John H. Day Psychology 491 Dr.

Leavy

Multiple Sclerosis and Cognitive Dysfunction: Untangling the Web of Interactions Multiple Sclerosis (MS) is an inflammatory, progressive disease without a cure. In MS, nerve fibers lose their myelin sheaths, through an attack by T-lymphocytes, white blood cells (Rose, Watt, White, & Carlson, 2004). The T-lymphocytes seem to perceive the myelin as an inflammation. Myelin is in the plasma membrane of the Schwann cell, and it is lipid-rich (Rothenberg & Chapman, 2000). With a loss myelin, the signals from the axons are impaired and/or interrupted. Commonly, lesions form around the demyelinated axons. The exact cause of MS has not been determined, but is believed to be linked to the X chromosome (Smith and McDonald, 1999). Symptoms of MS include, but are not limited to: ataxia, abnormal reflexes, tremors, sexual dysfunction, difficulty in urination, emotional instability, optic neuritis, heat sensitivity, cognitive difficulties, fatigue, dizziness, and, vertigo (Calabresi, 2004; Rothenberg & Chapman, 2000). Onset age of MS is typically 20-45, affecting twice as many females as males, and particularly affecting people of Northern European descent (Calabresi, 2004). In the United States, approximately 250 000 to 400 000 people have MS (Samkoff, 2002). There are four recognized varieties of MS: relapsing-remitting (RRMS), primary progressive (PPMS), secondary progressive (SPMS), and progressive-relapsing (PRMS). RRMS is found in 57.9% of persons with MS and is characterized by periods of relapse,

J.H. Day where symptoms exacerbate and periods of remission, where symptoms improve (Minden, Frankel, Hadden, Perloff, Srinath, & Hoaglin, 2006; National MS Society,

2005). PPMS is found in 12.6% of persons with MS and features no periods of remission. SPMS has a prevalence of 24.9% in persons with MS (Minden, et al., 2006) and is characterized by shorter periods of remission and more severe periods of relapse (National MS Society, 2005). PRMS is found in 4.5% of population (Minden, et al., 2006) and is characterized by periods of remission and periods worsening relapse (National MS Society, 2005). Diagnosis of MS is usually through the use of the McDonald Criteria (table 1) and requires the use of magnetic resonance imaging and generally, the determination of cerebrospinal fluid abnormalities (McDonald, et al., 2001). McDonald, et al., have noted that currently there is no definitive test for MS, other than during autopsy. A measure of physical disability is the Expanded Disability Status Scale (EDSS), which assigns a number (0, or no disability, through 10, death) for each stage of physical disability due to neurologic impairments (Kurtzke, 1983). Time since onset of MS to a score of 4, limited walking ability but able to walk 500m or more without aid or rest, has been established as 11.4 years for RRMS, and 0 years for the three progressive types of MS (Confavreux, Vukusic, Moreau, & Adeleine, 2000). A score of 4 is generally regarded as the beginning of the progressive stage of MS, but RRMS may not always become a more progressive form. The time of progression from a score of 4 to a score of 6, inability to walk more than 100m with or without aid, is virtually identical: 5.7 years for RRMS to 5.4 years. Cognitive dysfunction in MS is assumed to have a prevalence of 45 to 65 percent (Bagert, Camplair, & Bourdette, 2002; DeSousa, Albert, & Kalman, 2002; Minden, et al.,

J.H. Day 2006). The most common areas of cognitive function that are affected are: information processing, executive function (concept formation, planning ability, and working memory), and also immediate and delayed recall memory. MS is unlikely to cause a

global cognitive decline, as seen in Alzheimers (LaRocca, 2004). Because axons are one the areas in the brain that are responsible for processing neurotransmitters, it has been hypothesized that lesion size and total lesion amount (TLA) should be responsible for cognitive dysfunction in people with MS. It was commonly believed that axons were not destroyed during inflammation and lesion-formation (Figure 1) but had their transmissions blocked (Smith & McDonald, 1999). In a study by Trapp, et al. (1998), eleven brains of MS patients, and four control brains, were autopsied. Trapp, et al. found that over 11 000 axons were transected per cubic millimeter in active lesions. In the controls, they found 1 axon transected per cubic millimeter in normal-appearing white matter, the cerebrum. While they effectively were able to show that axons were indeed cut, Trapp, et al., were not able to deduce whether the transections were the direct result of demyelination or from a secondary reason. In effect then, axons have transmissions blocked and may be transected, which in theory, would lead to cognitive dysfunctions, depending on which axons were effected. While MS lesions generally affect white matter, recent studies have shown that lesions in the gray matter (Figure 2), the cerebral cortex, have a prevalence of 4-7% (Catalaa, et al., 1999). The cerebral cortex is responsible for higher mental functions, perception, and behavioral functions. The Catalaa, et al., study theorized that gray matter lesions may influence both EDSS scores and deficiencies on neurologic tests. Because of the importance of the cerebral cortex, it was a sensible theory. But, they did not find any

