Abstracts

COGNITIVE PROFILE OF PATIENTS WITH RELAPSING REMITTING MULTIPLE SCLEROSIS

VIVIAN M. ANDRADE^* * Universidade Federal de São Paulo (UNIFESP): Departamento de Psicobiologia; ** Departamento de Neurologia. Financial support: AFIP, CNPq. Aceite: 5-junho-1999. , ORLANDO F.A. BUENO^* * Universidade Federal de São Paulo (UNIFESP): Departamento de Psicobiologia; ** Departamento de Neurologia. Financial support: AFIP, CNPq. Aceite: 5-junho-1999. , MARIA GABRIELA M. OLIEVIRA^* * Universidade Federal de São Paulo (UNIFESP): Departamento de Psicobiologia; ** Departamento de Neurologia. Financial support: AFIP, CNPq. Aceite: 5-junho-1999. , ACARY S.B. OLIVEIRA^** * Universidade Federal de São Paulo (UNIFESP): Departamento de Psicobiologia; ** Departamento de Neurologia. Financial support: AFIP, CNPq. Aceite: 5-junho-1999. , ENEDINA M.L. OLIVEIRA^** * Universidade Federal de São Paulo (UNIFESP): Departamento de Psicobiologia; ** Departamento de Neurologia. Financial support: AFIP, CNPq. Aceite: 5-junho-1999. , MÔNICA C. MIRANDA^** * Universidade Federal de São Paulo (UNIFESP): Departamento de Psicobiologia; ** Departamento de Neurologia. Financial support: AFIP, CNPq. Aceite: 5-junho-1999.

ABSTRACT - Multiple sclerosis (MS) is a common disease in Western countries of temperate/cold climate, but in tropical countries an increasing number of cases have been diagnosticated. Moved by the lack of information about cognitive dysfunction of Brazilian MS patients, the present study attempted to describe features of neuropsychological alterations in patients with relapsing remitting MS living in the city of São Paulo. They were compared to healthy volunteers, matched for age and education. In the absence of global intellectual deterioration, the patients had a deficit: a) in learning and verbal long-term memory tasks and in visual long-term memory of complex figure; b) in timed tasks, accounted for by a slowness of mental processes; c) in tasks with a motor component. Tendency to depression was observed; anxiety levels were normal.

KEY WORDS: multiple sclerosis, relapsing remitting, neuropsychological evaluation, memory, cognition.

Perfil cognitivo de pacientes com esclerose múltipla do tipo surto-remissão

RESUMO - A esclerose múltipla (EM) é doença comum em países de clima temperado/frio, mas também em países tropicais um crescente número de casos tem sido diagnosticado. Motivado pela escassez de informações acerca da cognição dos portadores de EM em nosso país, o presente estudo procurou traçar o perfil neuropsicológico de pacientes com EM da forma surto-remissão, residentes no município de São Paulo, os quais foram comparados a pessoas sadias, com idade e escolaridade semelhantes. A inteligência geral dos pacientes estava preservada mas foram detectados déficits: a) em tarefas de aprendizagem e de memória verbal e visual de figura complexa, ambas de longo prazo; b) em tarefas cronometradas, explicados por lentificação do processamento mental; c) em tarefas com componente motor. Tendência a depressão foi observada; os níveis de ansiedade encontravam-se normais.

PALAVRAS-CHAVE: esclerose múltipla, surto-remissão, avaliação neuropsicológica, memória, cognição.

Multiple sclerosis (MS), also referred to in the British Commonwealth as disseminated sclerosis and among French-speaking physicians as sclérose en plaques, is one of the most chronic neurologic diseases¹. Diagnosis may be uncertain in the early stages of the disease, although the combination of (1) symptoms referable to white matter fiber tracts in optic nerves, brainstem and spinal cord, (2) a multiplicity of lesions, and (3) temporal dispersion of attacks eventually makes the diagnosis certain. According to clinical course, relapsing remitting (patients have a series of exacerbations of the disease with complete or partial remission) and steadily progressive (patients have progressive downhill course) are the two more frequent forms of presentation.

The etiology of MS remains unknown, no cure is presently at hand and the prevalence is high. In many regions of several countries of Europe and North America the distribution of MS is high (prevalence of 30 or more per 100,000 population), with the prevalence increasing with increasing latitude². In tropical countries as Brazil, recent studies have estimated a prevalence of 4.27 cases per 100,000 population in the City of São Paulo³, meaning that we are in a low frequency zone (less than 5 per 100,000), although this figure can change with new surveys. The standardization of diagnostic criteria carried out by Poser and collaborators⁴ and the general acceptance of the disability scale proposed by Kurtzke⁵ have constituted fundamental steps to promote the advancement of research in this area. Comparative studies using these international standards and aimed at elucidating the clinical profile and the evolutive course of the disease in countries of the southern hemisphere are being carried out. One interesting question have to do with possible differences or the lack of them in the manifestations of MS in tropical climate regions as compared to temperate and cold regions^6,7.

