Emily Evans1, Elizabeth Silbermann1,2, and Soe Mar3
1 Neurology Resident, Washington University in St. Louis, St. Louis, MO, USA
2 Department of Neurology, Oregon Health and Science University, Portland, OR, USA
3 Neurology and Pediatrics, Division of Pediatric Neurology, Washington University in St. Louis,
Multiple sclerosis (MS) is a chronic inflammatory disorder affecting the central nervous system. MS affects almost 2.3 million people worldwide and approximately 250,000–400,000 people in the United States. MS primarily affects the white matter with pathology characterized by the inflammatory plaque. Inflammatory plaques exist throughout the brain, spinal cord, and optic nerves with their locations corresponding to a myriad of clinical symptoms including weakness, numbness, bowel and bladder symptoms, vision loss, or other neuropsychiatric symptoms.
Inflammation in MS occurs in several phases and manifests with considerable variability. Our initial understanding of the pathophysiology of this disease focused on the inflammatory plaque. Inflammatory plaques are often characterized by their temporal pattern and their degree of inflammation. Early inflammatory plaques feature monocytes and lymphocytes with T‐cell predominant perivascular cuffing and demyelination. Early on, the blood–brain barrier remains intact with limited inflammation. Between six and twenty weeks of disease progression, lesions begin to show inflammatory infiltrates. Chronic plaques, on the other hand, feature hypo‐cellularity and glial scarring with varying degrees of active inflammation present at the plaque margin (Wu & Alvarez, 2011).
The robust presence of T cells in inflammatory lesions prompted investigation into their involvement in neuronal destruction. Several studies in animal models of MS have demonstrated that autoreactive CD4 cells and to a lesser extent CD8 cells lead to a phenotype similar to MS. There are ongoing investigations into the role of a particular lineage of CD4 T cells, TH17 cells, which secrete IL17, a proinflammatory cytokine. In experimental autoimmune encephalomyelitis (EAE), a commonly utilized animal model of MS, TH17 cells, participate in the robust inflammatory response seen in early CNS lesions (Ontaneda, Hyland, & Cohen, 2012). Further, human studies have shown that both the peripheral blood and cerebral spinal fluid (CSF) of patients with MS contain a greater proportion of TH17 cells than do controls. TH17 cells are found in perivascular infiltrates that further support their role in allowing penetration of the blood–brain barrier. B cells are also involved in CNS damage. While acute plaques feature robust active inflammation, chronic plaques often feature complement deposition and plasma cells (Weissert, 2013). This involvement is not entirely surprising; the presence of oligoclonal bands in the CSF of patients is highly suggestive of, although not specific for, a diagnosis of MS. In addition, B‐cell follicles have been reported in the meninges of patients with secondary progressive MS and have also been reported underlying pathology in the corresponding cortical gray matter. The exact target of these clonal B cells and their antibodies remains unclear but is an important area of ongoing research.
While MS was initially defined by abnormalities noted in plaques, there is now substantial evidence that pathology exists in normal‐appearing white matter (NAWM) and dirty‐appearing white matter (DAWM) (Moore et al., 2008). These extra‐lesional areas feature perivascular and parenchymal inflammation and have disruption of the blood–brain barrier that promotes proinflammatory cascades, fibrinogen deposition, and resultant demyelination. Similarly, DAWM also features demyelination and axonal loss. While the implications of NAWM and DAWM remain unclear, it does provide further evidence that MS exists as a more global inflammatory process as opposed to a clearly focal process.
In addition to white matter disease, postmortem studies have provided robust evidence that MS also involves gray matter structures (Gilmore et al., 2009). The cortex is frequently disrupted in MS with cortical pathology demonstrating demyelination, inflammation, and cell death. Similar to white matter lesions, this damage occurs both within discrete lesions as well as in normal‐appearing gray matter. The functioning of areas such as the prefrontal cortex, cingulate cortex, and hippocampus is preferentially affected, which explains the dysfunction in domains of executive function, learning, information processing, and memory displayed by MS patients. Finally, disruption of deep gray matter structures, including the thalamus and basal ganglia, is also seen. Atrophy in both the cortex and deeper gray matter regions leads to more global cognitive dysfunction that ultimately contributes to significant morbidity and potentially mortality in MS patients.
Cognitive impairment is a common complaint among MS patients and leads to considerable disability. The true prevalence of cognitive impairment varies by study; however, it is generally accepted that between 40 and 65% of MS patients experience it (Bobholz & Rao, 2003). Cognitive changes in MS are not clearly tied to disease duration or physical disability. In fact, cognitive changes can occur very early in the disease course and can even precede the diagnosis. Cognitive issues can worsen acutely during a relapse but persist even between relapses and often progress over time. Cognitive impairment seems to be more profound in the progressive subtypes of MS than in the relapsing subtypes.
