Background

This frustrating and devastating disease causes progressive loss of myelin in the brain and nervous system. Myelin is the fatty insulating layer that surrounds nerves that conduct electrical impulses to neurons and muscles. With progressive loss, nerve impulses are impaired and finally lost. Signs and symptoms depend upon which nerves and areas of the brain and spinal cord are affected. The earliest findings may be tingling and numbness. With time, these symptoms may progress leading to loss of function.

The cause is still unknown although an autoimmune and infectious cause have garnered the most research interest. Pathologists often play an important role in examining brain and nervous tissue, performing specialized tests to confirm the diagnosis and possibly elucidate the complex mechanisms of the disease.

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Prognosis and Treatment
Commonly Used Terms
Internet Links

 

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS
INCIDENCE
The prevalence of multiple sclerosis in the world: an update. Rosati G. Institute of Clinical Neurology, University of Sassari, Italy.	Neurol Sci 2001 Apr;22(2):117-39 Abstract quote The systematic study of multiple sclerosis (MS) in populations, started in 1929 by Sydney Allison, now consists of over 400 publications dealing with the prevalence of MS throughout the world. However, any attempt to redefine the pattern of geographical differences in MS frequency remains as difficult as ever. The comparison of prevalence studies carried out in different areas and times is made difficult by the variability in surveyed population sizes, age structures, ethnic origins and composition, and the difficult quantification of numerators, especially regarding the recognition of benign and very early cases. Additionally, complete case ascertainment depends on access to medical care, local medical expertise, number of neurologists, accessibility and availability of new diagnostic procedures, the degree of public awareness about MS, and the investigators' zeal and resources. Critical examination of the more recent data on MS prevalence leads to some revisions of previously held concepts, the most interesting of which is the appreciation of the greater influence of genetic factors on disease acquisition. The rarity of MS among Samis, Turkmen, Uzbeks, Kazakhs, Kyrgyzis, native Siberians, North and South Amerindians, Chinese, Japanese, African blacks and New Zealand Maoris, as well as the high risk among Sardinians, Parsis and Palestinians, clearly indicate that the different susceptibilities of distinct racial and ethnic groups are an important determinant of the uneven geographic distribution of the disease. The updated distribution of MS in Europe, showing many exceptions to the previously described north-south gradient, requires more explanation than simply a prevalence-latitude relationship. Prevalence data imply that racial and ethnic differences are important in influencing the worldwide distribution of MS and that its geography must be interpreted in terms of the probable discontinuous distribution of genetic susceptibility alleles, which can however be modified by environment. Because the environmental and genetic determinants of geographic gradients are by no means mutually exclusive, the race versus place controversy is, to some extent, a useless and sterile debate.
Incidence of seizures in patients with multiple sclerosis: a population-based study. Nyquist PA, Cascino GD, McClelland RL, Annegers JF, Rodriguez M. Department of Neurology, Mayo Clinic, Rochester, Minn 55905, USA.	Mayo Clin Proc 2002 Sep;77(9):910-2 Abstract quote OBJECTIVE: To determine whether multiple sclerosis (MS) is associated with occurrence of seizure activity. PATIENTS AND METHODS: The medical records of all incidence patients with MS in Olmsted County, Minnesota, from 1935 to 1991 were reviewed. The incidence of seizures was calculated by using 3 methods: including only seizures that occurred after definite diagnosis of MS, including all seizures occurring after onset of the first symptoms of MS, and including any seizures regardless of the time of onset relative to MS. These incidences were age-adjusted to the 1970 US population and then compared with the age-adjusted incidence rate of seizures in the general population of Olmsted County. RESULTS: The age-adjusted incidence of seizures among MS patients was not significantly higher than the age-adjusted incidence of seizures in the general population of Olmsted County. The age-adjusted incidence of first unprovoked seizures in Rochester, Minn, was 61 per 100,000 person-years. In patients with the definite diagnosis of MS, the age-adjusted Incidence was calculated at 61 per 100,000 person-years (95% confidence interval [CI], 7-114). In the group with seizures after onset of symptoms, the age-adjusted incidence rate was 80 per 100,000 person-years (95% CI, 24-135). In the group with seizures at any time in their life, the age-adjusted incidence rate was 82 per 100,000 person-years (95% CI, 41-158). CONCLUSION: The present study does not suggest that occurrence of seizures is more common in MS patients than in the general population.
