Dr. Prasanth Varghese C. Resident in Neurology. Month and Year of Submission: October 2013

Transcription

1 Frequency and pattern of cognitive dysfunction in Multiple Sclerosis and correlation with MRI lesion load from a Tertiary Referral centre in South India Thesis submitted in partial fulfilment of the rules and regulations for DM Degree Examination of Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram. By Dr. Prasanth Varghese C Resident in Neurology Month and Year of Submission: October 2013 i

2 CERTIFICATE I, Dr. Prasanth Varghese C, hereby declare that I have actually carried out the project under report. Date: Place: Thiruvananthapuram Dr. Prasanth Varghese C Resident in Neurology Forwarded: He has carried out the project under report. Dr. Muralidharan Nair, Professor & Head, Department of Neurology, SCTIMST ii

3 ACKNOWLEDGEMENT I express my sincere gratitude to my guide, Dr. Muralidharan Nair, Professor & Head of Department Neurology, SCTIMST who has been the guiding spirit behind the project all along with his in-depth knowledge and vast experience. His expert guidance, constant review, help, and keen interest has motivated and inspired me at each and every step during the completion of this study. I am grateful to Dr C Kesavadas, Professor, Department of Imaging and Interventional Radiology, and Dr Ramshekhar Menon, Assistant Professor, Department of Neurology, SCTIMST who have always found time to give me their insightful suggestions, every possible support and motivation at all stages of this work. I express my sincere thanks to Ms Sunitha, Ms Lekha, Ms Anju, Ms Shiji for assisting me in the detailed neuropsychology evaluation of the cases and the controls. I sincerely thank Dr P Sankara Sarma, Additional Professor, Achutha Menon Center for Health Science Studies for helping me with the statistical analysis of this study. I express my gratitude to the patients who took part in this study. Dr. Prasanth Varghese C. iii

4 CONTENTS Introduction 1 Review of Literature 7 Aims & Objectives 12 Material and Methods 13 Statistical Analysis 18 Results 19 Discussion 40 References 47 Appendix 60 Abbreviation 65 iv

5 INTRODUCTION Charcot, Carswell, Cruveilhier, and others more than 100 years ago described the clinical and pathological characteristics of multiple sclerosis (MS). 1 This enigmatic, relapsing, and often eventually progressive disorder of the white matter of the central nervous system continues to challenge investigators trying to understand the pathogenesis of the disease and prevent its progression. 2 There are 250, 000 to 350,000 patients with multiple sclerosis in the United States. 3 Fifty percent of patients will need help for walking within 15 years after the onset of disease. 4 Advanced magnetic resonance imaging (MRI) and spectroscopy may allow clinicians to follow the pathological progression of the disease and monitor the response to treatment. Recent progress has occurred in understanding the cause, the genetic components, and the pathologic process of multiple sclerosis. The short-term clinical and MRI manifestations of disease activity have been reduced by newer therapies, although the degree of presumed long-term benefit from these treatments will require further study. 1.1 CLINICAL COURSE AND DIAGNOSIS A patient s presenting symptoms and the temporal evolution of the clinical findings may suggest the correct diagnosis of multiple sclerosis. 80 percent of patients present with relapsing remitting type of multiple sclerosis. Symptoms and signs typically evolve over a period of several days, stabilize, and then often improve spontaneously or in response to corticosteroids, within weeks. Relapsing remitting multiple sclerosis typically begins in the second or third decade of life and has a female predominance of approximately 2:1. Twenty percent of affected patients have primary progressive multiple sclerosis, which is characterized by a gradually progressive clinical course and a similar incidence among men and women. Relapsing remitting multiple sclerosis typically starts with sensory disturbances, unilateral optic neuritis, diplopia (internuclear ophthalmoplegia), Lhermitte s sign 1

6 (trunk and limb paresthesias evoked by neck flexion), limb weakness, clumsiness, gait ataxia, neurogenic bladder and bowel symptoms. Some patients have prominent cortical signs (aphasia, apraxia, recurrent seizures, visual-field loss, and early dementia). Extrapyramidal phenomena (chorea and rigidity) only rarely dominate the clinical picture. Eventually cognitive impairment, depression, emotional lability, dysarthria, dysphagia, vertigo, progressive quadriparesis, sensory loss, ataxic tremors, pain, sexual dysfunction, spasticity, and other manifestations of central nervous system dysfunction may become troublesome. Patients who have primary progressive multiple sclerosis often present with a slowly evolving upper motor neuron syndrome of the legs ( chronic progressive myelopathy ). Typically, this variant worsens gradually, and quadriparesis, cognitive decline, visual loss, brain-stem syndromes, cerebellar, bowel, bladder, and sexual dysfunction may develop. The diagnosis is based on established clinical and, when necessary, laboratory criteria. 5 Advances in cerebrospinal fluid analysis and MRI, in particular, have simplified the diagnostic process. 6 The relapsing forms are considered clinically definite when neurologic dysfunction becomes disseminated in space and time. On MRI, findings of multifocal lesions of various ages, especially those involving the periventricular white matter, brain stem, cerebellum, and spinal cord white matter, support the clinical impression. The presence of gadoliniumenhancing lesions on MRI indicates current sites of presumed inflammatory demyelination (active lesions). When there is diagnostic uncertainty, repeated MRI after several months may provide evidence that the lesions are disseminated in time. Cerebrospinal fluid analysis often shows increased intrathecal synthesis of immunoglobulins of restricted specificity (oligoclonal bands may be present, or the synthesis of IgG may be increased), with moderate lymphocytic pleocytosis (almost invariably there are fewer than 50 mononuclear cells). 7 The course of multiple sclerosis in an individual patient is largely unpredictable. Patients who have a so-called clinically isolated syndrome (e.g., optic neuritis, brain-stem dysfunction, or incomplete transverse myelitis) as their first event have a greater risk of recurrent events (thereby confirming the diagnosis of 2

