**2. Cognitive functions and MS**

among Caucasians; the geographic gradient of the incidence increases together with the distance

Four types of the disease are recognized according to their clinical course. In the early years of the disease, the most common type is relapsing‐remitting MS (RRMS), occurring in 80–85% of patients and characterized by attacks and remissions. If a previous attack left no neurological deficit, remissions may be completely asymptomatic at the beginning of the disease. Half of these patients develop into the stage of secondary progression (SPMS) during the first 10 years of the disease's progression. This stage is characterized by a gradual increase in neurological deficits that are already irreversible, with both the presence and absence of relapses that are not as dramatic as in the remitting stage. The relapsing‐progressive (RPMS) form of the disease is characterized by an increased neurological deficit also evident between the relapses; it is thus prognostically the most unfavorable form of the disease. The primary progressive (PPMS) form affects about 10–15% of patients and is characterized by a gradual increase in neurological deficit. This form occurs more frequently among males and with a later onset of the disease [1].

In the relapsing‐remitting forms, approximately 20–30% of patients continue working following their first attack. It is uncommon for patients in the early stages of this form of MS to be physically disabled or to have noticeable alternations in terms of dementia. It is primarily the progressive form of MS, developing at a later age that tends to pose more difficulty in the cognitive domains, compared to the remitting one. Patients with the spinal form of the disease have trouble mostly with motor skills and mobility. This form often occurs in the primary progressive form. Cognitive deficits include impaired attention. The typical cognitive domains impaired in the cerebral forms of MS are described below. Psychosocial and maladaptive

A woman of 47 years reported the first symptoms of MS (optic neuritis and paresthesia) at the age of 17; later, the attacks recurred about once a year; the problems worsened after two child deliveries. Therefore, she did not breastfeed her children, for which she blames herself for until today. She underwent an abortion 2 years after the second birth due to the above‐mentioned difficulties, then was psychiatrically treated, and still has feelings of guilt. The diagnosis of MS was definitely confirmed about 4 years ago. The patient has since been considerably anxious, unreconciled with the diagnosis, dominated by hostility and distrust of the medical staff (the disease was not diagnosed correctly). MRI scans of the brain and spinal cord showed multiple demyelinating lesions or plaques in the white matter. Nobody in the family had MS. She was entitled to disability pension and has been taking antidepressants for 4 years, based on the psychiatrist's indication of anxiety and depressive problems. Formerly, she worked as a teacher. She feels very tired after only about a 3–4 km walk. She is married, has two adult sons, and lives with her family. When she learned about MS, she was overtaken by fear of dying and felt mentally ill, and thus stopped working. She did not observe any difficulties with cognition. Gradually, a panic anxiety developed; when she wakes up, she feels scared, but this

from the equator. Genetic predisposition plays a role.

problems are described in the case report.

*1.1.1. Case report 1*

**1.1. Types of the disease**

212 Trending Topics in Multiple Sclerosis

The most characteristic feature of cognitive dysfunction in MS is the slowing down of proc‐ essing speed [2]. Another often affected domain is long‐term episodic memory and attention (alternating and maintained). Less frequent but significant cognitive disorders include disorders of executive functions (especially abstract and conceptual reasoning and problem‐ solving) [3].

#### **2.1. Outline of basic neuropsychological techniques**

Due to the high incidence of cognitive disorders in patients with MS, the adequate evaluation and diagnosis of such deficits is of great importance. Their existence is often under diagnosed during an ordinary neurological examination. Various tests are used to identify these.

One of the most significant neuropsychological studies of MS patients was carried out by Rao [4]. The Brief Repeatable Battery (BRB) for neuropsychological impairment in MS [5] was created based on a set of highly sensitive tests, with a few modifications. The BRB tests were chosen with regard to time restrictions, and so the administration of the entire battery lasts only about 40–45 min. It contains the following subtests: The Paced Auditory Serial Addition Test (PASAT); The Symbol Digit Modalities Test (SDMT) measuring attention, visual accuracy, and executive functions; The Selective Reminding Test (SRT) measuring verbal memory and delayed recall periods; The Spatial Recall Test (SPART) measuring visuospatial memory and delayed recall; and The Word List Generation (WLG) measuring verbal fluency. The battery has 15 versions and is thus, despite its longer duration, the most commonly used battery for the longitudinal monitoring of patients with MS. Clinical research supports the high sensitivity of the battery. Its abbreviated version with 3 subtests has been under verification recently.