AGE RANGE-MEDIAN
Early onset multiple sclerosis: a longitudinal study. Boiko A, Vorobeychik G, Paty D, Devonshire V, Sadovnick D; University of British Columbia MS Clinic Neurologists. Division of Neurology and Neurosurgery, Russian State Medical University, Moscow, Russia	Neurology 2002 Oct 8;59(7):1006-10 Abstract quote OBJECTIVE: To evaluate the clinical course of MS in individuals with onset of MS before age 16. METHODS: Patients with onset of MS before age 16 (n = 116) with complete clinical information on the clinical course from the MS Clinic at The University of British Columbia (UBC) Site Hospital computerized database (MS-COSTAR) were included in this study. The data were compared to those from the Canadian natural history study for MS clinic attendees, regardless of age at onset. RESULTS: The mean duration of observation was 19.76 +/- 0.90 years; the mean age at MS onset was 12.73 +/- 0.25 years. Only three cases (2.6%) had a primary progressive (PP) MS course. To date, 60 (53.1%) of 113 subjects have developed secondary progressive (SP) MS. The 50% probability for SPMS was reached 23 years after onset. For patients with relapsing remitting (RR) or SPMS the mean disease duration from onset to the time of confirmed Expanded Disability Status Scale (EDSS) 3.0 was 16.03 +/- 1.17 years (at mean age 28.47 +/- 1.14); mean duration from onset to the time of EDSS 6.0 was 19.39 +/- 1.43 years (at mean age 32.32 +/- 1.44). Annual relapse rate was 0.54 +/- 0.05 per year. The correlation between the number of relapses during the first year of disease and the course of the disease was also significant. CONCLUSIONS: The prevalence of early onset MS (3.6%) in our study confirms the previous findings on early onset MS. A RR course was seen in the majority of cases of early onset MS. A high frequency of relapses, early age at permanent disability, and the presence of malignant cases raise the question of possible early use of disease-modifying therapy in patients with early onset MS.
GEOGRAPHY
MALTA
Multiple sclerosis in Malta in 1999: an update. Dean G, Elian M, de Bono AG, Asciak RP, Vella N, Mifsud V, Aquilina J. Health Research Board, Dublin, Ireland Central Middlesex Hospital, London, UK St Luke's Hospital, Guardamangia, Malta Department of Health Information, Guardamangia, Malta	J Neurol Neurosurg Psychiatry 2002 Sep;73(3):256-60 Abstract quote OBJECTIVES: To ascertain the prevalence of multiple sclerosis (MS) in the islands of Malta and compare it with a previous study undertaken 21 years earlier, when a remarkably low prevalence was found. METHOD: Deaths with MS on the death certificate since the last study were reviewed. Sources of information about new patients were the Hospital Activity Analysis scheme, the MS Society of Malta, the records of the state hospitals, long stay private hospitals and nursing homes, lists provided by the state pharmacies, and magnetic resonance imaging, cerebrospinal fluid, and evoked response studies. Prevalence day was 1 January 1999. The Poser classification was used. RESULTS: Since 1978, 17 patients had died with a verified diagnosis of MS on the death certificate. They included all 10 deaths with MS from the original study and two immigrants. Fifty patients had clinically definite MS (CDMS) and 13 clinically probable MS (CPMS). The prevalence