7 clinically definite multiple sclerosis). 8 The presence of oligoclonal bands in cerebrospinal fluid slightly increases the risk of recurrent disease. 9 Studies of the natural history of the disease have provided important prognostic information that is useful for counseling patients and planning clinical trials. 4,10. Suicide remains a risk, even for young patients with mild symptoms EPIDEMIOLOGIC FEATURES The prevalence of multiple sclerosis varies considerably around the world. 12 Kurtzke classified regions of the world according to prevalence: a low prevalence was considered less than 5 cases per 100,000 persons, an intermediate prevalence was 5 to 30 per 100,000 persons, and a high prevalence was more than 30 per 100,000 persons. 13 The prevalence is highest in northern Europe, southern Australia, and the middle part of North America. There has been a trend toward an increasing prevalence and incidence, particularly in southern Europe. 14,15 Even in areas with uniform methods of ascertainment and high prevalence, such as Olmsted County, Minnesota, the incidence has increased from 2 to 6 per 100,000 during the past century. 16 However, the incidence has actually declined in some, but not all, areas of northern Europe. 17 The apparent change in the frequency of multiple sclerosis among people and their offspring who migrate to and from high-prevalence areas is another factor that has been presented to support the existence of an environmental factor. 18,19 Increased risk of the disease among relatives and instead suggest that genetic factors may be responsible GENETIC FACTORS Evidence that genetic factors have a substantial effect on susceptibility to multiple sclerosis is unequivocal. The concordance rate of 31 percent among monozygotic twins is approximately six times the rate among dizygotic twins (5percent). 21 The absolute risk of the disease in a first-degree relative of a patient 3

8 with multiple sclerosis is less than 5 percent; however, the risk in such relatives is 20 to 40 times the risk in the general population. 22 The magnitude of the relative risk depends on the frequency of the HLA-DR2 allele in the general population. Given the high frequency of this allele in the population, the risk attributable to the HLA-DR2 allele is considerable. Candidategene studies were followed by four studies in which the entire genome was scanned, 23,24,25,26, regions of interest have been identified, although none have been linked to the disease with certainty. Further refinement of the linkage map is in progress. 27 IL 2 receptor antagonist genes, 28 immunoglobulin Fc receptor genes, and apolipoprotein E4gene have been associated with the course of the disease. 29, PATHOLOGICAL FEATURES Multiple sclerosis is generally believed to be an immune-mediated disorder that occurs in genetically susceptible people. 4 The pathological hallmark of chronic multiple sclerosis is the demyelinated plaque, which consists of a well-demarcated hypocellular area characterized by the loss of myelin, relative preservation of axons and the formation of astrocytic scars. Lesions have a predilection for the optic nerves, periventricular white matter, brain stem, cerebellum, and spinal cord white matter. The composition of the inflammatory infiltrate varies depending on the stage of demyelinating activity. In general, it is composed of lymphocytes and macrophages; the latter predominate in active lesions. 31 The lesions of chronic multiple sclerosis reportedly contain substantial numbers of oligodendrocyte precursor cells. 32 The regression of symptoms has been attributed to the resolution of inflammatory edema and to partial remyelination. 33 Irreversible axonal injury, gliotic scarring, and exhaustion of the oligodendrocyte progenitor pool may result from repeated episodes of disease activity and lead to progressive loss of neurologic function. 34,35,36 Antibodies against antigens located on the surface of the myelin sheath or oligodendrocyte can cause demyelination directly, possibly through the activation of complement, leading to complement-mediated cytolysis. 37 These antibodies may gain access to the central nervous system through the disruption of 4

9 the blood brain barrier as a consequence of a T cell initiated inflammatory response. 38 Antibodies against both myelin oligodendrocyte glycoprotein and myelin basic protein can be found in the brains of patients with multiple sclerosis. Deposits of immunoglobulin and activated complement may be present in multiple sclerosis lesions in which myelin is being degraded. 39 Other factors potentially toxic to oligodendroglial cells include, cytotoxicity mediated by the interaction of CD8+ T cells with class I major histocompatibility complex (MHC) antigens on antigen-presenting cells, and persistent viral infection. 40 In one study, Chlamydia pneumoniae was isolated from 64 percent of patients with multiple sclerosis, as compared with 11 percent of control patients with other neurologic diseases, and it was detected in cerebrospinal fluid by a polymerase chain reaction assay in 97 percent of patients with multiple sclerosis, as compared with 18 percent of control patients.these results have yet to be confirmed in other laboratories. 41 There is an important degree of variability among patients in the structural and immunologic features of the lesions of multiple sclerosis. 42 Although most lesions are characterized by an inflammatory reaction, composed mainly of T lymphocytes and macrophages, diverse patterns of myelin destruction have been described. 43 MRI and spectroscopy may be helpful in characterizing the underlying pathologic processes in multiple sclerosis. There is consensus that T2 weighted MRI reflects a broad spectrum of pathological changes, including inflammation, edema, demyelination, gliosis, and axonal loss. Changes in the number and volume of lesions on T2 weighted MRI (referred to as the T2 weighted lesion load) are sensitive but nonspecific indicators of disease activity and the response to treatment. New lesions and areas of gadolinium enhancement on T1 - weighted MRI suggest recent inflammatory demyelination with disruption of the blood brain barrier. Monitoring by means of serial MRI studies with gadolinium enhancement helps to identify agents that may be active against this early inflammatory stage of multiple sclerosis (e.g., corticosteroids, interferons, glatiramer acetate, and certain immunosuppressive 44, 45 agents). 5

10 There is MRI and pathological evidence that the normal-appearing white matter is not normal in patients with multiple sclerosis. 46 Serial MRI studies of normal-appearing white matter may be useful to determine where abnormalities are likely to develop. 47 6