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correlation with gray matter lesions and test scores. They believed that the reason for this was the fact that gray matter lesions comprise a small percentage of lesion load, but may be precursors to white matter lesions. But the question then becomes, does total lesion load affect cognitive function? Fulton, Grossman, Udupa, Mannon, Grossman, Wei, Polansky, and Kolson (1999) sought an answer to that question. They studied a cohort of nineteen persons with RRMS who had not been treated with interferon therapy for at least twelve months, and who were part of a larger longitudinal study. Participants were given a wide variety of neurological assessment tests, MRIs, and the EDSS. Fulton, et al., found almost no correlation between TLA and cognitive dysfunction (Table 2). Also, they found no correlation between EDSS score or disease duration in relation to TLA. The theory that they put forth for these results is that cognitive dysfunction must have a more global cause in persons with RRMS. A more specific theory that may be more accurate is the one put forth by Catalaa, et al., in which they stated that the precise location of lesions may be predictive of cognitive dysfunction. There is evidence that N-acetylaspartate (NAA), which is a marker for healthy axons, is affected by MS. NAA reductions show axonal injury in the absence of physical/cognitive testing (Trapp, et al., 1998; Reddy, Narayanan, Arnoutelis, Jenkinson, Antel, Matthews, & Arnold, 2000). Reddy, et al., studied dominant hand finger tapping in MS patients who had no noticeable physical deterioration in the dominant hand. The study was able to show that patients with reduced NAA levels had, what appears to be, compensatory cortical activity (Figure 3). While they were unable to determine why this occurs, it does seem to point to the possibility of more specific treatments to regain

J.H. Day physical loss. Though this study tested for physical changes, a study by Staffen, et al. (2002) explored cortical changes in attention tasks. Staffen, et al. (2002) used MS patients with RRMS who had been recently diagnosed (< three years). While they did not explore NAA concentrations, their fMRI

study was able to show that even in early stages of MS, cortical changes are evident. The control group, during a visual attention task, showed activation in the Brodmann area 32 (right gyrus cinguli). But the RRMS group showed completely different activation areas: Brodmann 6,8,9 (right hemisphere) and 39 (left hemisphere). Because the RRMS group had only been diagnosed with MS for less than three years, this is strong evidence for cortical changes occurring in the earliest stages of MS, and that the brain may have a system to repair axonal damage through the use of hierarchal areas of activation. In effect, when a primary area is damaged, a secondary area may come into expanded use and assume the role of the primary area. Having established some of the multivarious changes that occur in MS, it is evident that pharmaceutical treatment is quite necessary even in the earliest stages of MS. Interferon treatment is recommended for all MS patients (Table 3). Two large studies have established the effectiveness of early intervention with interferon: Comi, et al., 2001, and Jacobs, et al., 2000. Both studies showed that interferon slows disease progression. Reduction in the volume of brain lesions, and lower new or enlarging lesions was significantly reduced in patients administered interferon as opposed to patients without interferon therapy. Also, patients on interferon therapy had fewer relapses, 1.52 less per five years, than those without (Parkin, Jacoby, McNamee, Miller, Thomas, & Bates, 2000) and interferon therapy has been shown to reduce cognitive dysfunction,

J.H. Day varying improvement by each type of interferon (Barak & Achiron, 2002). But, not all persons with MS are on interferon therapies. One of the reasons is that the body can produce antibodies that interfere with the effectiveness of interferon (Bertolotto, et al.,