It has often been pointed out that patients with MS, mainly in late stages, have decreased cognitive capacities, related to size and site of the plaques. These cognitive alterations, however, may appear also in mild stages^8,9. This cognitive impoverishment was already registered by Charcot in the 19^th century⁹, but systematic cognitive studies have begun only recently. Memory and learning impairments are being repeatedly demonstrated since the late 60s (e.g.^9-14), while general intelligence and language seem to be less affected.

While a wealth of data concerning a variety of neuropsychological aspects of MS patients is continuously being gathered in northern countries (for reviews:^9,15,16), in South American countries neuropsychological data are very scarce. Aiming to contribute to the partial filling of this gap, the present study attempted to describe a cognitive profile of relapsing remitting MS patients living in the City of São Paulo, SP and under treatment in a public hospital of this city.

METHOD

Participants

The participants were 25 patients with clinically definite MS, as diagnosed by the criteria of Poser et al.⁴ and classified as having the relapsing remitting course of the disease. Further criteria of inclusion were: at least 4 years of formal education, 18-60 years of age, no history of other psychiatric or neurologic disease, no history of alcohol or drug abuse, no other complicating medical condition. All the patients were physically independent, with scores between 0-6 in the Expanded Disability Status Scale (EDSS)⁵. No patient with lesions limited only to spinal cord was included. At the time of evaluation the disease was in a clinically inactive state. The first relapse of most patients occurred in the second or third decade of life; only one patient had the first relapse after 50 years of age. The average number of relapses was 3 in 8 years of disease. The patients (76% females) were volunteers recruited among patients under treatment in the Department of Neurology of UNIFESP/Hospital São Paulo or from the Associação Brasileira de Esclerose Múltipla (ABEM). All the patients were receiving symptomatic medication, either interferon-beta 1b (on alternate days), azathioprine or methotrexate. Steroids were only prescribed to treat acute relapses of the disease.

The control group consisted of 24 volunteers (75% females) who fulfilled the same basic criteria for inclusion except the disease. Table 1 presents the distribution of age and education of both groups and also shows the occupational status of the participants . As the disease progressed, the occupational status of many patients changed, as they became unemployed, retired or stopped studying.

Neuropsychological evaluation

The procedures and consent form used in this study were approved by the Medical Ethics Committee of the Universidade Federal de São Paulo.

The neuropsicological battery employed aimed to briefly investigate the main cognitive functions using tests already reported in the literature^8,9 to make possible a comparison with international data. The choice of the tests was done in order to compare performance of patients with control subjects in several cognitive domains: general intelligence, memory (immediate and recent, verbal and non-verbal), perceptual and motor capacities, some aspects of language, and mood. The tests were administered by two trained psychologists. The order of presentation of the tests was pseudo-ramdomized in order to prevent any distortion that might be caused by fatigue; rest periods during the application sessions were allowed depending on the physical and emotional states of the subjects. All of them appeared to be motivated to perform the cognitive tasks. The battery was applied in three sessions of 2 hours each, and consisted of the following tests:

a) a shortened version of the Wechsler Adult Intelligence Scale-Revised (WAIS-R), which included 5 verbal and 4 non-verbal subtests: Comprehension, Arithmetic, Similarities, Vocabulary, Digit Span, Digit Symbol, Picture Completion, Block Design, Picture Arrangement¹⁷.

b) three subtests of the Wechsler Memory Scale (WMS): Logical Memory, Visual Reproduction and Associate Learning¹⁷.

c) Stroop Color Test. It is a measure of cognitive flexibility and focused attention. The Victoria version was used ¹⁸.

d) Rey-Osterrieth Complex Figure. It evaluates the perceptual and motor capacities required to copy a complexure, and assess delayed visual memory through a recovery test 30 minutes later¹⁸.

e) Corsi Block-tapping Test. It evaluates the immediate memory span for visuospatial material¹⁷.

f) Word Fluency Test (FAS). It evaluates verbal fluency and access to lexicon¹⁸.

g) Naming and Memory for Objects. Procedure I - Incidental memory: the subject is asked to name 15 small objects of everyday use, presented one at a time. Immediately after he/she is asked to remember which objects he /she has seen with no previous knowledge of the memory requirement. Procedure II - Intentional memory: the same task using 15 different objects, except that the subject knows in advance that a retention test will be done. Procedure III - Recognition test, 30 minutes later, of all objects presented among others not shown before.

h) Beck Depression Inventory ¹⁹.

i) State-Trait Anxiety Inventory (STAI) ^19,20.

