Neuropsychological Functions and Cognitive Neurorehabilitation in Multiple Sclerosis

1. Introduction

Historically the disease today known as multiple sclerosis (MS) has been referred to in the historical medical literature with a variety of terms, including, disseminated sclerosis and sclerose en plaque [1]. Lidwina van Schiedam, was the first potential case of MS dating as far back as 1421, when Jan van Berieren commented on her illness. Records showed that she had difficulties walking, paralysis of the right arm, decreased sensation and visual difficulties [2].

Today we know that MS is a chronic inflammatory autoimmune degenerative disease of the central nervous system (CNS). It is the most common non-traumatic neurological disorder among young adults leading to disability. The etiology of MS involves white matter pathology, cortical atrophy, cortical lesions, and microstructural abnormalities in deep gray matter that impact structural and functional connectivity [3]. Cognitive impairment in MS appears to be a result of this diffuse disruption in brain networks [4]. These patients may also present sensorimotor [5], visual [6], bladder, cerebellar [7] and emotional difficulties leading to functional disability [8] and poorer quality of life [9].

Environmental factors and especially geographical latitude may significantly influence the development of MS. However, genetic susceptibility as is evident from twin studies and familial cases, suggests that MS disease causality is due to a complex interaction between multiple genes and environmental factors, eventually leading to inflammatory-mediated central nervous system deterioration [10]. Genomic studies, with specific HLA antigens (HLA-DR2), have confirmed the genetic susceptibility of MS [10]. Numerous other environmental factors have been evaluated that may be associated with MS, but methodological caveats have casted doubts on their validity. On average, MS patients contracted common childhood illnesses at later ages than healthy controls [11]. A biomarker of Epstein-Barr virus (anti-EBNA IgG seropositivity), infectious mononucleosis, and smoking have shown the strongest consistent evidence of an association. However, additional data and better-designed studies are needed to establish robust evidence [12].

MS disease course is heterogeneous in nature and several types have been described: Relapsing remitting MS (RRMS), Active (with relapses and/or new lesions on MRI), Not Active (no relapses or MRI activity), Progressive MS (Secondary Progressive MS (SPMS) and Primary Progressive MS (PPMS), Active with Progression (relapses/MRI activity and clinical deterioration not due to relapses), Active but without Progression (relapses but no clinical deterioration), Not Active but with Progression, Not Active and without Progression (stable disease) [13]. The use of these terms is primarily for descriptive purposes and for setting reasonable expectations for treatment.

This chapter is not a comprehensive review of the extensive literature on neuropsychological functions and cognitive rehabilitation in multiple sclerosis, but rather a selective review of the most relevant features related to this topic.

2. Neuropsychological functions in multiple sclerosis

Dating back to the seminal writings on MS, Charcot’s observations of the adverse effects that MS exerts on memory, concept formation, and the intellect [14], were underestimated for many decades in the neurology literature. It was only with the emergence of the comprehensive care model in the early 1980s, that the nature and significance of cognitive dysfunction in MS became appreciated. The medical community, due to the often-subtle nature of cognitive deficits in MS, and the difficulty in detecting these deficits during routine clinical practice, was initially slow to appreciate them as a core clinical symptom of MS. Instead, they believed that cognitive impairment was a relatively rare entity in MS, occurred only in advanced cases with a high level of physical disability and was associated with subcortical dementia [15].

Cognitive difficulties are not frequently reported by patients among the initial symptoms of MS, although there is sufficient evidence that cognitive impairment is present from the early stage of the disease (see for e.g., the study by [16], which assessed MS patients neuropsychologically, not more than 2 years after experiencing their first neurological symptoms, and [17], who presents three cases evaluated at different stages of the disease). Moreover, cognitive impairment may be present in the early stages of the disease in patients with relatively low or mild physical disability (see for e.g. the studies by [18, 19] who found cognitive deficits in patients with an EDSS disability score of ≤3.5, that had not yet been influenced significantly in their daily functional abilities and employment status). A recent anatomofunctional study utilizing diffusion imaging and resting state functional MRI, revealed that disconnection in the default mode network (DMN) and attentional networks (ATT), may deprive the brain of the necessary compensatory mechanisms required to face the widespread structural damage during the early course of MS, providing a possible explanation for the cognitive dysfunction in these early stages of the disease [20].

Although it is now commonly accepted that roughly one-half of individuals with MS [21, 22], will experience clinical deficits over the course of the disease, prevalence rates are highly variable and depend to a large extent on the type of MS population studied, the clinical, demographic and sociodemographic characteristics and the year conducted. A recent study that included RRMS and SPMS patients attending an outpatient neurology clinic reported an overall cognitive dysfunction prevalence rate of 53.7% [23]. Moreover, the study by [22], reported that 47% of their MS patients recruited from an outpatient clinical setting, diagnosed with the revised McDonald criteria [24], the majority with RRMS and mean duration of illness at 9.6 years, assessed with a brief cognitive measure (BICAMS), performed below the 1SD cutoff set for impairment on at least one of the three tests that comprise this brief neuropsychological battery. In an interesting cross-sectional study that evaluated the patterns of cognitive impairment in patients with disease duration of up to 30 years, 20.9% performed below the 1SD cutoff for impairment by the 5th year from disease onset, by 10 years this had reached 29.3%. By utilizing regression modeling the authors suggested that cognitive impairment may precede MS onset by 1.2 years [25].