2002; Ross, Clemmesen, Srensen, Koch-Henriksen, & Bendtzen, 2006). Because of this complication, persons with MS can be forced to forgo a beneficial medication. Interferon therapy also poses significant cost-savings over the long term. Over 50% of persons in the US with MS are unemployed, whether because of the disease or by choice (Kendrick & Johnson, 2000; Minden, et al., 2006). Close to 80% of persons with MS have from 0 to 2 relapses per year (Minden, et al., 2006). While not all relapses require increased medical care, there are costs associated with each relapse. Interferon therapy costs about $14000 per year (Kendrick & Johnson, 2000; Parkin, Jacoby, McNamee, Miller, Thomas, & Bates, 2000). Parkin, et al., have established that the costsavings of reducing a single relapse is $750-4000. The savings of health services and to society has been established to be about $28000 per five years (Kendrick & Johnson, 2000). In all, though interferon therapy is expensive, the cost-savings are significant. Further support of the need for early treatment of MS comes from the study of Achiron and Barak (2003). They studied 67 patients with clinically probable MS, and tested them for cognitive changes. Patients were given a battery of standard neurologic tests and 53.7% of the patients were found to have some level of cognitive impairment (Table 4). The authors have stated that the need for early testing of probable and definite MS patients is necessary. They also have stated that the need for MS-specific neurological tests need to be developed.

J.H. Day There has been little support for a correlation between physical disability and cognitive dysfunction. Lynch, Parmenter, and Denney (2005) studied 253 MS patients, 164 with RRMS, and 56 with SPMS. The RRMS and SPMS groups scored similarly on

all cognitive batteries and only differed significantly on their respective EDSS means (2.7 v. 5.8). Both groups showed strong correlations on all tests with EDSS scores. This is fairly conclusive evidence that physical disability has some impact on cognitive impairments, which refutes several earlier studies that claimed otherwise (Ivnik, 1978; Rao, Hammeke, McQuillen, Khatri, & Lloyd, 1984). The authors have put forth the theory that the extent of cognitive dysfunction could be predictive of physical disability. The longest longitudinal study of cognitive dysfunction in MS is the one of Amato, Ponziani, Siracusa, and Sorbi (2001). Their study followed RRMS patients who were fairly newly diagnosed (M=1.58 years) at onset of the study for a period of ten years. Patients were paired with controls from their family or friends. At initial testing, 74% of patients had no impairment and had a mean EDSS of 1.98. At the four year mark, 51% had no impairment. In the final testing, at the ten year mark, only 44% had no impairment (Table 5), and the mean EDSS was 3.48. Amato, et al., were able to establish a pattern for cognitive loss, with memory functions, recall, and abstract reasoning being the first areas to be compromised, followed by linguistic abilities and attention. This was also one of the only studies to examine whether linguistic ability is compromised in MS, and the authors believe it does not arise from a break-down in ability but are derived from damage to other cognitive faculties. The Amato study is contrasted by the Zivadinov, et al., (2001) study. Zivadinov, et al., used a two year longitudinal study of 83 patients with definite RRMS and tracked

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them for cognitive decline and brain atrophy. At baseline, mean time since diagnosis was 3.8 years and mean EDSS was 1.6, and 14 (26.4%) of the patients were listed as cognitively impaired, based on a battery of eighteen neuropsychological tests. At the two year follow-up, that number of patients who were cognitively impaired had increased to 28 (52.8%), with an overall mean EDSS of 1.8. Interestingly, five (9.4%) patients were deemed to be cognitively improved and had a higher educational level than the other patients, and their educational level was statistically significant. Of the patients that were deemed to be cognitively impaired, they had a lower brain parenchymal volume (functional part of the brain, not including connective tissues) than the other patients. Zivadinov, et al., put forth the theory that brain atrophy is predictive of cognitive decline, as opposed to lesion volume. Why had the Zivadinov study established a greater than 50% cognitive dysfunction in two years, yet the Amato study required ten years to reach the same level? In the Amato study, the progression of EDSS scores was slightly greater than the progression seen in the Zivadinov study (Table 6), which theoretically should have led to more cognitive dysfunction if EDSS is representative of cognitive decline. Also, the Zivadinov study patients had MS twice as long as the Amato group (3.8 v. 1.58, respectively) at study onset. The major difference between the two groups was the fact that 100% of the Zivadinov group were clinically definite for MS, while the Amato group, initially, was only 42%. This seems to suggest that once MS is clinically established, cognitive decline is more rapid, while increases in EDSS may be slower. As stated by Bagert, Camplair, and Bourdette (2002), in a patient with MS, prior to diagnosing cognitive dysfunction, one has to control for depression and fatigue, as

J.H. Day these are commonly comorbid with MS. In the DSM-IV-TR (2000), fatigue and poor concentration and attention are listed as symptoms of depression. The question then becomes: does depression contribute to fatigue or the reverse, and how do they relate to cognitive dysfunction? Fatigue in MS has been widely studied, with varied results.