11 REVIEW OF LITERATURE Multiple sclerosis (MS) is a progressive disease of the CNS and is characterised by the production of widespread lesions, or plaques, in the brain and spinal cord. These lesions and plaques affect the myelin sheath, thus causing inhibition of axonal transmission. Inflammatory demyelination has traditionally been seen as the main disease process in MS; however, axonal damage or loss is increasingly being documented to occur early in the disease and to result in permanent disability. 48 Whether grey matter pathology is independent of that seen in white matter, is a result of axonal injury in the white matter, or is simply similar to the pathology seen in the white matter is debated. 49 Because of the widespread development of the plaques, MS results in a broad range of symptoms, which include motor, cognitive, and neuropsychiatric problems. 50 Cognitive deficits can occur independently of physical disability, which complicates their identification and recognition. This wide variability in symptoms and disease course hampers understanding of the disease process and identification of effective treatments. Although the precise cause of MS is not yet known, it is currently thought to be the result of immunological, genetic, and viral factors Cognitive deficits in MS Since the 1980s, research has indicated that cognitive impairment is a common concomitant of MS, with prevalence rates ranging from 43% to 70% at both the earlier and later stages of the disease. 52,53 MS detrimentally affects various aspects of cognitive functioning, including attention, 54,55 information processing efficiency, 54,56 executive functioning, 57 processing speed, 58 and long term memory. 59 Processing speed, and visual learning and memory seem to be most commonly affected in MS (in 51.9% and 54.3%), respectively. Areas of cognition that are not usually affected are simple attention (eg, repeating digits) and essential verbal skills (eg, word naming and comprehension). 50 Although most studies indicate that 7

12 general intelligence remains intact in patients with MS, 60 other investigations have detected slight but significant decrements. Overt dementia is rare in MS, and the more common clinical presentation is one of specific and subtle cognitive deficits that can vary substantially among patients Long-term memory Long-term memory refers to the ability to learn new information and to recall that information at a later time point. 62 Long-term memory is one of the most consistently impaired cognitive functions in MS and is seen in 40 65% of patients. 50 Early work on memory impairment in MS suggested that difficulty in retrieval from long term storage was the primary cause for the deficit in long-term memory. 63 More recently, however, research has shown that the primary memory problem is in the initial learning of information. 64 Patients with MS require more repetitions of information to reach a predetermined learning criterion, but once that information has been acquired, recall and recognition are at the same level as for healthy controls. 64, Efficiency of information processing Information processing efficiency refers to the ability to maintain and manipulate information in the brain for a short time period (working memory) 66 and to the speed with which one can process that information (processing speed). A reduced speed of processing is the most common cognitive deficit in MS 67 in some studies the extent of memory impairment has been positively correlated with deficits in processing speed. 50,68 Deficits in working memory and speed of processing affect each other in patients with MS: as the demands on working memory increase, both deficits in speed of processing and working memory become more prominent. 69 The Paced Auditory Serial Addition Test (PASAT), a test of working memory with substantial demands on processing speed, is a sensitive measure of cognitive dysfunction in MS and has a sensitivity and specificity of 74% and 65%, respectively. 70 The PASAT is the cognitive component of the widely used multiple sclerosis functional composite. Variability in the exact cognitive processes labeled 8

13 attention makes it difficult to draw conclusions about the effect of MS on attention processes. 71,72, Executive functions Deficits in executive functions (ie, abstract and conceptual reasoning, fluency, planning, and organisation) occur in patients with MS, albeit less frequently than deficits in memory and information processing efficiency. 74 Drew and coworkers 75 noted that 17% of patients with MS had difficulties across a range of executive abilities (i e; shifting, inhibition, and fluency). Fluency tests evaluate the spontaneous production of words under restricted search conditions, such as words that begin with a specific letter and words from a particular category, 76 perseverative errors (ie, errors that are repeated despite evidence that they are incorrect) have been repeatedly seen in patients with MS. 77 Measures of executive functioning are also particularly susceptible to the effects of depression in patients with MS Visual perceptual functions Up to about a quarter of people with MS might have deficits in visual perceptual functions. 79 Difficulties in primary visual processing (eg, from optic neuritis) in MS can have a detrimental effect on visual perceptual processing, although perceptual deficits that are independent of primary visual or other cognitive abnormalities can also occur. Primary visual problems can contribute to difficulties on higher-order cognitive tasks that have visual demands Assessment of cognitive functioning Given the high occurrence of cognitive dysfunction in patients with MS, adequate assessment and diagnosis of these deficits is essential. Clinicians and researchers have used various tests of cognitive functioning to identify the deficits commonly seen in these patients. As the cognitive deficits in MS frequently fall within specific cognitive domains and can be subtle and vary considerably among patients, a carefully selected neuropsychological test battery is essential. Various batteries have been recommended for use, although many have been criticised for 9

14 their emphasis on brevity rather than comprehensiveness and thus often fail to identify cognitive deficits accurately. 81 However, other tests have been deemed too comprehensive because areas that are not typically affected by MS are assessed and these tests are thus inefficient in terms of cost and time. 82 Consequently, an International Conference of MS Experts resulted in the development of the minimal assessment of cognitive function in MS test battery, which is now recommended for use with patients with MS. This battery is composed of seven tests that assess word fluency, visuospatial ability, verbal memory, visuospatial memory, processing speed, working memory, and executive function, and has been shown to be sensitive to the cognitive profiles characteristic of patients with MS. In an effort to increase the availability of screening assessments, researchers have also started to investigate the validity of internet-based cognitive testing Neuroimaging and cognition Structural neuroimaging has become a key element of diagnosis and care in MS. Various techniques designed to capture brain integrity MRI being the most widely used have shown correlations with cognitive functioning. Several measures can be obtained by use of MRI, including whole brain atrophy, cortical atrophy, and lesion volume. Studies have shown that patients with greater lesion burden have significantly more cognitive dysfunction than those with less lesion burden. 84 Measures of brain atrophy are particularly sensitive in elucidating the relation between brain integrity and cognitive status and sub cortical atrophy is more highly correlated with cognition than whole brain atrophy or lesion load. 85 Grey matter and white matter atrophy have been associated with performance in particular cognitive skills, which indicates that atrophy in these distinct tissue types could result in specific functional deficits. Similarly, left frontal atrophy has been associated with performance on tests of verbal memory, whereas right frontal atrophy has been associated with deficits in visual memory and working memory. Progression of brain atrophy early in the disease can predict cognitive impairment 5 years later. New technologies can help to maximise our ability to assess cerebral integrity in MS. Measures derived from magnetization transfer ratio have also consistently been 10

