Construct Validity and Frequency of Euphoria Sclerotica in Multiple Sclerosis

Construct Validity and Frequency of Euphoria Sclerotica in Multiple Sclerosis Inna Fishman, M.A. Ralph H. B. Benedict, Ph.D. Rohit Bakshi, M.D. Roger Priore, Sc.D. Bianca Weinstock-Guttman, M.D. Using the Neuropsychiatric Inventory (NPI), we studied euphoria and other behavioral changes in 75 consecutive, unselected multiple sclerosis (MS) patients and 25 healthy controls. We also assessed disease duration, clinical course, physical disability, personality, depression, insight, cognition, and caregiver distress. Factor analysis identified a cluster of symptoms labeled euphoria/disinhibition similar to the euphoria sclerotica syndrome originally described by Charcot and others. The euphoria/disinhibition factor score was elevated in 9% of patients and associated with secondary-progressive course, low agreeableness, poor insight, impaired cognition, and high caregiver distress. Thus, we used the NPI to validate the euphoria syndrome in multiple sclerosis (MS) and determined its frequency, and its neurological and psychological correlates. (The Journal ofneuropsychiatry and Clinical Neurosciences 2004; 16:350 356) A s noted in a recent historical review, 1 euphoria and related neurobehavioral phenomena have been observed in multiple sclerosis (MS) since Charcot 2 first noted that many patients exhibit a peculiar cheerful indifference without cause. More recent work 3,4,5 suggests that magnetic resonance imaging (MRI) lesion burden and atrophy are associated with dementia and euphoric personality change. However, while cognitive impairment in MS is well understood, there remains much uncertainty about the prevalence and scope ofthe euphoria syndrome. Two recent studies attempted to measure personality and behavior change using reliable and validated instruments. Our group 6 employed the NEO Personality Inventory (NEO-PI), 7 a standardized questionnaire based on the widely recognized Five Factor Model of personality. 8,9,10 Compared to healthy controls, cognitively impaired MS patients had higher degrees ofneuroticism and lower degrees ofextraversion, agreeableness and conscientiousness. Regression models demonstrated that informant reported decrements in altruism, a component ofagreeableness, and conscientiousness were associated with cognitive (especially executive function) impairment. Similar personality changes were previously identified in patients with Alz- Received August 21, 2002; revised March 13, 2003; accepted March 25, 2003. From the State University ofnew York (SUNY) Buffalo School of Medicine and Biomedical Sciences, Buffalo General Hospital, Buffalo, New York. Address correspondence to Dr. Benedict, 100 High Street, Buffalo, NY 14203; benedict@buffalo.edu (E-mail). Copyright 2004 American Psychiatric Publishing, Inc. 350 J Neuropsychiatry Clin Neurosci 16:3, Summer 2004

FISHMAN et al. heimer s disease. 11,12 In a study of44 MS patients, Diaz- Olavarrieta and colleagues 13 found that behavioral symptoms, assessed with the Neuropsychiatric Inventory (NPI) ofcummings, 14 are more common in MS (95%) than in controls (16%). Patients exhibited depression most commonly, but euphoria and disinhibition were also observed. Unfortunately, these studies were limited by small sample sizes, selection bias, and failure to account for personality, depression and behavior change in the same analysis. Thus, differences of opinion remain regarding the prevalence and scope ofthis neurobehavioral syndrome. Designed to address methodological problems in prior work, this study endeavored to (a) develop criteria for identifying a euphoria syndrome in MS; (b) determine the frequency of the syndrome in an unselected sample; and (c) identify other disease and psychological variables that are associated with the syndrome. METHODS Participants Seventy five patients with MS between the ages of18 and 65 were recruited