of CDMS was 13.2/100 000 (male 11.2, female 15.2). The prevalence of CDMS and CPMS combined was 16.7/100,000 (male 13.3, female 19.9). The annual incidence was 0.7/100,000. Twelve patients were found with CDMS among the 7213 immigrants resident in Malta (166/100,000). The expected rate was 1/100,000, determined at Maltese born rates. There were major changes in the population distribution during the 21 years between the two studies, with a big increase in the age groups with a high risk of MS. There is a longer expectation of life and the diagnosis in now made earlier. CONCLUSION: Malta still has a low MS prevalence. In comparison with Sicily and other Mediterranean countries of Europe it offers an opportunity to ascertain the genetic and environmental factors responsible for the disease.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
DIABETES MELLITUS
HLA-patterns in patients with multiple sclerosis and type I diabetes mellitus: evidence for possible mutual exclusion of both diseases. Lobnig BM, Chantelau E, Vidgren G, Van Landeghem AA, Kinnunen L, Tuomilehto-Wolf E. Department of Metabolic Diseases and Nutrition, Heinrich-Heine-University Dusseldorf, Moorenstrasse 5, D-40225 Dusseldorf, German.	Diabetes Metab 2002 Jun;28(3):217-21 Abstract quote BACKGROUND: Type I diabetes mellitus (T1DM) and multiple sclerosis (MS), both immune-mediated diseases, rarely co-exist in the same individual or co-segregate in families. HLA susceptibility genes for T1DM (DRB1*0401, DRB1*0404, DQB1*0302, DRB1*0301, DQB1*0201) rarely occur in MS patients. HLA genes known to confer "resistance" to T1DM (DRB1*1501, DQB1*0602-DQA1*0102) predispose to MS. To test the hypothesis of mutually exclusive HLA patterns, patients affected by T1DM plus MS were compared to those of patients affected by either of the diseases alone in a case-control study. METHODS: Blood was sampled for analysis of HLA class I and class II alleles from 66 patients of German ancestry, of whom 33 had T1DM plus MS, and 33 had MS-only. For comparison to patients with T1 DM-only we referred to published data. HLA typing was performed using conventional serology (immuno-magnetic beads) and genotyping (SSP-PCR Dynal(R) SSP low/high resolution kits). RESULTS: Individuals with co-existing MS plus T1DM displayed the expected T1DM associated HLA-pattern (75.8% carried DRB1*04, 69.7% carried DQB1*0302, 42% were DR4, DR3 heterozygous), but failed to display the expected MS associated HLA-pattern (0% carried DQB1*0602, 3.1% carried DQA1*0102).The expected MS associated HLA-pattern of Caucasoid patients, however, was found in the MS-only patients (42% carried DRB1*1501-DQB1*0602, 58% carried DQA1*0102), while the prevalence of T1DM susceptibility and 'resistance' alleles was not different from the general population. The allele frequency of DRB1*1501 was 16/66, 24.2% in the 33 MS-only patients, and 0% in the 33 MS plus T1DM patients. The allele frequency of DQB1*0602 was 16/66, 24.2% in the 33 MS-only patients, and 0% in the 33 MS plus T1DM patients. The allele frequency of DQA1*0102 was 18/66, 27.3%, in the 33 MS-only patients, and 1/66 1.5% in the 33 MS plus T1DM patients. CONCLUSION: These data confirm the hypothesis of mutually exclusive HLA-patterns of T1DM and MS, and are consistent with a low rate of co-morbidity of both diseases.