Lerdal, Celius, and Moum (2003) approached fatigue from a sociodemographic angle and found that higher levels of fatigue correlated with lower educational levels. This is a fairly unique finding, as in the Slifka Study (Minden, et al., 2006), fatigue was found across all educational levels, at a rate of 83.1%. In relation to cognitive dysfunction and fatigue, two recent studies did not find a significant relationship (Parmenter, Denney, & Lynch, 2003; Schwid, Tyler, Scheid, Weinstein, Goodman, & McDermott, 2003). But, what about the interaction of depression and fatigue? One finding of the Parmenter, Denney, and Lynch (2003) study did find that MS patients during a period of low fatigue did have a greater amount of depression as opposed to a period of high fatigue, but the differences were not significant. But, the study of Iriarte, Subir, and de Castro (2000) was able to establish a significant correlation between moderate-severe depression and fatigue. Also, they were able to show that fatigue in the pyramidal tract, the pathway in the medulla oblongata where the nerve fibers cross from one side of the brain to the other before entering the spinal cord (Rothenberg & Chapman, 2000), was over 80% predictive of depression. The logical question is then: would medical treatment be able to reduce fatigue and depression? Mohr, Hart, and Goldberg (2003) studied just that question. As they pointed out, a relationship between fatigue and depression has long been suspected in MS. They randomly assigned 60 MS patients with moderate to severe depression to one of three

J.H. Day 10 groups: cognitive behavior therapy (CBT), Sertraline(Z), or supportive group expressive psychotherapy (SEGP). The trial period lasted sixteen weeks. All study groups showed significant reduction in depression and in fatigue during the trial. Upon more complex analysis, overall depression score and depressive mood correlated significantly with a reduction in fatigue scores (Table 7). Not only did this study show the effectiveness of treatment on depression alone, it was also able to establish a specific link between depressive mood and fatigue. So depression can be assumed to be linked to fatigue, but how does depression then relate to cognitive dysfunction? Depression has an accepted lifetime prevalence in MS of 50%, with a reported range of 37-79% (Diaz-Olavarrieta, Cummings, Valazquez, & Garcia de la Cadena, 1999; Figved, et al., 2005; Minden, et al., 2006; van der Werf, Evers, Jongen, & Bleijenberg, 2003), with a point prevalence rate of significant depressive symptoms at 45% (Chwastiak, Ehde, Gibbons, Sullivan, Bowen, & Kraft, 2002). Several studies have linked depression to impairments in subjective cognitive function, metamemory, in patient-assessed belief of their own abilities. The studies of Goverover, Chiaravalloti, and DeLuca (2005) and of Maor, Olmer, and Mozes (2001) found that depression may not influence actual cognitive deficiencies, but does show a significant correlation in regards to a patients self-assessment. Duration of disease in both studies was similar (11.38 years v. 10.03 years). The two studies used different measures to assess patients physical disability and depression level. That both groups of authors found the same conclusion is certainly significant. A third study, one by Randolph, Arnett, and Freske (2004), attempted to discover the exact method that depression influences metamemory. Similar to the previously stated

J.H. Day 11 studies, patients had a mean disease duration of 9.9 years. EDSS score mean was similar to the study of Maor, Olmer, and Mozes (4.6 v. 4.86). One difference noted in the Randolph study was that patients with higher levels of depression also reported more memory problems, and analyses showed that depressive attitudes correlated significantly with memory complaints. The authors of all three studies have suggested that, like Bagert, Camplair, and Bourdette (2002), depression needs to be addressed prior to assessment of cognitive dysfunctions. In a follow-up study, Mohr, Classen, and Barrera, Jr. (2004) assessed the viability of increasing social support through mediation of depression. The general theory is that high social support leads to lower incidence of depression and high likelihood of depression remission (Oxman & Hull, 2001). Again, they randomly assigned 63 MS patients with moderate to severe depression to one of three groups: cognitive behavior therapy (CBT), Sertraline(Z), or supportive group expressive psychotherapy (SEGP). The trial period lasted sixteen weeks. At the end of the trial utilized social support, the use of contacts for support issues, and satisfaction with social support were significantly correlated with a reduction in overall depression scores. Also, van der Werf, Evers, Jongen, and Bleijenberg (2003) explored the relationship of helplessness, fatigue, and depression. This study had 89 MS patients who had a mean EDSS was 4.4 and mean duration of disease of 10.1 years. The authors theorized that helplessness mediated both depressive mood and fatigue severity. They found that helplessness significantly correlated with depressive mood, fatigue, and EDSS. They also found a weak correlation between depressive mood and fatigue. Fatigue severity also correlated significantly with pyramidal tract involvement. This study points

