underlie MS fatigue complaints. Anatomical neuroimaging studies demonstrate that cortical atrophy, rather than total white matter burden, is more likely to be associated with fatigue. White matter lesions involving frontal, parietal, and subcortical connections are also associated with fatigue, supporting a hypothesized role of the basal ganglia and frontal lobes in maintaining effort and parietal lobes in maintaining sustained attention. Functional imaging studies further show that patients with fatigue have increased activity in frontal and motor areas even when starting a task, suggesting that patients with fatigue are utilizing more cerebral resources with all activities and thus more susceptible to decompensation with continued performance.

Management

The first issue in the management of fatigue is to determine the extent to which other potential secondary causes of fatigue are present (Figure 11.1). Pain, depression, anxiety, sleep disorders, anemia, or other metabolic disorders should be treated first if detected before proceeding to other aspects of fatigue management. However, fatigue is frequently a primary symptom of MS and may occur without secondary cause and may persist despite successful treatment of secondary causes.

c11-fig-0001 — Figure 11.1 Algorithm for the treatment of fatigue.

For the primary treatment of fatigue, there are several pharmacological and nonpharmacological treatments that may be recommended. Despite several positive clinical trials, the effect sizes are generally small, and the benefit to individual patients is variable, with some patients experiencing meaningful benefit but many noting no improvement.

Among nonpharmacological interventions, exercise consisting of either aerobic activity or strength training can reduce fatigue. Patients should be encouraged to start at low levels of intensity and go up slowly to avoid exacerbating fatigue. Excessive heat should be avoided, and use of cooling jackets has also been found to decrease fatigue. Psychological and behavioral interventions that have shown efficacy include mindfulness-based meditation, self-efficacy, cognitive behavioral therapy (CBT), and energy conservation strategies.

In patients who fail to benefit or fully respond to nonpharmacological interventions, medications should be considered. Medications that have been studied for MS fatigue include modafinil, amantadine, and methylphenidate. Although not as commonly used in clinical practice, one study noted benefit with aspirin. With fatigue treatments, significant and sustained benefit is the exception rather than the rule. In patients with prior response, drug holidays should be considered, as benefits over time occasionally can become attenuated.

Cognition

Problems with cognitive functioning occur in more than half of all patients with MS. Because of the nature of the disorder, areas of impairment can range widely across patients but typically include slowed processing speed, decreased ability to concentrate and reason, and learning and memory problems. Visuomotor integration skills are also often affected.

Cognitive impairment affects all aspects life quality and can be especially debilitating for patients who are trying to maintain employment and household duties. Cognitively impaired patients are less likely to be socially engaged, are at risk for increased mood problems, and have increased problems with activities of daily living. Cognitive impairment has also been shown to increase caregiver burden. For these reasons, it is often listed as the most disabling symptom of the disorder.

Assessment

Cognitive impairment is difficult to detect, in part, because it is not strongly associated with other measurements of neurologic impairment. Studies have demonstrated no significant correlation between EDSS and cognitive impairment when controlling for mood. Cognitive impairment may also take more subtle forms that can be missed in routine examination.

Interview should include questions to both the patient and significant other (if present) about changes in cognitive functioning. Unfortunately, relying exclusively on the patient’s complaints can be misleading. For example, summary scores of structured patient-completed questionnaires addressing cognitive functions are much more closely associated with mood than with actual performance on neuropsychological tests. Therefore, objective testing is a much more reliable measure of cognitive performance. The routine mental status examination is too insensitive to identify the deficits routinely experienced by individuals with MS. While we have found that the Montreal Cognitive Assessment to be more sensitive than the MMSE, this assessment tool also fails to detect many impaired individuals. One strategy that has been recommended is to perform a routine screen with cognitive tests that are brief and can be administered by a nurse or physician. The Symbol Digit Modalities Test assesses processing speed and takes only a few minutes to administer. The test contains single digits paired with abstract symbols, and participants must say the number that corresponds to each symbol. If more time is available, then expanding the assessment to include two memory tasks, one assessing visual memory and verbal learning and the other measuring verbal memory, can provide a more comprehensive screen. An expanded screen takes approximately 15–20 min to administer. The normative values that correspond to these tests are available on the Brief International Cognitive Assessment in MS website (bicams.net). When there is any concern that cognitive functioning may be affected, formal neuropsychological evaluation is warranted. This evaluation will provide more in-depth detection of areas of cognitive involvement and also provide a baseline to evaluate for treatment effects or further decline. A neuropsychologist experienced with MS should be helpful in providing recommendations for management.