15 shown to be associated with cognition, as documented with many types of brain tissue, including cortical and subcortical regions, normal-appearing brain tissue on conventional imaging, 125 and normal-appearing white matter. Magnetic resonance spectroscopy, which provides a measure of metabolic changes in the cerebral cortex and white matter, is also a sensitive indicator of cognitive functioning in MS, particularly in normal-appearing white matter

16 AIMS AND OBJECTIVES 1. To study the frequency of cognitive dysfunction in Remitting Relapsing Multiple Sclerosis. 2. To study the pattern of cognitive dysfunction in Remitting Relapsing Multiple Sclerosis. 3 To identify the predictors of cognitive dysfunction in Remitting Relapsing Multiple Sclerosis. 4 To determine the MRI correlates of cognitive dysfunction in Remitting Relapsing Multiple Sclerosis 12

17 MATERIALS AND METHODS 1.1 Study design: The study was a hospital based case control study to assess the cognitive dysfunction in early remitting relapsing multiple sclerosis. Patients with multiple sclerosis undergoing treatment as in-patients and out-patients at Sree Chitra Tirunal Institute for Medical Sciences and Technology (SCTIMST), Thiruvananthapuram were identified as cases. They were subdivided depending up on the duration of the disease into early multiple sclerosis, who had their first attack of the disease with in last 24 months and late multiple sclerosis, who had their first attack of the disease more than 24 months. Healthy age, gender and educational status matched individuals were taken as controls. After getting informed consent, they were interviewed and examined based on a structured proforma. The data collected, included demographic details, details of the illness and EDSS score. A comprehensive neuropsychological test-battery was applied to MS cases and controls. The neuropsychological test-battery consisted of memory, executive functioning tests and a visuo-spatial functioning test. A computerized attention testbattery (PASAT) was also performed, which assess accuracy and speed of test responses. 1.2 Inclusion criteria: All patients with remitting relapsing multiple sclerosis (meeting the 2010 modified Macdonalds criteria) 87 were included in the study 1.3 Exclusion criteria: 1. When the diagnosis is not definite 2. Physical disability significant enough to impair the test results 3. Depression significant enough to impair the test results 4. Alcohol or substance abuse 13

18 5. Other medical conditions affecting cognition 1.4 Selection of subjects: Cases: Patients with remitting relapsing multiple sclerosis attending out-patient clinic or under in-patient care in SCTIMST were identified as cases. No age limit was set for the inclusion criteria. Multiple sclerosis was diagnosed according to the 2010 modified Macdonalds criteria. Reference population: Age, gender and educational status matched healthy individuals were taken as controls. Voluntary informed consent was obtained from each subject prior to enrollment in the study. Each subject, was given both verbal and written information describing the nature of the study, need for participating in the study and potential benefits and risks of the study. The informed consent process took place under conditions where the subject had sufficient time to consider the risks and benefits associated with participation in the study. He/she was also informed that the participation in the study was voluntary and that he/she may refuse to participate or withdraw from the trial, at any time, without affecting their care. 1.5Assessment of the cases: All the subjects selected were interviewed based on a structured proforma. The details included the following: 1.6 History The demographic profile of the person ; name, age, sex, occupation, educational status. Details of multiple sclerosis regarding the duration of disease and the number of relapses in the patient. 14

19 1.7 Physical examination A detailed neurological examination of the cases was conducted to identify the EDSS. If the patient presented with an acute episode, the EDSS was calculated only at three month review. 1.8 Investigations Neuropsychological assessment A detailed neuropsychology evaluation was done in all the cases and healthy controls. The neuropsychological test-battery was administered in two parts. The first part included attention and working memory tasks compiled in a computerized attention test battery, the Paced Auditory Serial Addition Test (PASAT). The second part consisted of a non computerized assessment of attention (forward and backward digit span), working memory and motor speed by The Symbol Digit Modalities Test (SDMT) as well as global cognitive assessment by Addenbrooke s Cognitive Assessment (ACE). Measures of short-term memory from the Wechsler Memory Scale (WMS-R) and Visuo Object and Space Perception (VOSP- PD) and Cube analysis were applied for visuo spatial performance. Finally, all patients were subjected to Beck s Depression Inventory (BDI), as depression could confound results of cognitive testing Paced Auditory Serial Addition test (PASAT) : PASAT is a measure of cognitive function that assesses auditory information processing speed and flexibility, as well as calculation ability. It was initially developed to monitor recovery in patients who had sustained concussions and has been widely used in studies of head-injured patients over the last 20 years. Stimulus presentation rates were modified for use in MS patients by Rao and colleagues. 88 Single digits are presented via audiotape at a rapid rate (every 3 sec) and the patient must add each new digit to the one immediately prior to it. The dependent variable is the number of correct sums given (out of 60 possible). 15