consecutively from an MS clinic registry. Refusal rate was 7 percent. All patients underwent neurological examination by MS specialists and met recent consensus diagnostic criteria for MS. 15 Patients were excluded ifthey had (a) current or past medical or psychiatrc disorder (including major depressive disorder and bipolar disorder) other than MS that could affect cognitive or psychological function; (b) abused drugs or alcohol; (c) severe motor or sensory defect that would interfere with psychometric testing; or (d) an MS relapse or corticosteroid pulse within four weeks of assessment. The majority ofthe sample (85%) was treated with an immunomodulatory medication (glatamir acetate, interferon beta 1a). Frequencies of other medications in the sample were as follows: anxiolytic or anticonvulsant (10% or 13%), antidepressant (17% or 23%), antipsychotic (1% or 1%), stimulants (including amantadine) (14% or 19%), pain (1% or 1%). Twenty-five healthy control volunteers were recruited via advertisement. Informants were required to have contact with the patient at least three times per week. Measures The NPI, 14 an informant-based rating scale designed to assess psychopathology in neurological disease, was administered to informants. The NPI covers ten domains including delusions, hallucinations, agitation, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability, and aberrant motor activity. Questions are standardized and ratings reflect changes in patient behavior following the onset of illness. Aberrant behaviors that have been present throughout life but have changed with progression ofillness are also included, but unchanging chronic behavior patterns are not. Control informants were asked about the primary participant s behavior over the past four weeks. 16 For each domain, informants were asked to judge the frequency of the target symptom on a 4-point scale from 1 (less than once per week) to 4 (once or more per day). Severity was rated on a 3-point scale from 1 (mild) to 3(marked). Ten composite domain scores were calculated as the products offrequency x severity (maximum 12). Ifthe symptom was not present, a score of0 was recorded. The NPI index was obtained by totaling the domain scores. Personality was assessed with the revised version of the NEO-PI, 7 a standardized, comprehensive, questionnaire-format test with well-established reliability and validity. The NEO-PI was derived from the Five-Factor Model ofpersonality which encompasses a wide spectrum oftraits comprising previously established personality models. 10,17,18 We employed both patient- and informant-report administrations of the test. Only two factors were included, agreeableness and conscientiousness. Agreeableness is the desire for socialization, honesty and altruism in relationships. Conscientiousness is the proclivity to be well organized and deliberate. These domains were chosen a priori because they tap features ofpersonality changes described in the early literature (e.g., egocentricity, low altruism or empathy, lack ofregard for duty and achievement). 1 In accordance with the NEO-PI manual, scores were converted to gender and age-based T scores (mean 50, SD 10), with higher scores indicating a stronger endorsement ofeach trait. Discrepancy scores, the absolute values ofdifferences between self- and informant-reports, were calculated as measures ofinsight. In the NEO-PI standardization sample, and in our own work with this instrument, healthy patient/informant dyads produced scores that did not differ statistically. 6,19 Two depression scales were employed. The Beck Depression Inventory (BDI) 20 is a widely used 21-item selfreport questionnaire. Because the BDI includes somatic items that overlap with neurological symptoms ofms, J Neuropsychiatry Clin Neurosci 16:3, Summer 2004 351