The cognitive impairment in MS is not global, but rather preferentially affects individual cognitive domains. For example, processing speed is commonly slow in patients with MS. Processing speed involves one’s ability to take in new information, manipulate it, and apply it to his environment. Attentional domains are also very commonly affected, especially sustained and shifting attention. When tested, patients with MS score poorly on tasks requiring them to divide their attention and attend to multiple tasks simultaneously. Other very commonly affected domains include visual memory, executive functioning, visual perception, and long‐term memory. Visual perception is often confounded by poor visual acuity as many patients with MS have suffered optic neuritis and have residual deficits in visual acuity. However visual perception deficits also occur independently of visual acuity loss. With regard to long‐term memory, the problem with memory is usually one of encoding memories and reflective of the poor attention of said patients. Conversely domains like language processing and naming are usually spared.
Cognitive impairment has real consequences for patients with MS and results in decreased productivity at work, high rates of unemployment, disrupted social relationships, and less ability to live independently. Cognitive deficits correlate with objective difficulties completing instrumental activities of daily living, such as managing one’s finances and medications, and with worsened scores on subjective quality of life (QOL) measures as reported from a patient’s perspective (Cutajar et al., 2000). QOL can be quantified using such tests as the Multiple Sclerosis Quality of Life Inventory or SF36 (part of health status questionnaire). Cognitive deficits can also interfere with the patient–physician therapeutic alliance or patient adherence to prescribed pharmacological or non‐pharmacological treatment regimens.
Cognitive impairment can be measured in various ways. Traditional clinical measures of screening cognition such as the Mini‐Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA) are insensitive to the specific deficits affected in MS. If these are the only screens used to assess MS patients, their deficits and complaints can go under‐recognized and underappreciated for years.
The gold standard for diagnosing cognitive impairment in MS patients is formal neuropsychiatric testing, which involves exposing patients to a battery of tests assessing multiple domains of cognition. However, such testing is time consuming, costly, and not available in all regions. A recent focus in the field has been on developing more clinic‐friendly cognitive screening assessments. Several validated screening assessments are now available, and there has been considerable debate regarding which are the “best” screens. Each varies in regard to sensitivities and specificities depending on the specific domain of cognition one is interested in analyzing. Two of the most commonly utilized assessments include the Minimal Assessment of Cognitive Function in MS (MACFIMS) and Brief International Cognitive Assessment for MS (BICAMS). The MACFIMS is a ninety‐minute battery, consisting of seven tests that was created by the consortium of MS centers that has been validated both in MS patients and in healthy controls (Benedict et al., 2006). The BICAMS is a fifteen‐minute test created by an international expert consensus committee and includes the symbol digit modalities test (SDMT), California Verbal Learning Test second edition (CVLT‐II), and revised Brief Visuospatial Memory Test (BVMT‐R) (Langdon et al., 2012). The BICAMS is designed to be administered by any healthcare practitioner and would not require formal neuropsychiatric training. It is currently undergoing validation studies in multiple countries.
One recent focus in the field has been on developing a computerized or Internet‐based screening test to ameliorate some of the cost and availability issues of our current screening methods. Several such screens have been developed and validated, such as the thirty‐minute Cognitive Stability Index (Younes et al., 2007), but none have yet been widely incorporated into clinical practice.
Pathophysiologically, it is not known what the exact cause of the cognitive dysfunction in MS is. Likely it is a combination of both gray matter and white matter damage (as detailed earlier in the pathophysiology of MS section) and the resultant atrophy associated with these inflammatory changes in the brain.
The cognitive changes in MS do correlate with quantifiable radiographic changes such as MRI patterns of cerebral atrophy. Both gray and white matter atrophy have been implicated. A recent review article published in Lancet (Rocca et al., 2015) compiled a table of more than thirty recently published studies reporting associations between cognitive function and radiographic measures of either white matter lesions, gray matter lesions, or total brain atrophy. For example, associations have been demonstrated between cognitive impairment and total lesion areas, T1 lesion volumes, T2 lesion volumes, FLAIR lesion volumes, the size of the corpus callosum, and the third ventricular width (Rocca et al., 2015). Moreover, cortical lesions burden has been associated with cognitive disability in MS. No one measure has been shown to fully explain or predict cognitive performance, and research remains ongoing in the field.
Several agents including disease‐modifying therapies aimed at tempering the inflammatory process in the CNS have been shown to decrease acute clinical relapses and decrease radiographic lesion burden among patients with MS. It is possible that these therapies slow the rate of progressive cognitive impairment; however no studies yet exist that clearly demonstrate this. No pharmacological therapies have yet been proven to reverse cognitive impairment among MS patients. Nonetheless several agents are used for symptomatic treatment of cognitive impairment in MS. These include stimulants (such as methylphenidate, amphetamine, and modafinil), cholinesterase inhibitors (such as donepezil, galantamine, and rivastigmine), and N‐methyl‐D‐aspartate (NMDA) receptor antagonists (such as memantine). A recent Cochrane review of the literature concluded that there is no convincing evidence that any of these agents were effective (He, Zhou, Guo, Hao, & Wu, 2011). Further investigations into pharmacotherapy to treat MS‐related cognitive impairment are warranted.
