Introduction

Charcot was the first to investigate the cognitive consequences of multiple sclerosis. He found that at a certain stage of the disease memory losses, slower formed conceptions and emotional deficits arise. It was not until a hundred years after Charcot’s discovery that neurologists started to believe in the cognitive effects of MS, because they equated this cognitive effects to Alzheimer’s dementia. Still, a lot of patients cannot be accurately enough assessed by a neurologist to discover cognitive effects, which makes the patients more vulnerable to negative effects of their cognitive deficits in social skills, employment and daily activities. Now is recognized that cognitive impairments are one of the most disabling symptoms of the disease.

It has also been a challenge to find the optimal combination of cognitive tests to assess the multiple areas affected by multiple sclerosis. Benedict and colleagues conducted the Minimal Assessment of Cognitive Function in MS (MACFIMS) for this problem. When early discovered, cognitive impairments can possibly be helped with neuropsychological counselling, cognitive rehabilitation training and pharmacological interventions.

Cognitive functions in MS

MS is a multifocal demyelinating disease of the CNS, produced by neuroinflammatory and degenerative processes. MS affects not only the white matter tracts but also the axons of the association neurons in the cerebral cortex. Different areas of the CNS can be demyelinated and this makes MS a heterogenic disease. But despite of the heterogenic aspect of this disease, some areas are more affected than others. There are differences in subtypes: relapsing remitting (RRMS) patients perform usually better on cognitive tasks than patients with progressive subtypes. This difference can be diminished by reducing the physical aspects. The most affected areas by MS are information processing speed and verbal memory. Cognitive flexibility and executive functions are also impaired in many cases. Also deficits in attention, caused by a working memory deficit, are found in MS patients. The working memory deficit is a result from white matter lesions, which lead to a disruption of the rehearsal sub-loops. These deficits can also be detected in the early stages of MS. Dementia , language impairments, aphasia, amnesia, apraxia and neglect are usually not involved in MS.

Magnetic resonance imaging parameters related to cognitive impairment

Traditional magnetic resonance imaging was not able to show the impairments, and the cognitive deficits were not strongly correlated to damaged areas. In more advanced versions of MRI these correlations can be made because these versions of MRI can detect abnormalities in the white matter. Studies showed that patients with damage on a MRI can perform as well as controls on attention tasks, due to compensatory mechanisms. Another study showed that patients do perform worse on attention tasks, suggesting exhaustion of compensatory mechanisms. Because of the regional fibre tract injury, connections for communicating in the working memory can be disturbed. Neurological plasticity can also diminish this problem.

Contribution of comorbidities on cognitive performance

Cognition can also be influenced by neuropsychiatric abnormalities accompanying MS, like depression, anxiety or fatigue. Depression is the most represented, with 50% of MS patients suffering from it. Depression can also be a cause of cognitive impairment by influencing the executive component of the working memory. Cognitive decline can also increase due to the overestimation of cognitive deficits, caused by depression. It is not known if treatment in depression will diminish the cognitive problems.

Even though fatigue also impacts controls, it is established as an important factor for cognitive impairments in MS patients. Especially in sustained attention and processing speed. Furthermore, CNS-active medications (anti-epileptics and SSRI’s) are also able to cause fatigue, so this should be considered during cognitive assessment, even though there is no direct evidence of cognitive decline linked to this medication.

Assessment of cognitive dysfunction in MS

Neuropsychological assessment is very time-consuming and expensive, and even though they are very important for MS patients, they are not always done. Besides that not much research has been done on indicating risk factors, which makes identification of at risk-patients hard. Some already established risk factors are: advanced age, low level of intelligence and depression. Combination of an advanced age and low level of intelligence is an even bigger risk factor. Employment status is another risk factor. Assessment should not be conducted before 8 weeks after a relapse or steroid treatment, because they might also cause cognitive deficits. Possible comorbidities should also be considered.

Recommendation for the optimal assessment of cognitive impairment in MS

A neuropsychological test should be able to distinguish between MS patients and healthy individuals, but also between cognitive impaired MS patients and not cognitive impaired MS patients. Benedict’s MACFIM (as discussed in introduction) contains of five domains: processing speed/working memory, learning and memory, executive function, visual-spatial processing and word retrieval. Recent studies showed that the Symbol Digit Modalities Test (SDMT) was the best discriminator between MS patients and controls, and the Brief Visuospatial Memory Test the second best. These studies also showed that the MACFIM was able to discriminate between relapsing-remitting MS and secondary progressive MS. MAFCIM is declared valid.

Cognitive screening in MS

Time limitation can be a problem with MACFIM. Sometimes short cognitive screening tests are used because of that, but they seem to be insensitive for MS. For this reason special tests for MS patients are developed. The Brief Repeatable Battery of Neuropsychological Tests (BRB) is the most used example of this. The authors of the BRB found that a 5-15 min. test with three subscales also had a high accuracy and made this a new test. According to Benedict and Zivadinov cognitive screening should idealistically done before medical examination. Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) was conducted with this purpose. This short screening can be filled in while waiting for an appointment in the hospital. A problem with the MSNQ is that self-reports are usually affected by the patient’s depression. Staff-training is very important for interpreting screening and tests.

Pharmacological and medical treatment of cognitive impairment in MS: Are we there yet?

Disease-modifying drugs/therapies can minimize the developing of new lesions, so minimizing the cognitive deficits. They are now the number one treatment of RRMS patients. It should be noted that research on this topic has not been optimal, because of a lack of control of confounding variable. Recent studies have shown that progressive forms of MS can be improved with mitoxantrone, improving physical abilities and cognitive status. For symptomatic treatment of MS there are four useful drugs, although not enough research is done yet on this topic. The used drugs are: donepezil, rivastigmine, galantamine and memantine. The first three are acetylcholinesterase inhibitors, which inhibit the breakdown of acetylcholine, so increasing the duration and activation of acetylcholine. Donezepil is found to increase memory and learning. Rivastigmine also inhibits butyrylcholinesterase, and seems to benefit MS patients’ cognition.

Non-pharmacological treatments

Currently there is no optimal non-pharmacological treatment but they may benefit some MS-patients. The purpose of these treatments is creating a therapeutic ambiance in which optimal cognitive function can be created. Another non-pharmacological treatment is changing life-style, like exercise, a balanced diet (reduced alcohol and caffeine), quitting smoking and better sleep patterns. Cognitive rehabilitation focuses on helping the patient coping with their physical and cognitive problems. There are two kinds of approaches: the restorative approach and the compensatory approach. The restorative approach is dependable on the brain’s plasticity. The compensatory approach focusses on modifying the patient’s environment. It is of great importance that these approaches are individualised, since no patient has the same comorbidity, lifestyle, and demographic characteristics.

Studies on non-pharmacological treatments show mixed results, with some showing improvements on mental speed and working memory and others showing no results. Recent fMRI studies showed that cognitive rehabilitation has a positive effect on the compensatory cerebral reorganisation.

Cognitive impairments can result in significant changes in employment status, relationships and quality of life, so the early identification of cognitive impairments is crucial.