ABSTRACT
RATIONALE FOR ASSESSING NEUROPSYCHOLOGICAL OUTCOMES IN MULTIPLE SCLEROSIS TRIALS
Cognitive function is often impaired in multiple sclerosis (MS) patients. Prevalence estimates derived from two large controlled cross-sectional studies are remarkably similar, once impairment rates in demographically matched healthy controls are taken into account: nearly half of all MS patients exhibit deficits on neuropsychological (NP) testing.[1,2] The functional consequences of MS-related cognitive impairment can be devastating. Cognitive impairment has a direct impact on the ability to maintain employment,[2-4] driving skills and safety,[5,6] involvement in social activities,[2] personal and community independence,[4,7-9] and the likelihood of benefiting from in-patient rehabilitation.[10] Not surprisingly, it is a major source of strain for caregivers.[11,12]
Cognitive impairment is directly related to cerebral abnormalities produced by MS: NP test performance correlates moderately to strongly with cerebral lesion burden on T2weighted magnetic resonance imaging (MRI),[13-15] brain atrophy (e.g. whole brain volume or brain parenchymal fraction, ventricular diameter, callosal area),[15-18] microscopic pathology both in lesions and in normal-appearing brain tissue (e.g. magnetization transfer ratios),[15,18-20] and cerebral glucose metabolism rates.[21] Furthermore, deteriorating cognitive function has been associated in longitudinal studies with increasing cerebral lesion burden over 1-year[22] and 4-year[23] intervals, and with decreasing brain parenchymal volume over a 2-year period.[24]
Disease course and progression also have an impact on cognitive function, albeit a more modest one than cerebral pathology. In general, secondary progressive MS patients perform more poorly on NP testing than patients with relapsing-remitting or primary progressive MS.[25-27] Even so, groups of relapsing-remitting patients and primary progressive patients exhibit deficits relative to healthy controls.[8,28-30] Correlations between cognitive dysfunction and MS duration or neurologic disability as assessed by the expanded disability status score (EDSS) are surprisingly weak.[2,31,32] weak.[2,31,32] As a result, traditional clinical outcome measures are notoriously insensitive to MSassociated cognitive deficits.[33]
The purpose of this chapter is threefold: first, to summarize briefly what is known about the nature and evolution of cognitive dysfunction in MS; second, to provide an overview of controlled clinical trials of disease-modifying and symptomatic medications in which NP outcomes have been explicitly assessed, and third, to make recommendations regarding NP outcome assessment in future MS clinical trials. It emphasizes study design and analysis of NP outcomes, extending concepts advanced in previous chapters.[34,35] Readers interested in the clinical management of cognitive
impairment in MS patients are referred to chapter 42. Those interested in a more extensive review of MS-related cognitive dysfunction are referred to Fischer.[36]
NATURE OF MS-RELATED COGNITIVE DYSFUNCTION
Not all cognitive functions are equally susceptible to disruption by MS. Learning and recall of new information (often referred to as ‘recent memory’) are among the most vulnerable: 22-31% of the patients in the sample studied by Rao et al. had severe learning and memory deficits (i.e. scored below the fifth percentile for demographically matched healthy controls).[2] Impairment in the speed of information processing and in working memory (i.e. the ability to buffer and manipulate information simultaneously) is also extremely common, with 22-25% of the sample studied by Rao et al. exhibiting severe deficits.[2] Visuospatial abilities and executive functions (including reasoning, problem solving, and planning and sequencing) are also compromised surprisingly often: severe impairment was observed in 12-19% of the sample studied by Rao et al.[2] Deficits in auditory attention span or verbal abilities occur less often (in 7-8% of the patients studied by Rao et al.[2]), although recent studies of the natural history of MS suggest that deficits in these domains become evident when cohorts are followed for longer periods of time time.[4,37]
Individual MS patients vary considerably in their specific cognitive deficits. Three distinct patterns of learning and memory performance have been consistently observed in cluster analytic studies of multitrial list learning task performance.[25,38,39] The most common pattern involves inefficient learning, which is characterized by deficient firsttrial recall, mildly inconsistent recall across learning trials, and mildly deficient recall after a delay (observed in 43-56% of the patients sampled). Other patients (20-22% of each sample) exhibit more pervasive learning and memory deficits, including a flattened learning curve, extremely poor delayed recall, and numerous intrusion errors. The performance of many patients (24-36% of those studied) remains essentially intact, however.