20 1.8.2 The Symbol Digit Modalities Test (SDMT) The SDMT is a simple, practical measure of information processing speed presented in the visual modality. Patients view a key presenting nine numbers paired with unique symbols. Below the key is an array of symbols paired with empty spaces, the patient s task is to write the matching number for each symbol as quickly as possible with in one minute. The test requires only five minutes to administer, and the SDMT is less aggravating because the processing is self-paced rather than in response to external fixed presentation rates ACE (Addenbrooke s Cognitive Examination) ACE is a brief bedside cognitive screening instrument. It is easy to use and has excellent sensitivity and diagnostic accuracy. ACE encompasses test of attention, orientation, memory, language, visuo-spatial skills and executive function with a total score of 100. Reliability of the ACE was evident from its high internal consistency. The design of the ACE allows sensitivity to the early stages of AD and FTD. The excellent performance of ACE has prompted its translation into a number of languages. These translation has facilitated the examination of ACE performance in a large number of independent patient cohort Wechsler Memory Scale (WMS) The Wechsler Memory Scale is a neuropsychological test that can be used with people from age 16 to 90.It evaluates early and late logical and verbal memory. In logical memory two brief stories are presented orally to the patient and he is e asked freely recall each story immediately and after 30 minutes. A delayed recall is also assessed. The total score for both immediate and delayed is MRI The lesion load was counted from the available MRI (latest, if multiple MRI in a given case) at the time of assessment of cognitive functions. Lesion load 16

21 calculation was made from T2 FLAIR sequences. Confluent lesions were counted as single. The lesion count was determined according to the areas involved (i.e. cortical gray matter, periventricular, juxtacortical, brainstem and cerebellum).the lesion count was done by a radiologist, who is an expert in the diagnosis of MS. Fig 1. MRI T2 FLAIR images of a 42 year old female with RRMS of duration of 6months (Early RRMS): Periventricular (a) and juxta cortical (b) lesions are seen. No lesions are seen in the brainstem or cerebellum(c) Fig 2. MRI T2 FLAIR images of a 55 year old female with RRMS of duration of 75 months (Late RRMS): Periventricular (a) and juxta cortical (b) lesions are seen. No lesions are seen in the brainstem or cerebellum(c) 17

22 STATISTICAL ANALYSIS Chi square test was used to compare the difference in the cognitive functions among the cases and the controls. They were analysed separately for both early and late MS cases. The total MS cases were subdivided into those with cognitive impairment and those without cognitive impairment based on three separate variables the PASAT, SDMT and ACE. The cut off for these variables was mean -1.5 SD from the control values. Factors affecting cognition were analyzed in each group. Data analysis was done using the statistical software, SPSS under the guidance of a medical statistician. 18

23 RESULTS The total number of cases for the study were cases of early RRMS out of which 9 were females and 27 cases of late RRMS out of this 16 were females. Table 1. Age-wise stratification of patients with Early Multiple Sclerosis Early multiple sclerosis Control Age N % N % > Total Figure 3. Age-wise stratification of patients with Early Multiple Sclerosis 19

24 Table 2.Gender-wise distribution of patients with Early Multiple Sclerosis Early multiple sclerosis Control Gender N % N % Male Female Total Figure 4. Gender-wise distribution of patients with Early Multiple Sclerosis 20

25 Table 3. Educational status of patients with Early Multiple Sclerosis Early multiple sclerosis Control Educational status N % N % Up to Plus two Graduate and above Total Figure 5.Educational status of patients with Early Multiple Sclerosis 21

26 Table 4.Comparison of Neuropsychological Battery test components between Patients with Early Multiple Sclerosis (< 24 months) and Controls N Mean SD t p value PASAT Early multiple sclerosis Control SDMT Early multiple sclerosis Control ACE Early multiple sclerosis Control MMSE Early multiple sclerosis Control Forward digit span Early multiple sclerosis Control Backward digit span Early multiple sclerosis Control Anterograde Early multiple sclerosis memory immediate Control Anterograde memory delayed Early multiple sclerosis Control Retrograde memory Early multiple sclerosis Control Letter fluency Early multiple sclerosis Control Category fluency Early multiple sclerosis Control WMS LM Immediate Early multiple sclerosis Control WMS LM Delayed Early multiple sclerosis Control WMS VM Early multiple sclerosis Immediate Control WMS VM Delayed Early multiple sclerosis Control VOSP PD Early multiple sclerosis Control VOSP Cube Early multiple sclerosis Control p Values in bold indicates statistical significance 22

27 Table 5. Age-wise stratification of patients with Late Multiple Sclerosis Late multiple sclerosis Control Age N % N % > Total Figure 6. Age-wise stratification of patients with Late Multiple Sclerosis 23

28 Table 6.Gender-wise distribution of patients with Late Multiple Sclerosis Late multiple sclerosis Control Gender N % N % Male Female Total Figure 7.Gender-wise distribution of patients with Late Multiple Sclerosis 24

29 Table 7. Educational status of patients with Late Multiple Sclerosis Late multiple sclerosis Control Educational status N % N % Up to Plus two Graduate and above Total Figure 8. Educational status of patients with Late Multiple Sclerosis 25

30 Table 8.Comparison of Neuropsychological battery test components between patients with Late Multiple Sclerosis and Controls N Mean SD t p value PASAT Late multiple sclerosis Control SDMT Late multiple sclerosis Control ACE Late multiple sclerosis Control MMSE Late multiple sclerosis Forward digit span Control Late multiple sclerosis Control Backward digit Late multiple sclerosis span Control Anterograde Late multiple sclerosis memory Control immediate Anterograde Late multiple sclerosis memory delayed Control Retrograde Late multiple sclerosis memory Control Letter fluency Late multiple sclerosis Control Category fluency Late multiple sclerosis Control WMS LM Late multiple sclerosis Immediate Control WMS LM Late multiple sclerosis Delayed Control WMS VM Late multiple sclerosis Immediate Control WMS VM Late multiple sclerosis Delayed Control VOSP PD Late multiple sclerosis Control VOSP Cube Late multiple sclerosis Control p Values in bold indicates statistical significance 26