EUPHORIA SCLEROTICA IN MULTIPLE SCLEROSIS a 10-item version ofthe Center for Epidemologic Studies-Depression Scale (CES-D) 21,22 was also used. For both, higher scores indicate greater subjective dysphoria or more depressive symptoms. Neurological exams were performed by neurologists specializing in MS in order to derive an Expanded Disability Status Scale (EDSS) 23 score and to categorize patients having a primarily relapsing-remitting or secondary progressive course. Information regarding course and disease duration was also obtained via chart review. The MS Neuropsychological Questionnaire, a newly developed 15-item test, was used to estimate the degree ofneuropsychological impairment. Informant ratings have been shown to predict cognitive impairment in MS patients. 24 The NPI Caregiver Distress Index 25 was used to measure informant distress. This validated index uses ratings on a scale from 0 (not at all) to 5 (extremely distressing), which are totaled across all NPI domains. Procedures The patients continued to receive their usual medical care while enrolled in the study. Informed consent was obtained, and the protocol was approved by a university review board. All participants underwent an initial telephone screening interview to evaluate inclusion criteria and confirm informant availability. Participants were evaluated in a single session ofthree hours (participants also underwent neuropsychological and imaging studies, analyses ofwhich will be carried out in future reports). Neurological exams were performed within six months ofthe study. All participants were paid 75 US dollars. Statistical Analyses Group means were compared by t and chi-square tests as appropriate. Significance was accepted at a conservative p.01 to reduce type I error. Frequency ofindividual behavioral symptoms on the NPI was based on a cut-off of 1 or higher. 14 Exploratory factor analysis was performed with the NPI domain scores. The domains delusions and hallucinations were excluded due to zero or near zero variance and aberrant motor behavior was excluded to avoid the confounding influence ofneurologic MS symptoms. After oblique rotation revealed that the emerged factors were not correlated with each other (r.30), an orthogonal varimax rotation was performed. Variable loadings with coefficient absolute values greater than.50 were used to describe the factors. To explore relationships between NPI factors and other measures, Pearson correlations were calculated and followed by regression models. RESULTS Descriptive Data and Group Comparisons Most participants were women (67% MS, 60% control) and Caucasian (86% MS, 100% control). The mean ( SD) ages were 43 ( 8) and 41 ( 8) years, for MS and controls respectively. The mean education level for both groups was 14.6 ( 2) years. Among MS patients, 44 (59%) of the informants were spouses or full-time domestic partners, 10 (13%) were parents, and 21 (28%) were other family members (e.g., siblings) or close friends. These informants had known the patients for an average of24 ( 13) years. Among control participants, 19 (76%) ofthe informants were spouses, and 6 (24%) were other family members or close friends. The control informants had known the primary participants for an average of19 ( 12) years. These characteristics did not differ significantly between the two groups (all p values 0.6). In addition, NEO-PI and NPI ratings did not differ among informant subgroups (domestic partners, parents, other). Mean disease duration was 12 ( 7) years (range 2 44). Most patients (54% or 72%) had relapsing-remitting disease. The mean EDSS score was 3 ( 2; range 0 7.5). There were no significant group differences on the NEO-PI. Among MS patients, mean BDI was 9.7 ( 7.4) and mean CES-D was 8.8 ( 6.1). For the control group, these values were 4.9 ( 4.2) and 4.7 ( 3.6), respectively. Mean differences were significant (BDI p 0.004; CES-D p 0.003). The two groups also differed significantly on the informant-rated MS Neuropsychological Screening Questionnaire (p 0.001), with higher values reported for patients (23.3 13.6) vs controls (13 7.8). On the NPI Caregiver Distress Index, mean distress among MS informants was 7.5 ( 7.2) compared to 1.1 ( 2.2) for controls (p 0.001). Neuropsychiatric symptoms (Table 1) were more common in patients. Most (66% or 88%) exhibited at least one behavioral disturbance and 36 patients (as compared to one control) exhibited a marked disorder as operationalized by Wood et al (domain score greater than 4). 