For cognitive screenings, Beatty [6] developed the Screening Examination for Cognitive Impairment (SEFCI) neuropsychological battery, which proved to confirm cognitive deficits typical of MS in a comparative study (duration 22 min) with other time‐consuming neuropsy‐ chological batteries. It does not have variants and is thus not suitable for longitudinal obser‐ vations. The study compared the battery with the Neuropsychological Screening Battery for Multiple Sclerosis (NPSBMS) for which the administration period lasted 31 min. Both batteries identified significantly more patients with cognitive impairment in MS than the Mini‐Mental State Exam (MMSE) [7]. The Multiple Sclerosis Functional Composite (MSFC) is a score used in clinical studies, measuring the function of the lower limb—timed walk, upper limb function (nine‐hole peg test), and cognitive function (PASAT) [8, 9].

In 2001, the battery Minimal Assessment of Cognitive Function in MS (MACFIMS) [10] was created with respect to neglected domains (higher cognitive functions and spatial processing), and its reliability and validity has been verified in several studies. The MACFIMS battery includes the following tests: Controlled Oral Word Association Test (COWAT); Judgement of Line Orientation Test (JLO); California Verbal Learning Test, Second edition (CVLT‐II); Brief Visuospatial Memory Test‐Revised (BVMT‐R); Paced Auditory Serial Addition Test (PASAT); Symbol Digit Modalities Test (SDMT); and the Sorting Test from the Delis‐Kaplan Executive Function System (D‐KEFS). However, the MACFIMS battery is limited by time constraints and for its need to be carried out by an experienced neuropsychologist. For this reason, a shorter battery of cognitive tests has recently been designed. This consists of three subtests from the MACFIMS battery and may be administered by neuropsychological workers without training —International Brief Cognitive Assessment for Multiple Sclerosis—BICAMS [11]. It is suitable for use in routine clinical practices in centers with no neuropsychologist to administrate the MACFIMS. The BICAMS screening battery consists of three tests that are included in the MACFIMS battery: SDMT, CVLT‐II (the first five experiments), BVMT‐R (the first three trials).

#### **2.2. Cognitive domains and their examination**

Cognitive deficits observed within MS can have almost any composition [12]; a typical profile shows impairment of processing speed, memory, and often of executive skills as well [2].

#### *2.2.1. Intellectual skills*

Over the past two decades, numerous studies using neuropsychological assessment showed that approximately half the patients exhibit some degree of cognitive impairment. We also know that cognitive disorders may occur at any time during the illness and are not bound to the presence of physical disorders [13]. Generally, a substantial variability of cognitive impairments in MS in terms of their gravity and types has been described. Although approx‐ imately 10% of MS patients have severe problems that display extensive impairment even when measuring overall intelligence, the vast majority (90%) of patients is affected only mildly to moderately [14]. It should be emphasized that patients with MS as a group display a relatively small decline on intelligence measures, and overall dementia is rare in MS [13]. Cognitive deficits in MS are usually more focal than generalized. Verbal IQ, therefore, often remains intact during the first signs of MS [4].

#### *2.2.2. Visuomotor skills, visuospatial skills, and attention*

Visual disorders including diplopia, reduced color discrimination, blurred vision, and transient blindness, and motor symptoms such as limb weakness, spasticity, incoordination, or a combination of all the problems, as well as sensory disorders including numbness or paresthesia, contribute to the alteration of visuomotor skills in neuropsychological examina‐ tions. Deficits of visual attention in MS patients significantly influence their level of visuomotor skills. When evaluating visual attention, it is thus necessary to take into account the visual disorders. For example, test results in automatic attention (reaction time) and focused attention may be in norm in terms of errors, but the patient completes them in a longer period of time. In contrast, controlled attention and divided attention are often deficient [15].