31 Table 9.Derivation of mean cut-off values of PASAT, SDMT and ACE Among the controls N Minimum Maximum Mean SD 1.5 SD Mean SD PASAT SDMT ACE Table 10.Age-wise distribution of PASAT scores in Early and Late Multiple Sclerosis patients PASAT 33.3 >33.3 Total Age N % N % N % > Total χ 2 =2.523 df =1 p=

32 Figure 9.Age-wise distribution of PASAT scores in Early and Late Multiple Sclerosis patients 28

33 Table 11. Gender-wise distribution of PASAT scores in early and late multiple sclerosis patients PASAT 33.3 >33.3 Total Gender N % N % N % Male Female Total χ 2 =2.523 df =1 p=0.112 Figure 10. Gender-wise distribution of PASAT scores in early and late multiple sclerosis patients 29

34 Table 12. Distribution of PASAT scores in early and late multiple sclerosis patients according to educational status PASAT Educational status 33.3 >33.3 Total N % N % N % Up to Plus two Graduate and above Total χ 2 =1.292 df =1 p=0.256 Figure 11. Distribution of PASAT scores in early and late multiple sclerosis patients according to educational status 30

35 Table 13. Comparison of disease characteristics, EDSS scores and MRI correlates among cognitively intact and impaired cases based on PASAT scores PASAT N Mean SD t P value Duration of disease in years > No. of episodes > EDSS > Periventricular > Juxtacortical > Brainstem > Cerebellum > Gray > p Values in bold indicates statistical significance 31

36 Table 14.Age-wise distribution of SDMT scores in early and late multiple sclerosis patients SDMT 45.4 >45.4 Total Age N % N % N % > Total χ 2 =2.612 df =1 p=0.106 Figure 12.Age-wise distribution of SDMT scores in Early and Late Multiple Sclerosis patients 32

37 Table 15.Gender-wise distribution of SDMT scores in Early and Late Multiple Sclerosis patients SDMT 45.4 >45.4 Total Gender N % N % N % Male Female Total χ 2 =0.003 df =1 p=0.953 Figure 13.Gender-wise distribution of SDMT scores in Early and Late Multiple Sclerosis patients 33

38 Table 16. Distribution of SDMT scores in Early and Late Multiple Sclerosis patients according to educational status SDMT 45.4 >45.4 Total Educational status N % N % N % Up to Plus two Graduate and above Total χ 2 =2.874 df =1 p=0.090 Figure 14. Distribution of SDMT scores in Early and Late Multiple Sclerosis patients according to educational status 34

39 Table 17. Comparison of disease characteristics, EDSS scores and MRI correlates among cognitively intact and impaired cases based on SDMT scores SDMT N Mean sd t p Duration of disease in years < > no of episodes < > EDSS < > Periventricular < > Juxtacortical < > Brainstem < > Cerebellum < > Gray < > p Values in bold indicates statistical significance 35

40 Table 18.Age-wise distribution of ACE scores in Early and Late Multiple Sclerosis patients ACE 93.6 >93.6 Total Age N % N % N % > Total χ 2 =1.827 df =1 p=0.176 Figure 15. Age-wise distribution of ACE scores in Early and Late Multiple Sclerosis patients 36

41 Table 19.Gender-wise distribution of ACE scores in Early and Late Multiple Sclerosis patients ACE 93.6 >93.6 Total Gender N % N % N % Male Female Total χ 2 =1.387 df =1 p=0.239 Figure 16.Gender-wise distribution of ACE scores in Early and Late Multiple Sclerosis patients 37

42 Table 20. Distribution of ACE scores in Early and Late Multiple Sclerosis patients according to educational status ACE 93.6 >93.6 Total Educational status N % N % N % Up to Plus two Graduate and above Total χ 2 =0.009 df =1 p=0.924 Figure 17. Distribution of ACE scores in Early and Late Multiple Sclerosis patients according to educational status 38

43 Table 21. Comparison of disease characteristics, EDSS scores and MRI correlates among cognitively intact and impaired cases based on ACE scores ACE N Mean sd t p Duration of disease in years > no of episodes > EDSS > periventricular > juxtacortical > brainstem > cerebellum > gray > p Values in bold indicates statistical significance 39

44 DISCUSSION Though there is data regarding cognitive dysfunction in multiple sclerosis in world literature, most of it is based on studies from the West. There is a dearth of studies emphasizing prevalence and pattern of cognitive dysfunction in Indian patients with relapsing remitting multiple sclerosis, more so in the early phases of the MS. We looked into the prevalence of cognitive dysfunction in multiple sclerosis, after classifying the patients with RRMS into two subgroups-early and late RRMS. Early RRMS was defined as RRMS patients with disease duration less than 24 months and late RRMS as those with disease duration more than 24 months. Apart from analyzing the pattern of cognitive dysfunction in multiple sclerosis, the various predictors of cognitive dysfunction in RRMS and the imaging correlates were also systemically examined. Cognitive dysfunction in early RRMS Our study revealed cognitive impairments on neuropsychological assessment in MS-patients quite early on in their disease course. Patients with early MS were compared to age, gender and educational status matched controls. Tests which attained statistical significance (p value < 0.05) include PASAT, SDMT, ACE, WMS LM (both immediate and delayed), delayed anterograde memory and backward digit span. The other cognitive tests namely, forward digit span, immediate anterograde memory, retrograde memory, letter and category fluency, WMS-verbal memory (immediate and delayed), VOSP PD and VOSP cube analysis did not achieve any statistical significance. Previous studies on cognitive impairment in MS patients had assessed cognition in more advanced stages of the disease. The pattern of deficits in the early stages is similar to the pattern that is usually obtained in MS patients with further advanced stages of the disease. 154 Early MS patients displayed significantly lengthened reaction times, deficient attention and poor verbal memory and intact visual memory. Reduced speed of information processing may be a fundamental neuropsychological deficit in the earliest stages of the disease. ACE scores, but not 40