Most of the evidence suggests that cognitive impairment in MS patients is present during all disease stages and across all disease clinical subtypes [26, 27, 28], including, RRMS, PPMS, SPMS, Clinically Isolated Syndrome (CIS) and “benign MS” [29, 30], and even Radiologically Isolated Syndrome—(RIS) [31]. Based on the majority of studies that have compared cognitive functions across disease subtype, deficits appear to be more frequent and more widespread in the progressive type rather than in the relapsing form of the disease [23, 29, 31, 32].

The dissemination of lesions in cerebral white matter including their affinity for periventricular regions provides the basis for some cognitive dysfunction commonalities [33]. In this respect, some cognitive domains appear to be more commonly compromised than others. Information processing efficiency, episodic memory, attention, and executive functioning are the domains found predominantly to be detrimentally affected in MS [21, 34, 35]. Among these domains the most common pattern involves circumscribed deficits as a combination of one or two of the above-mentioned domains (e.g., attention/processing speed, learning/memory, and or executive functions [11, 15, 21].

Symptoms like cognitive and physical fatigue, which are often accompanied by depression and anxiety, may negatively influence cognition in MS patients. This is especially true when extended periods are required to complete and appear more relevant for the patient’s daily life than what may be assumed by many physicians treating MS patients [11].

Although cognitive impairment is highly prevalent among MS patients, some have a tendency to withstand severe disease burden (e.g., white matter lesions and cerebral atrophy), and present with overall lower levels of cognitive decline. One possible explanation for this protective mechanism is the brain reserve hypothesis and the cognitive reserve theory [36]. Recently, it has been verified that highly significant protection for cognitive impairment is provided by brain reserve, defined as the maximal lifetime brain growth (MLBG), and estimated with intracranial volume or head circumference. Larger MLBG a proxy for neuronal and synaptic count has been linked to lower risk for cognitive impairment in MS [37]. This larger MLBG appears to be associated with more robust neural networks resistant to disease-related disruption and also provides more potential degrees of freedom for the brain to plastically reorganize in the face of MS disease related challenges.

3. Interventions for cognitive dysfunction in multiple sclerosis

Recent evidence from empirical research has indicated that cognitive dysfunction in MS patients is highly related to everyday functioning abilities [45]. One such study that evaluated associations between cognitive functions and objective performance on measures of everyday functioning in MS, [46], reported that MS patients had significantly more difficulties in simple and more complex cooking abilities, using the phone, taking medication, and paying the bills, compared to healthy participants. An interesting study by O’Brien et al. [47] and a more ecologically valid study by Goverover et al [48], utilizing an actual reality (AR) approach through the use of everyday tasks requiring the internet (e.g. booking an airline ticket, purchasing cookies and ordering pizza), the authors report significant correlations between these tasks and performance on mental processing speed (SDMT), concluding that this measure contributes significantly to predicting everyday functioning capacity in MS. A more recent study, [48], examined the ability of MS patients to manage their finances. The authors found that MS patients demonstrated and reported more difficulties in managing their finances compared to healthy controls. Moreover, MS patient’s difficulties in handling their finances were associated with the severity of cognitive dysfunction. As this important everyday task requires intact mental processing ability and executive-attentional abilities, domains usually impaired in MS individuals, these findings may serve as potential intervention indicators when planning cognitive rehabilitation interventions.

From the findings reported by the studies mentioned previously, it becomes obvious that interventions to alleviate, stabilize, reduce or compensate for cognitive impairment are of an extremely high priority, in order to provide MS individuals with the necessary mechanisms to better handle their everyday functioning disabilities. The evidence up till now is only modest regarding the efficacy of pharmacological agents on cognitive dysfunction [49, 50], and non-pharmacological interventions such as cognitive rehabilitation also provide incomplete evidence on whether they might improve or stabilize cognitive impairment and especially over long follow up periods [51]. Despite this general consensus, there are studies that have reported the efficacy of pharmacological agents [52] and cognitive rehabilitation [28, 53, 54] in reducing MS associated cognitive deficits.

4. Conclusions

Cognitive impairment is frequently encountered in MS individuals, irrespective of disease duration, severity of physical disability, and at both the earlier and later disease stages. Moreover, cognitive dysfunction in this population may have a significant negative impact on quality of life, activities of daily living and employment status. Furthermore, past and current pharmacological treatments have shown inconsistent findings in alleviating cognitive impairment in individuals with MS requiring further clarification. This inconsistency regarding the effects of pharmacological interventions on cognition, coupled with the reduced ability to effectively handle everyday tasks, loss of employment and social interaction capacity, prioritizes the need for utilizing potentially more effective non-pharmacological, neurobehavioral interventions to address cognitive dysfunction and everyday functioning abilities. Neurobehavioral interventions utilizing cognitive rehabilitation have shown favorable effects on MS patients cognitive performance and other related skills, and in some cases, have managed to generalize these positive effects to MS individual’s everyday life functioning ability. In this respect it becomes obvious that there is a need for rigorous new cognitive neurorehabilitation studies that may overcome some of the methodological limitations of older studies, and provide robust evidence regarding the efficiency of such cognitive interventions for the MS population.

Conflict of interest

The authors have no conflict of interest.

Declarations

Parts of this chapter originate from my Doctoral Dissertation entitled: Neuropsychological functions and association with Single Photon Emission Computed Tomography (SPECT) in Greek Multiple Sclerosis patients: Efficacy of a Computerized Cognitive Rehabilitation Intervention (2017). Department of Neurology, University of Patras Medical School, Patras, Greece.