The subjects of the present study had also participated in a related study to be reported separatedly in which word free recall tests were administered, intermingled with the battery listed above.

The Student t test was used to analyse statistically the results. For differences considered to be statistically significant (p<0.05), we also calculated the effect size, that expresses the degree to which two sample means differ in terms of pooled standard deviations²¹. Conventionally, a medium effect size is about 50-79% of the group standard deviation and a large effect size is 80% or more of the standard deviation. When appropriate, some results were analysed by a 2-way ANOVA followed by the Tukey a posteriori test.

RESULTS

Table 2 shows cognitive test scores means, standard deviations, t values and probability values derived from Student test comparisons. Effect size values of significant differences are also indicated. These ranged from 0.68-0.76 (medium degree of separation between means) to 0.81-1.12 (large degree of separation).

There were no significant differences between the MS patients and their controls regarding Full scale IQ and Verbal IQ of the WAIS-R.

The MS patients showed normal performance in the span measures, in both digit span and visuospatial span (Corsi block-tapping test). The backward digit span as well as the backward visuospatial span also were not different from controls.

Significant differences were found in tests that involved a motor component, such as the Performance IQ that encompasses the Picture Completion, the Picture Arrangement and the Digit Symbol tests. In the delayed test of the Rey-Osterrieth Figure the patients' performance was also lower than that of the controls (the effect size indicated a medium degree of separation between the means of both groups), but the copy of this figure was within the normal range.

Immediate and delayed visual reproduction is a visual drawing memory test in which no differences were apparent between patients and their controls, nor there was any interaction group x trial [F(1,45)=0.914; p=0.34], as revealed by a 2-way ANOVA [F(1,45)=2.68; p=0.1]. The trial effect was significant [F(1,45)=40.96; p<0.001], reflecting the decay of performance in the delayed test in both groups (Fig 1C).

Significant differences in tests that evaluate cognitive functions relatively uncontaminated with a motor component were also found: FAS (medium degree of separation between means, according to the effect size value), Stroop Color, Associate Learning (immediate and delayed), Logical Memory (immediate and delayed; medium degree of separation of means). Incidental and intentional memory as well as delayed recognition of concrete material (objects from daily usage) were normal.

A 2-way ANOVA was performed to verify if Associate Learning had occurred. It showed an increasing learning curve for both groups [F(3,141)=230.67; p<0.0001], and no interaction between groups and trials [F(1,141)=0.2499; p=0.86], indicating that the rate of learning was similar in both groups, although the amount of learning of the controls was higher than that of the patients [F(1,47)=13.34; p=0.0007] (Fig 1A).

Regarding the Logical Memory Test (Fig 1B), a 2-way ANOVA showed that in the second trial the subjects remembered less words than in the first trial [F(1,47)=6.308; p=0.01]. There was no group x trial interaction [F(1,47)=0.0006; p=0.98], indicating that the rate of forgetting was similar in both groups, in spite of the fact that the patients remembered less fragments of the story [F(1,47)=63.515; p<0.0001).

The number of errors in the Stroop Color test was not greater in the patients group than in the controls group in none of the three cards that constitute the task, but the patients were significantly slower in reading the words of Cards I and III.

As shown in Table 3, the patients showed a higher score on the Beck Scale than the controls. The anxiety inventory did not reveal differences between the groups.

DISCUSSION

The Digit Span test is widely used to measure verbal short-term memory and also evaluates auditory attention¹⁷, while the blocks of Corsi do the same thing with visuospatial material. The results here presented are in agreement with several reports of normal verbal and visuospatial span^{8,10,12-14,22-24}.

The known sensorimotor disturbances presented by MS patients may cause marked impairments on tasks that require motor responses^11,14,25. Thus, disturbances in motor function could explain the poorer performance of our MS patients in some tasks contaminated with motor components, as the Digit Symbols and the Picture Arrangement tests. Impairment on these tests was reported previously^8,26,27. Nonetheless, motor disturbances cannot account for deficits in many other tests. For instance, the score attained by our patients in the delayed Osterrieth-Rey Figure was low, but the copy was as good as the controls. Thus, it is necessary to invoke further impairment in other cognitive functions to explain the deficit in this delayed test.

The WAIS Similarities was found to be impaired by Klonoff et al.⁸ but not by others^10,14. Deficits in the WAIS Block Design are not commonly reported. To our knowledge, in this latter test and in other tests of the WAIS battery, only Rao et al.²⁸ have found significant differences in part of their sample of MS patients.