45 MMSE scores were found to be significantly lower in early MS patients when compared to controls clearly showing that MMSE is a poor tool to identify the subtle cognitive deficits in RRMS, early into the illness. These results are comparable to the results published by Doreen Schulz et al 95, wherein the main deficits identified in early RRMS patients were in attention and working memory, immediate memory (backward digit span), verbal memory and visuospatial functions. However, visuospatial functions appeared to be intact in early MS cases in our study. This difference could be due to the difference in the method of test used. In their study, the test used 27 cubes for analysis where as in the conventional VOSP cube analysis which was used in our study, used 10 cubes. Our findings are based on a relatively small sample of selected patients reporting to a specialized center, which may have led to the overestimation of the occurrence of cognitive dysfunction in the MS population as a whole. One of the most important outcome of this study is that we could identify cognitive dysfunction in patients even in the early stages of MS. Furthermore the pattern of cognitive dysfunction observed in our patients, resembled the pattern described in world literature. Another forthcoming observation is that, to identify cognitive dysfunction in early multiple sclerosis further dedicated test battery may be required and commonly used bedside screening tools like MMSE may not be adequate to detect the subtle cognitive dysfunction seen in this subset of patients. Cognitive dysfunction in late RRMS cases The fact that neuropsychological assessment reveals cognitive impairment in late stages of RRMS is largely undisputed. Late MS cases were compared with age, gender and educational status matched controls. Tests which attained statistical significance include PASAT, SDMT, ACE, MMSE, WMS- LM (both immediate and delayed), delayed anterograde memory, letter and category fluency, WMS logical and verbal memory ( both immediate and delayed). Other cognitive tests, the forward and backward digit span, immediate anterograde memory, VOSP-PD and VOSP cube did not achieve any statistical significance. As the disease advances, the cognitive deficits become added and in addition to verbal memory impairment, 41

46 lapses in visual memory performances also becomes prominent. Both ACE and MMSE scores were significantly lower in the late MS patients as compared to controls whereas in early MS patients, MMSE was not significantly different. However, it is noteworthy that the difference in mean between cases and controls for MMSE is much less when compared to that of the ACE (mean values for MMSE were and respectively for cases and controls whereas similar values for ACE were and 96.93). The results are comparable with a recent study from Fischer et al. 90, who described various patterns of cognitive dysfunction in patients with MS. Nearly 33% were cognitively unimpaired, 25% showed information processing and visuo-spatial deficits, 10 to 15% showed memory deficits, 10 to 15% showed dysexecutive functions, 10 to 15% showed reduced speed, memory and visuo spatial deficits. In our study, visuospatial functions as assessed by VOSP position discrimination and cube test were unimpaired in both early and late MS cases. Predictors of cognitive impairment in RRMS The total cohort of RRMS patients were grouped together and were further subdivided into two groups- cognitively intact group and cognitively impaired group based on three important variables, the PASAT, SDMT and ACE. Since no unanimously accepted cut off values for these variables are available, the cut off values for these variables were calculated as 1.5 standard deviations below the mean value of controls.the values obtained for PASAT, SDMT and ACE were 33.31, 45.44, 93.6 respectively. The frequency of cognitive impairment varied according to the test used when PASAT was used with the cut off being Mean(control) 1.5 SD, 58 % were cognitively impaired, where as when ACE was used 69% had cognitive impairment. These results are comparable to the frequency of cognitive impairment published by Rao et al, with frequency in the study ranging from 43% to 70% 105 Several studies have found only weak association between cognitive impairments and disease duration. 91, 92 In the present study, disease duration was not significant as a contributing factor to cognitive impairment. Kujala et al 100 reported that patients who initially did not have cognitive impairment were still unaffected 3 42

47 years later, whereas incipient cognitive decline seemed to be widespread and progressive in nature. In the study published by Kujala et al The cognitively preserved multiple sclerosis group showed substantial neuropsychological stability compared to controls both at baseline and at follow-up. By contrast, the initially cognitively mildly deteriorated group demonstrated progressive cognitive decline on many neuropsychological tests 100. The disability scores as measured by EDSS correlated with cognitive performance when tested across three neuropsychological test scores (PASAT, SDMT, ACE). This finding is in accordance with the data published by Maria Pia Amato et al. 101 where higher EDSS scores and progressive course of the disorder were correlated with the total number of cognitive tests failed. Lesion load in MRI and correlation with cognitive impairment showed significant correlation between lesion load in cerebellum and cognitive impairment in RRMS when tested across PASAT, and showed significant correlation between lesion load in periventricular area and cognitive impairment in RRMS when tested across SDMT. Lesion load in other areas did not appear to have any significant correlation with the cognitive impairment. This finding appears logically plausible considering the role of cerebellum in cognition and the subcortical type of cognitive impairment observed in RRMS. Studies have shown that patients with greater lesion burden have significantly more cognitive dysfunction than those with less lesion burden. 96, 97 But most of these studies have looked in to the total lesional area as well as white matter and gray matter atrophy rather than total lesion count. Measures of brain atrophy are particularly sensitive in elucidating the relation between brain integrity and cognitive status. The width of the third ventricle has a strong association with cognitive status and sub cortical atrophy is more highly correlated with cognition than whole brain atrophy or lesion load. 98 The width of the third ventricle correlates not only with cognitive performance in MS, but also provides predictive validity for cognition. Atrophy in the thalamus is also shown to be strong predictor of cognitive dysfunction in various studies. 96, 97 Left frontal atrophy has been associated with performance on 43