J.H. Day 12 to the possibility that fatigue is mediated by both helplessness and depressive mood, and also that depressive mood is mediated by helplessness. The authors suggested that psychological intervention needs to address helplessness as a necessary part of treatment. Only one study found to date addresses retraining an area of cognitive deficit as a theory: Plohmann, Kappos, Ammann, Thordai, Wittwer, Huber, Bellaiche, and LechnerScott (1998). Twenty-two MS patients with mean EDSS of 3.8 and mean disease duration of 16.9 years, were selected to undergo computer retraining of attentional deficits. After one training session, which was comprised of twelve forty minute sessions over a three week period, scores for attention improved significantly. The improvements were still present up to six weeks later, on retesting. Patients reported lower distractibility and fatigue in their daily lives, and that the experience of improving their cognitive performance improved their self esteem. The authors concluded that more exploration into this area of retraining needs be done, with an eye to ecological validity of the retraining methods. So where do we go from here? First and foremost, depression needs to be controlled for, by using CBT and/or pharmacological means. Depression is fairly controllable, even in healthy populations. That depression has been shown to be related to fatigue, and given that fatigue is the most common MS-related complaint, adds more support for early intervention. While tests with greater ecological validity are always a good idea, they are not vital for diagnosis of depression, as the standard tests have considerable replication and validity. It can be safely argued that any dramatic, lifechanging, event will cause depression. Social support has been previously shown to lessen the impact of traumatic news, and is a preventative of developing depression.

J.H. Day 13 There must be a system established that provides social support at the time of diagnosis of MS. What is hard to grasp is why depression tests are not a first-line preventative measure in MS. While lessening depression has little impact on objective cognitive dysfunction, it has been shown to be linked to metamemory. Also, with the impact of helplessness having been shown to effect depressive mood and fatigue, improvement of metamemory should also lessen helplessness (Table 8). Striking out at depression from initial diagnosis of MS could reduce the impact of this nefarious condition, MS. Also, since interferon therapies have been shown to reduce the number of relapses a person with MS has, and have also been shown to actually garner a large cost-savings through the prevention, it only makes sense that more people with MS receive this therapy. Yes, for some, taking interferon will not be possible because of antibodies, but there are other medications in clinical phase trial now that seem to be as effective, or more effective, than interferon. Until the body builds up antibodies, these people should be on interferon therapies. Having shown that NAA levels are indicative of axonal damage, and having shown that even in the earliest stages of MS there are changes in synaptic activations, a contraposed argument against interferon therapy would be a weak one. As several studies have presented evidence that cognitive dysfunction in MS can occur at the onset of the disease, and that it does seem to progress regardless of physical disability, the need for specific medications, targeted at preserving cognition need to be explored further. Perhaps a breakthrough will come from the Alzheimers research communities. Donezepril is currently in phase trial for MS (DeSousa, Albert, & Kalman,

J.H. Day 14 2002). But, as MS does not normally show global cognitive loss like Alzheimers, an MS-specific medication needs to be developed. The Plohmann study shows great promise, as it is an attempt to reprogram cognition deficits. The theory for this is a fairly sound one, especially considering that it has been shown that in early stage MS that normal activation of Brodmann areas are compromised, and somehow rerouted to apparent redundant areas of the brain. Because of this, there is great promise in deficit specific retraining. Also, more research needs to be done to attempt to document the changes in areas of activation in persons with MS, as little is actually known. An area of research that has not been addressed is education level and MS. In the Slifka Study and the National Health Interview Survey MS sample, persons with educations at the graduate level and above have a higher prevalence of MS in the US as opposed to the US Census (16.0%, 13.4%, 9.0%, respectively) (Minden, et al., 2006). While the differences are not significant (Kruskal, H=.065(2,N=15), p=>.05), possibly because of population sizes, it does appear to be an area in question that deserves more attention. Why would persons with higher educations, and presumably higher intelligences, have a higher prevalence of MS? So what can be reasonably be done? What I would advise is first, a strict adherence to the McDonald Criteria. It is a comprehensive tool for identifying and classifying MS, barring the development of an accurate test for MS. Further, upon a diagnosis of clinically probable MS, I would advise immediate interferon treatment, especially since it has been shown to forestall the development of clinically definite MS. Also, I would establish more community support