26 The mean MS NPI Index was 11.5 ( 13.1; median 6, range 0 54), almost 10 times higher than the control group mean (1.2 2.1, p.001). Significant 352 J Neuropsychiatry Clin Neurosci 16:3, Summer 2004

FISHMAN et al. group differences were also apparent on Agitation/Aggression, Dysphoria/Depression, and Irritability/Lability (p.01). Factor Analysis of the Behavioral Symptoms in MS Patients Factor analysis ofnpi domain scores yielded a two-factor solution, accounting for 68% of the variance. The first factor contained agitation/aggression, euphoria, disinhibition and irritability/lability and accounted for 40% ofthe variance (loadings of.85,.87,.78, and.66, respectively). The domains ofdysphoria/depression, anxiety and apathy emerged as the second factor, accounting for 28% ofthe variance (loadings.73,.70 and.73, respectively). The eigenvalues for the two factors were 3.15 and 1.66, respectively. The oblique structure matrix showed essentially the same pattern ofitem loadings as the orthogonal rotation. As such, two factor scores were calculated from NPI raw data. The first, the sum of the agitation/aggression, euphoria, disinhibition and irritability/lability scores, was labeled euphoria/disinhibition. This factor is descriptive of euphoria patients in the classical literature. 1 The 2 nd factor, labeled dysphoria/apathy, was calculated as the sum ofdysphoria/depression, anxiety, and apathy domain scores. Frequency Among MS patients, the mean euphoria/disinhibition score was 6.8 ( 8.3), and the mean dysphoria/apathy score was 4.0 ( 5.5). Both were significantly higher (p 0.001) when compared to controls (1.0 1.8 and 0.2 0.8, respectively). The euphoria/disinhibition factor was operationalized by applying a cutoff score of 16 (four domains 4), as suggested in prior research. 26 A score 16 was judged to reflect marked disturbance. Seven patients, or 9% ofthe sample, met this standard. Correlates and Predictors of Behavioral Disinhibition Pearson correlations appear in Table 2. The following clinical and demographic variables were entered into a stepwise regression model predicting euphoria/disinhibition: age, gender, education level, years informant has known patient, disease course (relapsing vs progressive), disease duration, and EDSS. In this model, only disease course emerged as a significant predictor (R 2 0.13, p 0.01). A second model was tested with course entered and held in block 1, and the remaining psychological variables from Table 2 entered stepwise in block 2. Agreeableness and the Neuropsychological Screening Questionnaire were retained in the model, explaining 51% ofthe variance (p 0.001). Table 3 presents data from patients with euphoria/disinhibition contrasted against the remaining sample. Note that the syndrome is somewhat more likely to occur in men and that patients with the syndrome are lower in agreeableness and somewhat lower in conscientiousness. Patient-informant discrepancies are higher in the euphoria/disinhibition patients, suggesting diminished insight in this subgroup. Patients with high euphoria/disinhibition scores were judged to be more cognitively impaired and to have more distressed caregivers. DISCUSSION Euphoria and associated neurobehavioral signs in MS have intrigued clinicians for over a century; but here- TABLE 1. Frequency of NPI Symptoms MS Patients Control Group Present Absent Total Present Absent Total NPI Domain N % N % Mean SD N % N % Mean SD p Delusions 2 3 73 97 0.1 0.7 0 0 25 100 0.0 0.0 