Patients with multiple sclerosis and risk of type 1 diabetes mellitus in Sardinia, Italy: a cohort study. Marrosu MG, Cocco E, Lai M, Spinicci G, Pischedda MP, Contu P. Dipartimento di Neuroscienze, Centro Sclerosi Multipla, Ospedale Binaghi, Via Is Guadazzonis 2, 09126 Cagliari, Italy	Lancet 2002 Apr 27;359(9316):1461-5 Abstract quote BACKGROUND: Individuals from Sardinia, Italy, are at high risk of developing multiple sclerosis and type 1 diabetes mellitus. We attempted to assess the prevalence in this region of type 1 diabetes mellitus in individuals with multiple sclerosis, and to ascertain disease risk factors. METHODS: We did a cohort study to assess prevalence of type 1 diabetes in 1090 people with multiple sclerosis, and in their parents (n=2180) and siblings (n=3300), all born and living in Sardinia. All participants were patients at the multiple sclerosis clinic in Cagliari, and were judged representative of the total Sardinian outpatients and inpatients. We asked patients whether their parents or siblings had multiple sclerosis or diabetes, confirming replies by examining clinical records. We identified risk factors for diabetes with univariate and multivariate logistic regression analyses. FINDINGS: Diabetes prevalence in people with multiple sclerosis was, respectively, about three-fold and five-fold that in their healthy siblings (p=0.001) and in the general population (p<0.0001). Presence of other relatives with multiple sclerosis conferred increased risk of type 1 diabetes to healthy siblings of individuals with multiple sclerosis (odds ratio=3.41, p=0.0019). Diabetes risk was six-fold higher in patients with relatives having multiple sclerosis than in healthy siblings of multiple sclerosis patients without other relatives with the disease (p=0.0001). INTERPRETATION: In Sardinian families with genetic inheritance of multiple sclerosis type 1 diabetes is prevalent, both in multiple sclerosis patients and in healthy siblings. This finding indicates that common genes contribute to susceptibility to both diseases in this population.
INFECTIONS
Prospective study on the relationship between infections and multiple sclerosis exacerbations. Buljevac D, Flach HZ, Hop WC, Hijdra D, Laman JD, Savelkoul HF, van Der Meche FG, van Doorn PA, Hintzen RQ. Department of Neurology, Erasmus MC, Rotterdam, The Netherlands.	Brain 2002 May;125(Pt 5):952-60 Abstract quote One of the characteristics of multiple sclerosis is the unpredictable occurrence of exacerbations and remissions. These fluctuations in disease activity are related to alterations in (auto-)immune activity. Exacerbations lead to short-term morbidity, but may also influence long-term disability. This longitudinal study in 73 patients with relapsing-remitting multiple sclerosis assessed the contribution of systemic infections to the natural course of exacerbations. In addition, we analysed whether infections lead to an increase in the number of gadolinium-enhancing lesions. A total of 167 infections and 145 exacerbations were observed during 6466 patient weeks. During a predefined at-risk period (ARP) of 2 weeks before until 5 weeks after the onset of a clinical infection (predominantly upper airway infections), there was an increased risk of exacerbations (rate ratio 2.1), which is in accordance with previous studies. Exacerbations with onset during the ARP led more frequently to sustained deficit [increase of > or =1 Expanded Disability Status Scale (EDSS) point or > or =0.5 above EDSS 5.5 for >3 months] than exacerbations with onset outside the ARP, with a rate ratio of 3.8. Minor and major exacerbations were equally distributed between the ARP and non-ARP onset groups. ARP exacerbations were associated with significantly higher plasma levels of the inflammatory marker soluble intracellular adhesion molecule 1 than non-ARP exacerbations, indicating relatively enhanced immune activation during ARP relapses. Three serial MRI scans were performed after the onset of an infection over a 6-week period. There was no difference in the number of gadolinium-enhancing lesions between the three time points. In conclusion, exacerbations in the context of a systemic infection lead to more sustained damage than other exacerbations. There is no indication that this effect occurs through enhanced opening of the blood-brain barrier.