Cognitive rehabilitation is a non‐pharmacological form of treatment being increasingly explored to combat MS‐related cognitive impairment. Cognitive rehabilitation is an individualized treatment regimen, which combines restorative techniques with compensatory activities. Restorative techniques are designed to help restore normal brain functioning to a previously damaged area and focuses on repeated exposures and practice to harness the brain’s natural repair mechanisms and plasticity. Conversely compensatory techniques focus on finding ways around the cognitive difficulties a patient has by utilizing what remaining domains a patient has. For example, behavioral interventions like employing reminders such as personal organizers, calendars, or alarms can be useful for patients with attentional or working memory difficulties. Studies have showed that cognitive rehabilitation strategies can both improve a patient’s quality of life and lead to improved performance on memory tasks.
Both mood disorders and fatigue are very prevalent in MS patients with estimates that up to sixty and ninety percent of patients suffer from these conditions, respectively. Depression and other emotional disorders are associated with reduced functioning, reduced adherence to medical therapies, and overall decreased quality of life. The lifetime prevalence of major depression in patients with MS is elevated and estimated at 46–54% versus 16.2% in the general public (Minden et al., 2014). In addition, MS patients are more likely to have clinical diagnoses of anxiety, and suicide is twice as common in the MS population relative to controls. Recent studies suggest a relationship between depression and demyelination, particularly when demyelination involves the limbic system. Functional MRI studies have shown differences in activation between the prefrontal cortex and the amygdala in patients with concurrent MS and depression. Similar studies have also shown patients with concurrent MS and affective disorders had overall higher global disease burdens suggesting a link between structural damage and comorbid psychiatric disease.
Fatigue is also highly prevalent in MS patients. Patients complain of both cognitive and global fatigue. Researchers have demonstrated an association between cognitive fatigue and slower information processing (Andreasen, Spliid, Andersen, & Jakobsen, 2010). The impact of global fatigue, however, has been more difficult to quantify. Radiographic studies have correlated global fatigue with preferential frontoparietal cortical atrophy and disruption of frontal and parietal pathways (Sepulcre et al., 2009). Recent studies have utilized fMRI scanning to explore MS subjects undergoing cognitive evaluation of working memory and attention via Paced Auditory Serial Addition Test (PASAT) or the Paced Visual Serial Addition Test (PVSAT). Subjects with MS have demonstrated more sustained and widespread cortical activation despite worse task performance. It was hypothesized that this may contribute to “neural fatigue.” The interplay between fatigue and cognitive dysfunction requires further investigation.
Screening for fatigue and affective disorders like depression is very important, because when untreated, such conditions lead to disability. Independent evaluation of these disorders is challenging as fatigue, depression, and cognitive impairment are intricately linked. A few screening tools are currently available. Fatigue can be assessed using validated scales such as the Modified Fatigue Impact Scale (MFIS), Fatigue Severity Scale (FSS), or the Chalder Fatigue Scale. Depression can be assessed using the Beck Depression Inventory. In addition, the General Health Questionnaire can be useful in evaluating more globally for difficulty in regulating emotions. Finally, the Center for Neurologic Study Emotional Lability Scale can be useful in detecting pseudobulbar affect, which can be another important consideration in evaluating depression in MS patients. Clinicians must carefully consider the confounding impact of other related factors, such as insomnia, restless legs syndrome, and circadian rhythm abnormalities, all of which are experienced by MS patients and can influence both fatigue and depression.
Emily Evans, MD, completed her undergraduate studies at Tulane University and earned a medical degree from the Perelman School of Medicine at the University of Pennsylvania. She completed her residency training in neurology at Washington University in Saint Louis. She is currently a clinical fellow in neuroimmunology at the John L. Trotter MS Center associated with Washington University in Saint Louis where she is specializing in the clinical care of patients with MS and the conduct of clinical trials related to MS.
Elizabeth Silbermann, MD, completed her undergraduate studies at Brown University and earned a medical degree at Warren Alpert Medical School, Providence, RI. She completed a residency in neurology at Washington University School of Medicine in Saint Louis, where she distinguished herself as a neurology chief resident. She is currently a neuroimmunology fellow at Oregon Health and Science University. She is the recipient of a National MS Society sponsored Sylvia Lawry Physician Fellowship grant and is currently involved in Phase I, Phase II, and observational trials of drug and rehabilitation interventions.
Soe Mar, MD, completed her undergraduate and medical school training in Myanmar. She completed her residency and fellowship training at the Albert Einstein College of Medicine in New York, NY. She is the program director of the Pediatric Neurology Residency Training Program at Saint Louis Children’s Hospital (SLCH) associated with Washington University in Saint Louis. She is also the director of the Pediatric Multiple Sclerosis & Demyelinating Disease Center at SLCH, which is one of twelve nationwide National MS Society (NMMS) recognized pediatric MS centers. She has been the recipient of numerous distinguished teaching awards and published more than seventy papers relating not only to MS but also to leukodystrophies, headache disorders, and CNS lymphomas to name a few.