0.37 Hallucinations 0 0 75 100 0.0 0.0 0 0 25 100 0.0 0.0 * Agitation/Aggression 28 37 47 63 2.1 3.1 4 16 21 84 0.3 0.9 0.006 Dysphoria/Depression 40 53 35 47 2.5 3.4 2 8 23 92 0.1 0.3 0.000 Anxiety 11 15 64 85 0.6 1.6 0 0 25 100 0.0 0.0 0.04 Elation/Euphoria 11 15 64 85 0.7 1.7 0 0 25 100 0.0 0.0 0.07 Apathy 14 19 61 81 0.9 2.2 1 4 24 96 0.2 0.8 0.12 Disinhibition 19 25 56 75 1.0 2.1 1 4 24 96 0.1 0.6 0.06 Irritability/Lability 46 61 29 39 3.1 3.4 6 24 19 76 0.5 1.3 0.000 Aberrant Motor Behavior 3 4 72 96 0.3 1.5 0 0 25 100 0.0 0.0 0.37 Total 58 77 17 23 11.5 13.1 10 40 15 60 1.2 2.1 0.000 Note. The table presents the number ofpatients and percentage ofsample with positive endorsement for each NPI symptom using a cut-off total score (frequency X severity) of 1 or higher. Group mean scores are compared by t test except as denoted by * where t could not be computed because SD 0 in both groups. J Neuropsychiatry Clin Neurosci 16:3, Summer 2004 353

EUPHORIA SCLEROTICA IN MULTIPLE SCLEROSIS tofore, the syndrome, originally called euphoria sclerotica 27 had not been operationalized with objective criteria. We used the NPI to measure this construct in 75 consecutive, non-referred MS patients. This euphoria/ disinhibition factor was present in 7% or 9% of the sample. These patients were characterized by secondary progressive course, low agreeableness on personality testing, poor insight, and impaired cognition. Caregivers ofthese patients were markedly distressed, suggesting that this syndrome has deleterious effects on caregiver- patient interactions. Ours is the first study to measure the prevalence ofthis syndrome in a consecutive, unselected clinical sample, using a valid and reliable psychometric test. The euphoria/disinhibition factor captures not only euphoria, but other behaviors that have been associated with euphoria sclerotica such as disinhibition, impulsivility, and emotional lability. 2,27,28,29 Several informants referred to distressing behaviors such as childishness, anger outbursts, and lack ofempathy. Elevated euphoria/ disinhibition scores were also associated with low agreeableness which characterizes patients as impatient, inconsiderate, and quarrelsome. Altogether, these traits resemble the syndrome as described in the classic literature. 1 The NPI does not include a measure ofunawareness or, in the terms ofcharcot, indifference. However, the NEO-PI provides an indirect measure of awareness by comparing self- and informant-reports of TABLE 2. Correlations Between Behavioral Factors, Personality, Depression, and Clinical Variables in MS Group NPI E/D NPI D/A A-I A-D C-I C-D BDI CES-D MSNQ-I EDSS Duration NPI D/A.47** A-I.52**.40** A-D.52 **.29.60** C-I.31 *.28.33 *.38 * C-D.33 *.10.32 *.32*.74** BDI.03.20.01.03.04.34* CES-D.24.32*.21.10.16.11.85** MSNQ.64**.45**.43**.45**.55**.46**.09.16 EDSS.20.09.04.08.29.22.06.06.30 Dis Duration.01.22.12.11.21.20.10.07.06.34* CG Distress.79**.76**.50**.37*.35*.32*.06.25.53**.12.09 Note. **p.001; *p.01. E/D Euphoria/Disinhibition factor from NPI; D/A Dysphoria/Apathy factor; A-I Agreeableness, informant-report; A-D Agreeableness Self-Informant Difference score; C-I Conscientiousness, informant-report; C-D Conscientiousness Self-Informant Difference score; BDI Beck Depression Inventory; CES-D Center for Epidemiologic Studies Depression Scale; MSNQ Multiple Sclerosis Neuropsychological Screening Questionnaire, informant-report; EDSS Expanded Disability Status Scale; Dis Duration Disease duration; CG Distress Caregiver Distress. TABLE 3. Comparisons Between the Patients With and Without Euphoria Sclerotica Positive Syndrome M SD Unless Otherwise Specified No Syndrome M SD Unless Otherwise Specified n 7 (9%) 68 (91%) Gender: female/male 2/5 (29% females) 48/20 (72% females) Time since symptoms onset 12 6 12 7 Disease course: RR/Progressive 3/4 (45% RR) 48/20 (75% RR) EDSS 4 2 3 2 NEO Agreeableness 34.9 7.1** 48.0 8.6 NEO Conscientiousness 35.3 15.7 44.2 13.5 NEO Agreeableness Self-Inf. D 12.0 7.3*.5 9.5 NEO Conscientiousness Self-Inf. D 13.1 15.2 9.6 7.7 BDI 9.9 3.0 9.6 7.7 CES-D 13.0 4.0 8.4 6.0 MSNQ-Total 41.4 16.0** 21.3 11.6 Caregiver Total Distress 24.4 7.0** 5.9 4.9 Note. RR relapsing-remitting course ofms, Progressive course included Secondary-Progressive, Primary Progressive, and Progressive Relapsing courses. EDSS Expanded Disability Status Scale, Self-Inf. D Self-Informant Difference score, MSNQ-Total Informant-rated MSNQ Total score. * p 0.01; ** p 0.001. 