J.H. Day 15 groups for persons and families of persons with MS, and require all hospitals that render diagnosis of MS to have a genetic counselor on staff. By following this, social support is enhanced, and that has been shown to be interrelated to depression. I would recommend all persons with MS, probable or definite, to undergo testing for depression at least quarterly, and if present, CBT therapy begun immediately. Since CBT has been shown to be as effective as medication for treating depression and given that persons with MS take on average four medications per day (National MS Society, 2005), it only makes sense to use a non-medication approach. If the depression that is prevalent in MS can be identified early, quality of life can be maintained (DeSousa, Albert, & Kalman, 2002). Once a person with MS has been diagnosed with depression, I would recommend testing for cognitive dysfunction, through the use of neuropsychological batteries, ones that are ecologically valid, and through the use of fMRI, which is more sensitive to changes in the brain than traditional MRIs. There is no known cause of MS and there is no cure. The best we can do is to deal with the known symptoms and comorbidities.

J.H. Day 16 References Achiron, A., & Barak, Y. (2003). Cognitive impairment in probable multiple sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry, 74, 443-446. Amato, M.P., Ponziani, G., Siracusa, G., & Sorbi, S. (2001). Cognitive dysfunction in early-onset Multiple Sclerosis: a reappraisal after 10 years. Archives of Neurology, 58, 1602-1606. American Psychiatric Association (APA). (2000). Diagnostic and statistical manual of mental disorders, 4th ed., Washington D.C.: American Psychiatric Association. Bagert, B., Camplair, P., & Bourdette, D. (2002). Cognitive dysfunction in Multiple Sclerosis. CNS Drugs, 16, 445-455. Barak, Y., & Achiron, A. (2002). Effect of Interferon-beta-1b on Cognitive Functions in Multiple Sclerosis. European Neurology, 47, 11-14. Bertolotto, A., Malucchi, S., Sala, A., Orefice, G., Carrieri, P.B., Capobianco, M., Milano, E., Melis, F., & Giordana, M.T. (2002). Differential effects of three interferon betas on neutralising antibodies in patients with multiple sclerosis: a follow up study in an independent laboratory. Journal of Neurology, Neurosurgery, and Psychiatry, 73, 148153. Calabresi, P.A. (2004). Diagnosis and management of multiple sclerosis. American Family Physician, 70, 1935-1944. Catalaa, I., Fulton, J.C., Zhang, X., Udupa, J.K., Kolson, D., Grossman, M., Wei, L., McGowan, J.C., Polansky, M., & Grossman, R.I. (1999). MR imaging quantitation of gray matter involvement in multiple sclerosis and its correlation with disability measures and neurocognitive testing. American Journal of Neuroradiology, 20, 1613-1618.

J.H. Day 17 Chwastiak, L., Ehde, D.M., Gibbons, L.E., Sullivan, M., Bowen, J.D., & Kraft, G.H. (2002). Depressive symptoms and severity of illness in multiple sclerosis: epidemiologic study of a large community sample. American Journal of Psychiatry, 159, 1862-1868. Comi, G., Filippi, M., Barkhof, F., Durelli, L., Edan, G., Fernndez, O., Hartung, HP., Seeldrayers, P., Sorensen, P.S., Rovaris, M., Martinelli, V., & Hommes, O.R. (2001). Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomized study. The Lancet, 357, 1576-1582. Confavreux, C., Vukusic, S., Moreau, T., & Adeleine, P. (2000). Relapses and the progression of disability in Multiple Sclerosis. The New England Journal of Medicine, 343, 1430-1438. DeSousa, E.A., Albert, R.H., & Kalman,B. (2002). Cognitive impairments in multiple sclerosis: A review. American Journal of Alzheimers Disease and Other Dementias, 17, 23-29. Diaz-Olavarrieta, C., Cummings, J.L., Velazquez, J., & Garcia de al Cadena, C. (1999). Neuropsychiatric manifestations of Multiple Sclerosis. Journal of Neuropsychiatry and Clinical Neuroscience, 11, 51-57. Figved, N., Klevan, G., Myhr, K.M., Glad, S., Nyland, H., Larsen, J.P., Harboe, E., Omdal, R., & Aarsland, D. (2005). Neuropsychiatric symptoms in patients with multiple sclerosis. Acta Psychiatrica Scandinavica, 112, 463-468. Fulton, J.C., Grossman, R.I., Udupa, J., Mannon, L.J., Grossman, M., Wei, L., Polansky, M., & Kolson, D.L. (1999). MR lesion load and cognitive function in patients with relapsing-remitting multiple sclerosis. American Journal of Neuroradiology, 20, 19511955.