 

PATHOGENESIS	CHARACTERIZATION
APOPTOSIS
CD95-mediated apoptosis and DNA fragmentation in MS. Heesen C, Georghiu S, Gbadamosi J, Schoser BG. Department of Neurology, University of Hamburg, Germany.	Acta Neurol Scand 2000 Nov;102(5):333-6 Abstract quote OBJECTIVE: To investigate possible associations of soluble CD95 (sCD95) serum levels and DNA defragmentation with different MS disease stages and activities. METHODS: Sera of 114 patients were analysed by an ELISA technique for sCD95. In a subgroup of 18 relapsing-remitting MS patients and controls we studied DNA fragmentation by the TUNEL-method in CSF cytospins. RESULTS: sCD95 was detectable in sera of MS patients, healthy controls and meningitis patients without significant differences. CSF specimens showed modest amounts of apoptotic cells in MS and controls. CONCLUSION: We could not demonstrate an association of MS disease course or activity with the expression of sCD95 in sera. DNA fragmentation in the CSF was not significantly enhanced compared to controls. Thus the analysed markers of programmed cell death appear not suitable to monitor MS disease courses.
CHLAMYDIA
Comparative study of the presence of Chlamydia pneumoniae in cerebrospinal fluid of Patients with clinically definite and monosymptomatic multiple sclerosis. Sriram S, Yao SY, Stratton C, Calabresi P, Mitchell W, Ikejima H, Yamamoto Y. Department of Neurology. Department of Pathology, Vanderbilt School of Medicine, Nashville, Tennessee, USA.	Clin Diagn Lab Immunol 2002 Nov;9(6):1332-7 Abstract quote There is considerable controversy concerning the evidence for the presence of Chlamydia pneumoniae in the cerebrospinal fluid (CSF) of both multiple sclerosis (MS) patients and patients with other neurological diseases (OND). In order to clarify this issue, the laboratories at Vanderbilt University Medical Center (VUMC) and the University of South Florida (USF) examined the reproducibility of their respective PCR assays for the detection of C. pneumoniae DNA in the CSF of a common group of MS patients and OND controls. The two laboratories used different DNA extraction and PCR techniques in order to determine the prevalence of the C. pneumoniae genome in both monosymptomatic and clinically definite MS patients as well as in OND controls. In clinically definite MS patients, the VUMC and USF detection rates were 72 and 61%, respectively, and in patients with monosymptomatic MS, the VUMC and USF detection rates were 41 and 54%, respectively. The PCR signal was positive for 7% of the OND controls at VUMC and for 16% at USF. These studies confirm our previous reports concerning the high prevalence of C. pneumoniae in the CSF of MS patients. The presence of C. pneumoniae in patients with monosymptomatic MS would also suggest that infection with the organism occurs early in the course of the disease.
EPSTEIN-BARR VIRUS
Temporal relationship between elevation of epstein-barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D, Ascherio A. Division of Preventive Medicine, Walter Reed Army Institute of Research, Silver Spring, Md, USA.	JAMA. 2005 May 25;293(20):2496-500. Abstract quote   CONTEXT: Infection with Epstein-Barr virus (EBV) has been associated with an increased risk of multiple sclerosis (MS), but the temporal relationship remains unclear. OBJECTIVE: To determine whether antibodies to EBV are elevated before the onset of MS. DESIGN, SETTING, AND PARTICIPANTS: Nested case-control study conducted among more than 3 million US military personnel with blood samples collected between 1988 and 2000 and stored in the Department of Defense Serum Repository. Cases were identified as individuals granted temporary or permanent disability because of MS. For each case (n = 83), 2 controls matched by age, sex, race/ethnicity, and dates of blood sample collection were selected. Serial samples collected before the onset of symptoms were available for 69 matched case-control sets. MAIN OUTCOME MEASURES: Antibodies including IgA against EBV viral capsid antigen (VCA), and IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse and restricted early antigens, and cytomegalovirus. RESULTS: The average time between blood collection and MS onset was 4 years (range, <1-11 years). The strongest predictors of MS were serum levels of IgG antibodies to EBNA complex or EBNA-1. Among individuals who developed MS, serum antibody titers to EBNA complex were similar to those of controls before the age of 20 years (geometric mean titers: cases = 245, controls = 265), but 2- to 3-fold higher at age 25 years and older (cases = 684, controls = 282; P<.001). The risk of MS increased with these antibody titers; the relative risk (RR) in persons with EBNA complex titers of at least 1280 compared with those with titers less than 80 was 9.4 (95% confidence interval [CI], 2.5-35.4; P for trend <.001). In longitudinal analyses, a 4-fold increase in anti-EBNA complex or anti-EBNA-1 titers during the follow-up was associated with a 3-fold increase in MS risk (EBNA complex: RR , 3.0; 95% CI, 1.3-6.5; EBNA-1: RR, 3.0; 95% CI, 1.2-7.3). No association was found between cytomegalovirus antibodies and MS. CONCLUSION: These results suggest an age-dependent relationship between EBV infection and development of MS.
Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. Ascherio A, Munger KL, Lennette ET, Spiegelman D, Hernan MA, Olek MJ, Hankinson SE, Hunter DJ. Harvard School of Public Health, Nutrition Department, 665 Huntington Ave, Boston, MA 02115, USA.	JAMA 2001 Dec 26;286(24):3083-8 Abstract quote CONTEXT: Epidemiological studies suggest an association between infection with Epstein-Barr virus (EBV) and risk of multiple sclerosis (MS). OBJECTIVE: To determine whether elevation in serum antibody titers to EBV viral capsid antigen (VCA), nuclear antigens (EBNA, EBNA-1, and EBNA-2), and diffuse and restricted early antigen (EA-D and EA-R) as well as to cytomegalovirus (CMV) precede the occurrence of MS. DESIGN, SETTING, AND SUBJECTS: Prospective, nested case-control study. Of 62 439 women participating in the Nurses' Health Study (aged 30-55 years in 1976) and Nurses' Health Study II (aged 25-42 years in 1989) who gave blood samples in 1989-1990 and 1996-1999, respectively, and were followed up through 1999, 144 women with definite or probable MS and 288 healthy age-matched controls were included in the analysis. MAIN OUTCOME MEASURE: Serum antibody titers to the specific EBV and CMV antigens, compared between cases and controls. RESULTS: We documented 18 cases of MS with blood collected before disease onset. Compared with their matched controls, these women had higher serum geometric mean titers (GMTs) of antibodies to EBV but not CMV. Elevations were significant for antibodies to EBNA-1 (GMT, 515 vs 203; P =.03), EBNA-2 (GMT, 91 vs 40; P =.01), and EA-D (15.9 vs 5.9; P =.04). The strongest association was found for antibodies to EBNA-2; a 4-fold difference in titers was associated with a relative risk (RR) of MS of 3.9 (95% confidence interval [CI], 1.1-13.7). The corresponding RRs were 1.6 (95% CI, 0.7-3.7) for VCA, 2.5 (95% CI, 1.0-6.3) for EBNA, 1.8 (95% CI, 1.0-3.1) for EA-D, and 1.0 (95% CI, 0.6-1.7) for CMV. Significant but generally weaker elevations in anti-EBV antibodies were also found in analyses of 126 cases of MS with blood collected after disease onset and their matched controls. CONCLUSIONS: Our results support a role of EBV in the etiology of MS.
HEAT SHOCK PROTEIN
Heat shock protein 70 gene polymorphism in Japanese patients with multiple sclerosis. Niino M, Kikuchi S, Fukazawa T, Yabe I, Sasaki H, Tashiro K. Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.	Tissue Antigens 2001 Aug;58(2):93-6 Abstract quote Despite the strength of the association of multiple sclerosis (MS) and human leukocyte antigen (HLA)-DR2, other genetic elements could have a role in the pathophysiology of MS. We investigated possible associations with polymorphic susceptibility genes located within the HLA complex, i.e., heat-shock protein (HSP)70-1, HSP70-2, and HSP70-hom in Japanese patients with MS. Furthermore, we analyzed the influence of HSP70 gene polymorphisms on the severity of the disease, clinical course, magnetic resonance imaging findings, and oligoclonal bands in the cerebrospinal fluid, and HLA in MS patients. The results of the present study indicated that there were no significant differences in the distribution of all HSP70 genotypes and allele frequencies between Japanese MS patients and controls. In MS patients, there were no associations between HSP70 gene polymorphisms and the clinical data. Moreover, there were no significant differences in HSP70 genotype or allele frequencies between MS patients positive for HLA-DRB1*1501 alleles and matched controls. Our data indicate that HSP70 gene polymorphisms are not relevant in the susceptibility to or the severity of Japanese MS patients.