#### *2.2.3. Memory and learning*

includes the following tests: Controlled Oral Word Association Test (COWAT); Judgement of Line Orientation Test (JLO); California Verbal Learning Test, Second edition (CVLT‐II); Brief Visuospatial Memory Test‐Revised (BVMT‐R); Paced Auditory Serial Addition Test (PASAT); Symbol Digit Modalities Test (SDMT); and the Sorting Test from the Delis‐Kaplan Executive Function System (D‐KEFS). However, the MACFIMS battery is limited by time constraints and for its need to be carried out by an experienced neuropsychologist. For this reason, a shorter battery of cognitive tests has recently been designed. This consists of three subtests from the MACFIMS battery and may be administered by neuropsychological workers without training —International Brief Cognitive Assessment for Multiple Sclerosis—BICAMS [11]. It is suitable for use in routine clinical practices in centers with no neuropsychologist to administrate the MACFIMS. The BICAMS screening battery consists of three tests that are included in the MACFIMS battery: SDMT, CVLT‐II (the first five experiments), BVMT‐R (the first three trials).

Cognitive deficits observed within MS can have almost any composition [12]; a typical profile shows impairment of processing speed, memory, and often of executive skills as well [2].

Over the past two decades, numerous studies using neuropsychological assessment showed that approximately half the patients exhibit some degree of cognitive impairment. We also know that cognitive disorders may occur at any time during the illness and are not bound to the presence of physical disorders [13]. Generally, a substantial variability of cognitive impairments in MS in terms of their gravity and types has been described. Although approx‐ imately 10% of MS patients have severe problems that display extensive impairment even when measuring overall intelligence, the vast majority (90%) of patients is affected only mildly to moderately [14]. It should be emphasized that patients with MS as a group display a relatively small decline on intelligence measures, and overall dementia is rare in MS [13]. Cognitive deficits in MS are usually more focal than generalized. Verbal IQ, therefore, often

Visual disorders including diplopia, reduced color discrimination, blurred vision, and transient blindness, and motor symptoms such as limb weakness, spasticity, incoordination, or a combination of all the problems, as well as sensory disorders including numbness or paresthesia, contribute to the alteration of visuomotor skills in neuropsychological examina‐ tions. Deficits of visual attention in MS patients significantly influence their level of visuomotor skills. When evaluating visual attention, it is thus necessary to take into account the visual disorders. For example, test results in automatic attention (reaction time) and focused attention may be in norm in terms of errors, but the patient completes them in a longer period of time.

In contrast, controlled attention and divided attention are often deficient [15].

**2.2. Cognitive domains and their examination**

remains intact during the first signs of MS [4].

*2.2.2. Visuomotor skills, visuospatial skills, and attention*

*2.2.1. Intellectual skills*

214 Trending Topics in Multiple Sclerosis

Long‐term memory is related to the learning and retrieval of new information. Patients with MS often have difficulties with memory—the prevalence is reported between 40 and 65%. The most common verbal memory tests are tasks in which the patient learns a wordlist [16]. Visuospatial memory, too, is affected in patients with MS [13]. Patients with MS have signifi‐ cant abnormalities of the hippocampal functional connectivity, even before spatial memory impairment is apparent [17]. Patients with MS in the initial stages of the disease display a relatively intact short‐term memory and learning ability, measured by tests of memory skills. More patients experience problems in recalling new material, while recognition is rarely altered.

#### *2.2.4. Verbal ability and executive functions*

Executive functions are related to planning and goal‐directed behavior. Drew and colleagues [18] reported a series of executive dysfunctions—including disinhibition, poor fluency, and an inability to shift sets. Overall, 17% of their sample of MS patients displayed this kind of deficit. Language functions typically remain intact in MS; however, some minor deficits in under‐ standing were demonstrated. Weakened sentence comprehension has been associated with slower information processing. Deficits in semantic memory and visual processing were also observed [19].