J.H. Day 18 Goverover, Y., Chiaravalloti, N., & DeLuca, J. (2005). The relationship between selfawareness of neurobehavioral symptoms, cognitive functioning, and emotional symptoms in multiple sclerosis. Multiple Sclerosis, 11, 203-212. Iriarte, J., Subir, M.L., & de Castro, P. (2000). Modalities of fatigue in multiple sclerosis: correlation with clinical and biological factors. Multiple Sclerosis, 6, 124-130. Ivnik, R.J. (1978). Neuropsychological test performance as a function of the duration of MS-related symptomatology. Journal of Clinical Psychiatry, 30, 304-307. Jacobs, L.D., Beck, R.W., Simon, J.H., Kinkel, R.P., Brownscheidle, C.M., Murray, T.J., Simonian, N.A., Slasor, P.J., & Sandrock, A.W. (2000). Intramuscular interferon beta-1A therapy initiated during a first demyelinating event in Multiple Sclerosis. The New England Journal of Medicine, 343, 898-904. Kendrick, M. & Johnson, K.I. (2000). Long term treatment of Multiple Sclerosis with interferon- may be cost effective. Pharmacoeconomics, 18, 45-53. Kurtzke, J.F. (1983). Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology, 33, 1444-1452. LaRocca, N. (2004). Introducing MS-related emotional and cognitive issues. MS in focus, 4, 4-6. Lerdal, A., Celius, E.G., & Moum, T. (2003). Fatigue and its association with sociodemographic variables among multiple sclerosis patients. Multiple Sclerosis, 9, 509514. Lynch, S.G., Parmenter, B.A., & Denney, D.R. (2005). The association between cognitive impairment and physical disability in multiple sclerosis. Multiple Sclerosis, 11, 469-476.

J.H. Day 19 Maor, Y., Olmer, L., & Mozes, B. (2001). The relation between objective and subjective impairment in cognitive function among multiple sclerosis patients the role of depression. Multiple Sclerosis, 7, 131-135. McDonald, W.I., Compston, A., Edan, G., Goodkin, D., Hartung, HP., Lublin, F.D., McFarland, H.F., Paty, D.W., Polman, C.H., Reingold, S.C., Sandberg-Wollheim, M., Sibley, W., Thompson, A., van den Noort, S., Weinshenker, B.Y., & Wolinsky, J.S. (2001). Recommended diagnostic criteria for Multiple Sclerosis: Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Annals of Neurology, 50, 121127. Minden, S.L., Frankel, D., Hadden, L., Perloff, J., Srinath, K.P., & Hoaglin, D.C. (2006). The Sonya Slifka longitudinal Multiple Sclerosis study: methods and sample characteristics. Multiple Sclerosis, 12, 24-38. Mohr, D.C., Classen, C., & Barrerra Jr., M. (2004). The relationship between social support, depression and treatment for depression in people with multiple sclerosis. Psychological Medicine, 34, 533-541. Mohr, D.C., Hart, S.L., & Goldberg, A. (2003). Effects of treatment for depression on fatigue in multiple sclerosis. Psychosomatic Medicine, 65, 542-547. National Multiple Sclerosis Society. (2005). Depression and multiple sclerosis. Retrieved January 27, 2006, from National MS Society: http://www.nationalmssociety.org. Oxman, T.E. & Hull, J.G. (2001). Social support and treatment response in older depressed primary care patients. Journal of Gerontology: Psychological Sciences, 56B, 35-45.