HHV6 AND CHLAMYDIA
Human herpes virus 6 and multiple sclerosis. Moore FG, Wolfson C. Department of Nurology, McGill University, Montereal, Quebec, Canada.	Acta Neurol Scand 2002 Aug;106(2):63-83 Abstract quote OBJECTIVES: To systematically review the published evidence for a relationship between human herpes virus 6 (HHV-6) and multiple sclerosis (MS). MATERIALS AND METHODS: The medical literature was searched using MEDLINE and the Cochrane database. Retrieved studies are presented according to the experimental technique(s) used. The studies are rated for quality using a priori defined criteria. RESULTS: Twenty-eight studies were retrieved. A total of 12 different experimental techniques were used. Four of these techniques provided evidence for a relationship between HHV-6 and MS, but none were able to show a causative relationship. CONCLUSIONS: The available literature provides some support for a relationship between HHV-6 and MS. The limitations of the available studies and directions for future research are discussed.
Human herpesvirus 6 and Chlamydia pneumoniae as etiologic agents in multiple sclerosis - a critical review. Swanborg RH, Whittum-Hudson JA, Hudson AP. Departments Immunology and Microbiology, Wayne State University School of Medicine, Gordon H. Scott Hall, 540 East Canfield Avenue, 48201, Detroit, MI, USA	Microbes Infect 2002 Nov;4(13):1327-33 Abstract quote Multiple sclerosis (MS) is thought by many investigators to have an infectious component, and several microorganisms have been associated with the disease during the last three decades. Recent studies have implicated both human herpesvirus 6 (HHV-6) and the obligate intracellular bacterium Chlamydia pneumoniae in the etiology of MS. As with earlier studies of other potential agents, however, evidence linking either of these organisms to the disease is equivocal. In this article, we review data for and against involvement of HHV-6 and C. pneumoniae in MS, as well as evidence concerning auxiliary factors, such as possession of the APOE epsilon4 allele, which may influence the role of these organisms in pathogenesis. Further, we suggest several lines of investigation that should clarify whether either or both pathogens are associated meaningfully with this disease.
Correlation between HHV-6 reactivation and multiple sclerosis disease activity. Chapenko S, Millers A, Nora Z, Logina I, Kukaine R, Murovska M. August Kirchenstein Institute of Microbiology and Virology, University of Latvia, Riga, Latvia.	J Med Virol 2003 Jan;69(1):111-7 Abstract quote This study examined the association between HHV-6 infection and multiple sclerosis (MS) and the relationship between HHV-6 reactivation and disease activity. The frequency of HHV-6 genomic sequences in peripheral blood mononuclear cells (PBMCs), the incidence of plasma viremia (nPCR), the transcription of viral mRNA in PBMCs (RT-PCR), the presence of antiviral IgM and IgG class antibodies in the plasma (IFA) of 16 relapsing/remitting and secondary progressive MS patients were studied in comparison with clinical manifestations of the disease, magnetic resonance imaging (MRI) of brain, and serum interleukin (IL)-12 concentrations (ELISA). The prevalence of HHV-6 infection was significantly higher in patients with MS (16/26) than in patients with other neurological diseases (6/21) and in blood donors (43/150). HHV-6 reactivation was found during periods of disease activity with Gadolinium-enhancing lesions on MRI in both relapsing/remitting and secondary progressive MS (10/13; 76.9%). In patients with active MS disease, serum concentrations of IL-12 were significantly higher in those patients with active HHV-6 infection than in patients with latent infection. The data confirm an association between HHV-6 infection and MS and show a correlation between HHV-6 reactivation and disease activity in relapsing/remitting and secondary progressive MS. The risk of an exacerbation of MS was significantly higher (P < 0.005) in patients with active HHV-6 infection than in patients with latent infection. A clear correlation between HHV-6 reactivation and serum IL-12 concentrations during disease activity has been demonstrated. The results suggest that HHV-6 reactivation is implicated in exacerbation of MS, possibly through modulation of IL-12 synthesis.