Overall verbal skills in patients with MS are usually preserved for a long time, depending on premorbid mental performance, flexibility, and vocabulary; a low level of verbal fluency is observed. Dysarthria or problems with articulation are more prevalent in speech. The best and longest preserved of all verbal skills is naming. Recalling information from long‐term memory, vocabulary, and conceptual reasoning are often normal. If these abilities are altered, it is usually the result of a generalized deterioration, or of the patient having low levels of pre‐ morbid education and of cognitive reserve. Some studies have found lower levels of conceptual reasoning in patients with chronic progressive MS. A more detailed examination of verbal and oral skills is possible with a complex speech assessment.

Cognitive impairment in MS, however, does not correlate with the degree of physical disability (Expanded Disability Status Scale EDSS Kurtzke [20]); some studies showed a correlation with disease duration, yet other studies did not prove this. The impairment of cognitive functions correlates positively with some MRI abnormalities—mostly concerning atrophy, ventricular dilatation, and the total volume of impaired white matter on W T2 lesion load. The sites of predilection are areas of the corpus callosum, and extensive demyelination further affects circuits linking the prefrontal and subcortical areas. Large confluent periventricular lesions are also typical. As a whole, the huge variability in cognitive impairment may depend on many factors, such as the patient's age, sex, age at disease onset, level of education, and cognitive reserve [3]. Dysexecutive and prefrontal behavioral syndromes in a patient with a cerebral, relapsing–remitting form are illustrated in the following case report.

#### **2.3. Case report 2**

A woman of 54 years was treated for MS and migraine for 15 years. A cognition and personality assessment was recommended by a neurologist for her memory problems. MRI of the brain showed unique plaque lesions in the white matter, predominantly in the right frontal lobe; the spinal cord was not affected. There has been improvement when comparing MRI scans, the lesions were less apparent. The patient was entitled to a full disability pension 10 years ago. She was a skilled saleswoman. She has been married for 35 years; her sons are adults. There is no report of MS in the family. She commutes to a psychiatric clinic where antidepressants are prescribed. She is oriented in contact, talkative, often gets lost, and exhibits signs of the prefrontal syndrome. Memory problems have occurred for a longer period, approximately 10 or even more years. She misplaces thing and then cannot find them, someone talks about something and she does not know about it, and she does not remember old information. She also experiences sudden interruptions of activities when she goes off to do another one, although she had not planned it; it is impulsive. She experiences confusions in her mind; she wanted something and suddenly does not know what she was thinking about. It troubles her. She "masks" these difficulties in front of her family and friends. Headaches occur daily. Neuropsychologically, it is mainly attention that is impaired, and the generalized deterioration of intellect is also striking, considering her education. It is possible to explain the problems behaviorally, mainly through the prefrontal behavioral and dysexecutive syndromes, which might be related to the largest findings of plaques in the frontal lobes. Cognitive behavioral therapy and training of cognitive functions was advised.

### **3. The course of cognitive deficit**

Studies on large MS patient samples have shown that the range of cognitive impairment prevalence in MS is between 40 and 70% and appears in all stages and types of the disease (which also includes the clinically isolated syndrome—CIS) [21]. It seems that observations carried out for long enough are able to show cognitive impairment in progressive stages [22]. Several studies have confirmed the relationship between the dysexecutive syndrome and frontal lesions, and others have focused on deficits in interhemispheric transfer (i.e., discon‐ nection syndrome) in the atrophy of the corpus callosum.

The course of a cognitive deficit without progression but with behavioral disorders is illus‐ trated in the following case report.

#### **3.1. Case report 3**

A 43‐year‐old man with the relapsing‐remitting form, treated for MS for 18 years, was initially assessed due to problems with memory, concentration, exhaustion, and no sexual appetite. An MRI scan of the brain showed small plaque lesions subcortically, compared with no progression found on MRI scans 4 years ago. The patient had been treated with interferons for 3 years. He is left‐handed, a skilled auto‐mechanic, has his own workshop at home, and works 17 h a day. He has been married for 22 years, has two children and "does not get on well" with his wife, and he admits to extramarital relations. They are currently in a divorce proceeding. The main problem is with his erection. Neuropsychologically, no striking impairment of cognitive domains was found, and only anxiety and a conflictive family environment were found. Marriage counseling, a sexologist, and conflict solving were recommended. The patient refused the proposed recommendations and increasingly adopted strange and promiscuous behaviors; he forced his wife and their children to move out of the house. He was incapable of rational thinking; he explained the promiscuity as a verification of his sexual functions. A 1‐year follow‐up neuropsychological assessment showed no impairment of cognitive domains and intellect, but a psychiatric examination was recommended due to paranoid thinking and aggressiveness.