Deficits in planning and organizational skills are generally associated with disorders in the frontal systems. In our patients, the constructional ability, as evaluated by the copy of the Rey-Osterrieth Figure was found to be within the normal limits; organizational, planning and copying abilities were not loosed, although slowness had been observed in some cases. Backward span requires additional mental processing and therefore can be considered a test of working memory, a function believed to be related to executive frontal systems²⁹. Both verbal and visuospatial backward span were found to be normal. Thus, the executive frontal functions of our patients do not appear to be affected by the disease. Nonetheless, evidence for frontal dysfunction was reported by some authors based on the Wisconsin Card Sorting Test^22,30, but Beatty and Monson³¹ interpreted the results usually obtained in MS as a deficit in concept formation.

The Stroop test revealed that the patients were slower than the control subjects in reading the words, a result that is in agreement with Jennekens-Schinkel et al.³² and van den Burg et al.³⁴ who obtained a similar result. Information processing speed assessed by different techiques was reported by others to be lower as well in MS patients^14,25,33.

Disorders in language functions were not detected by the Vocabulary subtest of the WAIS-R and by object naming. Naming was also found to be undisturbed in previous reports^32.33. Word generation was unimpaired in one study³², but in the present study the patients produced a significantly smaller number of words in the FAS test, in agreement with most published results that show that impaired verbal fluency is a common finding in MS patients ^{8,22,23,26,30}. A deficit in word generation can be due to a slowing in mental processes, as the test requires the subject to produce as many words as possible within a fixed limit of time.

Immediate and delayed measures of Visual Reproduction were not significantly reduced in our patients. Memory for concrete objects was not impaired at all. In contrast, performance on tests that involve immediate and delayed verbal memory (Logical Memory and Paired Associate Learning) was impaired. This pattern of results suggests a deficit specific to verbal memory and verbal learning. Running counter to this hypothesis, the delayed recall of the Complex Figure of Rey-Osterrieth, a nonverbal memory test, was also poorer in our MS group. No explanation is available at the time for these discrepancies on memory measures, but one can speculate that the complexity of the task constitutes an important factor in determining memory impairments in these patients, as the tasks that were impaired, Logical Memory, Paired Associates and Rey-Osterrieth Figure seem to be the more complex tests, either in the number of items to be remembered or in the structure of the test.

How do our results in long-term memory tests compare to results in similar tasks reported in the international literature? The WMS Logical Memory and similar story recall tests are consistently found to be impaired in patiens with MS^12,13,23,28, as well as the difficult pairs and the delayed testing of paired associates^8,13,24,35. Visual reproduction was also found to be impaired by Rao et al.¹³ in chronic progressive patients.

Depression appears with a high rate of occurrence in patients with MS³⁶. As cognitive impairment occurs in depressed patients, the cognitive impoverishment of patients with MS may be related to the their depressive state. In our sample, the patients attained higher scores on the Beck inventory than the controls, but their mean score of 15.5 ± 11.3 is not indicative of clinical depression¹⁹. A similar result in relapsing remitting patients was also found by others^33,37, who considered that the depression found in their patients, although more pronounced than in normal people, cannot account for their cognitive deficits. It may be concluded, then, that the results of the group as a whole cannot be explained by depressive state, although it cannot be ruled out that depression had affected the individual results of some patients. Anxiety, on the contrary, remained in the same levels attained by the controls of our sample.

Changes in the professional life of the patients, reflecting probably in their financial status, had occurred as the demographic data suggest (Table 1). It is clear that the disease has an impact on the lives of the patients not restricted to their physical conditions, but also affecting their social functioning, family relationships, employment conditions, and their psychic and cognitive conditions³⁸.

In the absence of global intellectual deterioration, the patients presented a deficit in performing several cognitive tests. The pattern of deficits seen in our MS relapsing remitting patients comprises: a) impairment in verbal and visual memory and learning tasks; b) impairment in timed tasks, accounted for by a slowness of mental processes; c) impairment in tasks with a motor component, explained, at least partially, by a difficulty in perform motor responses. Some of these tasks, however, are also timed (e.g. Digit Symbols), so the deficit may lie on the slowness of processing instead of on impairment of motor functioning.

These results are similar to those obtained in neuropsychological studies of European and North American countries. Although clearly impaired, the magnitude of the deficits can be classified as moderate. Some authors, indeed, have found less severe impairments on cognitive tests of relapsing remitting patients than in chronic progressive patients^22,33, but the question whether the degree of cognitive impairment depends or not on the type of course of disease is still a matter for debate. The degree of cognitive impairment is variable but the incidence is high even in patients physically independent. According to Rao and his colleagues²⁸, some degree of cognitive impairment affects about 54% to 65% of the patients.

Dr. Orlando F.A. Bueno - Departamento de Psicobiologia UNIFESP - Rua Botucatu 862, 1^º andar - 04023-062 São Paulo SP - Brasil. E-mail: mgabi@psicobio.epm.br

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