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J.H. Day 22 experienced fatigue and depression in patients with multiple sclerosis. Multiple Sclerosis, 9, 89-94. Zivadinov, R., Sepcic, J., Nasuelli, D., DeMasi, R., Monti Bragadin, L., Tommasi, M.A., Zambito-Marsala, S., Moretti, R., Bratina, A., Ukmar, M., Pozzi-Mucelli, R.S., Grop, A., Cazzato, G., & Zorzon, M. (2001). A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry, 70, 773-780.

J.H. Day 23 Figures and Tables Table 1. The McDonald Criteria for diagnosing MS. Adapted from McDonald, et al., 2001. Clinical Presentation Additional Data needed for MS Diagnosis 2 or more attacks; objective clinical evidence of 2 or more lesions 2 or more attacks; objective clinical evidence of 1 lesion None Dissemination in space, demonstrated by MRI Or Two or more MRI-detected lesions consistent with MS plus positive CSF Or Await further clinical attack implicating a different site Dissemination in time, demonstrated by MRI Or Second clinical attack Dissemination in space, demonstrated by MRI Or Two or more MRI-detected lesions consistent with MS plus positive CSF And Dissemination in time, demonstrated by MRI Or Second clinical attack Positive CSF And Dissemination in space, demonstrated by 1) Nine or more T2 lesions in brain or 2) Two or more lesions in spinal cord, or 3) 4-8 brain plus 1 spinal cord lesion Or Abnormal VEP associated with 4-8 brain lesions, or with fewer than 4 brain lesions plus 1 spinal cord lesion demonstrated by MRI And Dissemination in time, demonstrated by MRI or Continued progression of 1 year

One attack; objective clinical evidence of 2 or more lesions One attack; objective clinical evidence of 1 lesion (monosymptomatic presentation; clinically isolated syndrome)

Insidious neurological progression suggestive of MS

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Figure 1. An injection of spermine NONOate into a demyelinating lesion. The injection caused conduction block in approximately half of the axons. Adapted from Smith and McDonald, 1999.

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Figure 2. The image on the left shows a lesion (green color) that affects both white and gray matter. The image on the right is the gray matter lesion, once the white matter has been removed manually on a computer. Adapted from Catalaa, et al., 1999.

J.H. Day 26 Table 2. Correlation between TLA and scores on the EDSS and various neurological assessment tests. Adapted from Fulton, et al., 1999.

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Figure 3. Activation map of dominant hand movement. Controls (A), MS with normal to high NAA/creatine ratio (B), and MS with lower than normal NAA/creatine ratio (C). Adapted from Reddy, et al., 2000.

J.H. Day 28 Table 3. The various types of interferon medication prescribed to MS patients. Avonex(Interferon beta-1a) Slows the accumulation of physical disability and decrease the frequency of clinical exacerbations, in Relapsing forms of Multiple Sclerosis. The dose is 30 mcg, taken once a week. Betaseron(Interferon beta-1b) Reduces the frequency of clinical exacerbations, in ambulatory, Relapsing/Remitting MS. The dose is 8 MIU, taken every other day. Copaxone(Glatiramer acetate) Decreases the frequency of clinical exacerbations, in Relapsing/Remitting Multiple Sclerosis. The dose is 20mg, taken every day. Rebif(Interferon beta-1a) Is chemically identical to Avonex, but Rebif is injected subcutaneously, in a larger dosage (44 mcg three times per week).

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Table 4. Neuropsychological tests of patients with probable MS. Taken from Achiron and Barak, 2003.

J.H. Day 30 Table 5. Cognitive dysfunction through time in persons with MS. Adapted from Amato, et al., 2001. First Testing 74 % 8% 18 % Second Testing 51 % 33 % 16 % Third Testing 44 % 34 % 22 %

No Impairment Mild Impairment Moderate Impairment

J.H. Day 31 Table 6. Comparing the rate of EDSS advancement between the Amato, et al. (2001) study versus the Zivadinov, et al. (2001) study. Amato Zivadinov Baseline EDSS 1.98 1.60 EOS EDSS 3.48 1.80 (E-B)/L (3.48-1.98)/10 (1.80-1.60)/2 # change/ year 0.15 0.01

J.H. Day 32 Table 7. Relationship of Depression to Fatigue. Adapted from Mohr, Hart, & Goldberg, 2003.

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Table 8. A priori model of interactions of depression, helplessness, social support, metamemory, and cognitive dysfunction.

Metamemory Depressive Attitudes

Helplessness

Social Support

Depressive Moods

CBT

Fatigue

CBT

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