48 tests of verbal memory, whereas right frontal atrophy has been associated with deficits in visual memory. 98 Total lesional area or brain atrophy was not tested in our study because of technical reasons and software requirements, It is proposed that this should be done in future studies It is now recognized that axonal injury due to inflammation and neurodegenerative processes already occurs in the early stages of MS. Irreversible axonal injury, gliotic scarring, and exhaustion of the oligodendrocyte progenitor pool may result from repeated episodes of disease activity and lead to progressive loss of neurologic function and may lead on to progressive cognitive impairment also. Thus, neuropsychological assessment should routinely be accomplished in the early stages of the disease even if brain imaging does not reveal extensive lesions. Any neuropsychological test battery for MS should best assess attention through measures of reaction speed, learning, memory (in particular verbal memory), and executive functioning like visuo-constructive problem-solving strategies. Identifying the cognitive deficits have therapeutic implications also, the treatment of MS with disease-modifying drugs is naturally expected to bring some benefits in cognitive functioning, in parallel with the improvement in clinical outcomes. In a randomized control study published by Fischer et al 94 positive results in cognition were seen with interferon beta-1a in RRMS. In a recent study 104 similar results were obtained with interferon beta-1a in early and mildly disabled patients RRMS and the findings from the study supported the clinical benefit of initiating IFN beta-1a treatment as early as possible in the course of multiple sclerosis The cognitive deficits observed in RRMS cases have a lot of practical significance, as the disease strikes young active and often professionally employed individuals. Previous studies have been shown that cognitively impaired MS-patients have a higher risk of unemployment and are partially prone to social withdrawal. MS-patients showing attention impairments were less likely to be employed than MS-patients without these impairment, and the severity of cognitive dysfunctions seemed to be related to the employment situation of the MS-patients

49 In one study 67% of cognitively unimpaired MS-patients were still employed whereas 73% of the cognitively impaired MS-patients were unemployed. 99 Identifying early cognitive deficits is of practical relevance as specific early and extensive cognitive rehabilitation can prove useful for these patients though there are no randomized controlled trials to support this hypothesis Summary A case control study to assess the frequency, pattern and predictors of cognitive impairment in early and late multiple sclerosis was undertaken separately. The study comprised of total 43 cases out of which 16 were early RRMS (< 24 months) and 27 were late RRMS ( > 24 months) Neuropsychological assessment reveals cognitive impairments of MSpatients in the early stages of their disease itself. Previous neuropsychological studies of MS patients assessed cognition in more advanced stages of the disease. The results obtained in our study demonstrate discrete cognitive dysfunctions in the early stages of MS. The pattern of deficits in the early stages resembles the pattern that is usually obtained from MS patients in advanced stages of the disease. Early MS patients displayed significantly lengthened reaction times, deficient attention and poor verbal memory. Reduced speed of information processing may be a fundamental neuropsychological deficit in the earliest stages of the disease. Furthermore, as the disease advances, the cognitive deficits become pronounced and in addition to verbal memory impairment, lapses in visual memory performances are also observed. ACE scores, but not MMSE scores were found to be significantly lower in early MS patients; however, both ACE and MMSE scores were significantly lower in the late MS cases as compared to controls. Further in our study visuospatial functions as assessed by VOSP position discrimination and cube test were unimpaired in both early and late MS cases. The results are comparable with a recent study from Fischer et al. 94, who described various patterns of cognitive dysfunction in patients with MS. The frequency of cognitive impairment when tested over the total RRMS cases varied from 58% to 69% depending on the test used. 45

50 In our study, disease duration was not significant as a contributing factor to cognitive impairment but the disability scores as measured by EDSS correlated with cognitive performance when tested across 3 neuropsychological test scores (PASAT, SDMT, ACE). Lesion load within the cerebellum and periventricular white matter correlated with cognitive impairment Axonal injury due to inflammation and neurodegenerative processes already occur in the early stages of MS, thus, neuropsychological assessment should routinely be accomplished in the early stages of the disease even if brain imaging does not reveal extensive lesions. Any neuropsychological test battery for MS should best assess attention, reaction speed, learning, memory (in particular verbal memory), and executive functioning like visuo-constructive problem-solving strategies. Conclusion.The results obtained in this study reveal discrete cognitive dysfunctions in the early stages of MS. Early MS patients displayed significantly lengthened reaction times, deficient attention and poor verbal memory. In late RRMS the cognitive deficits become more prominent with both verbal and visual memory impairment and visuo-spatial dysfunction.. ACE scores, but not MMSE scores were found to be significantly lower in early MS patients; however, both ACE and MMSE scores were significantly lower in the late MS cases as compared to controls. In this study, EDSS but not disease duration was significantly related to cognitive impairment. MRI lesion load in cerebellum and periventricular white matter correlated with the cognitive impairment. Any neuropsychological test battery for MS should best assess attention through measures of reaction speed, learning, memory and executive functioning. 46

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62 PROFORMA 1. Identification information 1.1 Serial number 1.2 Hospital number 1.3 Name 1.4 Residential address 1.5 Phone number 2. Demographic data 2.1 Age years 2.2 Sex Male 2. Female 2.3 Occupation Education status Clinical data 3.1 Handedness Right Left 3.2 Disease duration in months 3.3 Total number of episodes 3.4 EDSS 58

63 4. cognitive testing ( 1= Yes, 0 = No) 4.1 PASAT 4. 2 SDMT 4. 3 ACE 4. 4 MMSE 4. 5 WMS LM( Immediate and delayed) 4. 6 WMS VM(Immediate and delayed) 4. 7 CDT 4. 8 VOSP( PD and cube) 4. 9 Forward digit Span Backward digit Span 4.11Anterograde memory 4.12Retrograde memory 4.13 Letter fluency 4.14 Category fluency 5 MRI lesion load 5.1 Cortical grey 5.2 Juxtacortical 5.3 Periventricular 5.4 Brainstem 5.5 Cerebellum 59

64 APPENDIX I.. 60