354 J Neuropsychiatry Clin Neurosci 16:3, Summer 2004

FISHMAN et al. personality and behavioral tendencies. In healthy volunteers, these discrepancies were minimal. In our previous work, 6 we found that patient/informant discrepancies were associated with executive function deficits in patients. To measure the original construct as described by Charcot, the NPI would have to be complemented by the NEO-PI or some similar measure that compares patient and informant reports of personality and behavior. We propose that euphoria sclerotica as defined here is probably neuropsychologically mediated and caused by a combination ofstrategically located lesions and premorbid personality traits. The syndrome might be explained by white matter lesions causing disconnection ofprefrontal cortex and limbic structures. Conversely, gray matter pathology is increasingly recognized in MS 30 and focal pathology to inferior frontal cortex could also account for significant variance in this disorder. Studies investigating MRI correlates ofthe syndrome are underway. This study is based on a consecutive series ofnonreferred patients and in our view, the results represent a reasonable estimate ofthe prevalence ofthis syndrome in MS clinic attendees. The frequency may be lower in a random, population based sample. A limitation ofthis study is the reliance upon informant-ratings. We view this as a necessary evil, given the impracticality ofdirectly observing patients in their natural milieu. In the future, investigators may wish to validate this NPI construct with video recordings ofstaged social interactions. Validity data supporting the NPI and the NEO-PI notwithstanding, we should consider that factors other than a patient s behavior may influence informant ratings. An additional weakness ofthe study is its crosssectional design, which does not allow for the study of emerging behavior change. A prospective, longitudinal study ofthese phenomena will be the natural next step in this research program. These limitations aside, we conclude that abnormal behavior is common in MS and a syndrome characterized by euphoria, lability, and disinhibition and can be reliably detected using the NPI. We estimate the frequency of euphoria sclerotica to be 9%. The syndrome is associated with low agreeableness on personality measures, poor insight, cognitive impairment, and high levels ofcaregiver distress. Identification ofthis syndrome could impact favorably on the clinical care of MS patients via the development ofnew pharmacological treatments 31 and counseling strategies for improving patient/caregiver interactions. 32 References 1. Finger S: A happy state ofmind. Archives ofneurology 1998; 55:241 250 2. Charcot JM: Lectures on the Diseases ofthe Nervous System. 1877 3. Rabins Peter V, Brooks Benjamin R, O Donnell Pat, et al.: Structural brain correlates ofemotional disorders in multiple sclerosis. Brain 1986; 109:585 597 4. Rabins Peter V: Euphoria in Multiple Sclerosis. 1990; 180 185 5. Swirsky-Sacchetti, T, Mitchell, DR, Seward, J, et al.: Neuropsychological and structural brain lesions in multiple sclerosis: A regional analysis. Neurology 1992; 42:1291 1295 6. Benedict RHB, Priore RL, Miller C, et al.: Personality disorder in MS correlates with cognitive impairment. Journal ofneuropsychiatry and Clinical Neurosciences 2001; 13:70 76 7. Costa PT, McCrae RR: NEO PI-R Professional Manual. 