On the contrary, a rapid development of cognitive deficits into dementia can be seen in the following case report.

#### **3.2. Case report 4**

**2.3. Case report 2**

216 Trending Topics in Multiple Sclerosis

A woman of 54 years was treated for MS and migraine for 15 years. A cognition and personality assessment was recommended by a neurologist for her memory problems. MRI of the brain showed unique plaque lesions in the white matter, predominantly in the right frontal lobe; the spinal cord was not affected. There has been improvement when comparing MRI scans, the lesions were less apparent. The patient was entitled to a full disability pension 10 years ago. She was a skilled saleswoman. She has been married for 35 years; her sons are adults. There is no report of MS in the family. She commutes to a psychiatric clinic where antidepressants are prescribed. She is oriented in contact, talkative, often gets lost, and exhibits signs of the prefrontal syndrome. Memory problems have occurred for a longer period, approximately 10 or even more years. She misplaces thing and then cannot find them, someone talks about something and she does not know about it, and she does not remember old information. She also experiences sudden interruptions of activities when she goes off to do another one, although she had not planned it; it is impulsive. She experiences confusions in her mind; she wanted something and suddenly does not know what she was thinking about. It troubles her. She "masks" these difficulties in front of her family and friends. Headaches occur daily. Neuropsychologically, it is mainly attention that is impaired, and the generalized deterioration of intellect is also striking, considering her education. It is possible to explain the problems behaviorally, mainly through the prefrontal behavioral and dysexecutive syndromes, which might be related to the largest findings of plaques in the frontal lobes. Cognitive behavioral

Studies on large MS patient samples have shown that the range of cognitive impairment prevalence in MS is between 40 and 70% and appears in all stages and types of the disease (which also includes the clinically isolated syndrome—CIS) [21]. It seems that observations carried out for long enough are able to show cognitive impairment in progressive stages [22]. Several studies have confirmed the relationship between the dysexecutive syndrome and frontal lesions, and others have focused on deficits in interhemispheric transfer (i.e., discon‐

The course of a cognitive deficit without progression but with behavioral disorders is illus‐

A 43‐year‐old man with the relapsing‐remitting form, treated for MS for 18 years, was initially assessed due to problems with memory, concentration, exhaustion, and no sexual appetite. An MRI scan of the brain showed small plaque lesions subcortically, compared with no progression found on MRI scans 4 years ago. The patient had been treated with interferons for 3 years. He is left‐handed, a skilled auto‐mechanic, has his own workshop at home, and works

therapy and training of cognitive functions was advised.

nection syndrome) in the atrophy of the corpus callosum.

**3. The course of cognitive deficit**

trated in the following case report.

**3.1. Case report 3**

A 42‐year‐old woman diagnosed with chronic progressive MS for 10 years was treated by interferons for 6 years. At the time of her visit, eye problems are dominant for the first time; she uses a white cane. She also experiences hearing difficulties, but does not complain about memory at all. A former governess, now entitled to full disability pension, divorced, with two children, both studying, not in contact with her ex‐husband. Her mother and brother help her mostly, but the patient feels dependent and helpless. According to an MRI scan of the brain, periventricular plaque lesions are apparent in the white matter of both hemispheres. There has been a slight progression of plaque and atrophy when compared to an MRI from 4 years ago. The initial psychological examination suggested a multi‐domain impairment, a decrease of more than 2 SDs (verbal mnestic and visual skills, construction, executive functioning), with severe anosognosia. The performance may have been influenced by her impaired visual and auditory perception. Two years later, she comes fundamentally oriented, and the right eye is blind. The outcome of the examination is a multi‐domain cognitive disorder; cognitive abilities are significantly impaired across the whole profile.