8. Digman JM: Personality structure: Emergence ofthe five-factor model. Anual Review ofpsychology 1990; 41:417 440 9. Digman JM: Higher-order factors of the Big Five. Journal of Personality & Social Psychology 1997; 73:1246 1256 10. Goldberg Lewis R: The structure ofphenotypic personality traits. American Psychologist 1993; 48:26 34 11. Chatterjee A, Strauss ME, Smyth KA, et al.: Personality changes in Alzheimer s disease. Archives ofneurology 1992; 49:486 491 12. Welleford EA, Harkins SW, Taylor, et al.: Personality change in dementia ofthe Alzheimer s type: Relations to Caregiver Personality and Burden. Experimental Aging Research 1995; 21:295 314 13. Diaz-Olavarrieta C, Cummings JL, Velazquez J, et al.: Neuropsychiatric manifestations of multiple sclerosis. Journal of Neuropsychiatry and Clinical Neurosciences 1999; 11:51 57 14. Cummings JL, Mega M, Gray K, et al: The Neuropsychiatric Inventory: Comprehensive assessment ofpsychopathology in dementia. Neurology 1994; 44:2308 2314 15. McDonald WI, Compston A, Edan G, et al.: Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis ofmultiple sclerosis. Annals ofneurology 2001; 50:121 127 16. Mega MS, Cummings JL, Fiorello T, et al.: The spectrum ofbehavioral changes in Alzheimer s disease. Neurology 1996; 46:130 135 17. Eysenck HJ: Personality and Individual Differences: A Natural Science Approach 18. Goldberg LR: The development of markers for the Big-Five factor structure. Psychological Assessment 1992; 4:26 42 19. Costa PT, McCrae RR: Professional Manual for the Revised NEO Personality Inventory and NEO Five-Factor Inventory. 20. Beck AT: Beck Depression Inventory. 1993 21. Andresen EM, Malmgren JA, Carter WB, et al: Screening for depression in well older adults: evaluation ofa short form ofthe CES-D (Center for Epidemiologic Studies Depression Scale). American Journal ofpreventive Medicine 1994; 10:77 84 22. Kohout FJ, Berkman LF, Evans DA, et al.: Two shorter forms of the CES-D (Center for Epidemiological Studies Depression) depression symptoms index. Journal ofaging & Health 1993; 5:179 193 J Neuropsychiatry Clin Neurosci 16:3, Summer 2004 355

EUPHORIA SCLEROTICA IN MULTIPLE SCLEROSIS 23. Kurtzke JF: Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Annals ofneurology 1983; 13:227 231 24. Benedict RHB, Munschauer FE, Linn R, et al.: Screening for multiple sclerosis cognitive impairment using a self-administered 15-item questionnaire. Multiple Sclerosis 2003; 9:95 101 25. Kaufer Daniel I, Cummings JL, Christine D, et al.: Assessing the impact ofneuropsychiatric symptoms in Alzheimer s disease: The Neuropsychiatric Inventory Caregiver Distress Scale. Journal ofthe American Geriatrics Society 2-21-1998; 46:210 215 26. Wood Stacey A, Cummings JL, Barclay T, et al.: Assessing the impact ofneuropsychiatric symptoms on distress in professional caregivers. Aging & Mental Health 8-24-1999; 3:241 245 27. Cottrell Samual Smith, Wilson SA Kinnier: The affective symptomatology ofdisseminated sclerosis. Journal ofneurology and Psychopathology 1926; 1 30 28. Brown Sanger, Davis Thomas K.: The mental symptoms ofmultiple sclerosis. Archives ofneurology and Psychiatry 1922; 7:629 634 29. Surridge David: An investigation into some psychiatric aspects ofmultiple sclerosis. British Journal ofpsychiatry 1969; 115:749 764 30. Bakshi R, Benedict RH, Bermel RA, et al.: Regional brain atrophy is associated with physical disability in multiple sclerosis: semiquantitative magnetic resonance imaging and relationship to clinical findings. Journal ofneuroimaging 2001; 11:129 136 31. Iannaccone S, Ferini-Strambi L: Pharmacologic treatment of emotional lability. Clinical Neuropharmacology 1996; 19:532 535 32. Benedict RHB, Shapiro A, Priore RL, et al.: Neuropsychological counseling improves social behavior in cognitively-impaired multiple sclerosis patients. Multiple Sclerosis 2001; 6:391 396 356 J Neuropsychiatry Clin Neurosci 16:3, Summer 2004