MS ASSOCIATED RETROVIRUS
Multiple sclerosis-associated retrovirus and MS prognosis: an observational study. Sotgiu S, Serra C, Mameli G, Pugliatti M, Rosati G, Arru G, Dolei A. Institute of Clinical Neurology, University of Sassari, Italy.	Neurology 2002 Oct 8;59(7):1071-3 Abstract quote MS-associated retrovirus (MSRV) in the CSF may have gliotoxic properties and could be associated with a more disabling MS. The authors tested this hypothesis in 15 untreated patients with MS: 6 MSRV- and 9 MSRV+ at the time of CSF withdrawal. After a 3-year mean follow-up, MSRV- patients showed a stable MS course, whereas MSRV+ patients had a progressive course (p = 0.01).
PROTEASOME AUTOANTIBODIES
The proteasome is a major autoantigen in multiple sclerosis. Mayo I, Arribas J, Villoslada P, Alvarez DoForno R, Rodriguez-Vilarino S, Montalban X, De Sagarra MR, Castano JG. Instituto de Investigaciones Biomedicas 'Alberto Sols', UAM-CSIC, Facultad de Medicina, UAM, Servicio de Inmunologia, Hospital Universitario 'La Paz', Madrid and Unitat de Neuroinmunologia Clinica. Hospital Vall d'Hebron, Barcelona, Spain. Present addresses: Laboratori de Recerca Oncologica, Unitat B, Hospital Vall d'Hebron, Barcelona and Departmento de Neurologia, Clinica Universitaria de Navarra, Pamplona, Navarra, Spain.	Brain 2002 Dec;125(Pt 12):2658-2667 Abstract quote Multiple sclerosis seems to be an autoimmune disease of unknown aetiology affecting the white matter of the CNS. It is generally accepted that the autoimmune response is directed against specific components of myelin. We show here that proteasome, a ubiquitous protease complex composed of 14 different subunits, is a target for autoantibodies (IgG and IgM classes) present in the serum (66%, 73 out of 110) and in the CSF (61%, 16 out of 26) of patients with multiple sclerosis. Using recombinant proteasomal subunits we demonstrate the presence of specific autoantibodies against subunits C2, C8, C9 and C5 in multiple sclerosis patients. Recombinant C2 constructs allow us to localize an immunodominant autoepitope recognized by the sera of multiple sclerosis patients within the C-terminal of C2 proteasomal subunit (251-DEPAEKADEPMEH-263). In addition, two constructs of the recombinant proteasomal subunits C2 and C8 were also used to study the proliferation of peripheral blood mononuclear cells from multiple sclerosis patients; 12 out of 30 (40%) multiple sclerosis patients show positive proliferation with one or both of these recombinant subunits. The high prevalence of anti-proteasome autoantibodies in multiple sclerosis sera compared with sera from patients with other chronic inflammatory conditions: systemic lupus erythematosus (35%, 35 out of 100), primary Sjogren's syndrome (16%, 5 out of 31), vasculitis (0 out of 20), sarcoidosis (7%, 1 out of 13) and Behcet's disease (19%, 4 out of 21) suggest that humoral autoreactivity to proteasome could be a useful test in multiple sclerosis patients that may be of help in the diagnosis and/or progression of this chronic inflammatory disease. Finally, these results suggest that some global abnormality in B and/or T cell function is also involved in the chronic inflammatory response observed in multiple sclerosis patients, as it is frequently observed in other human organ-specific autoimmune diseases.

 

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
Correlating multiple MRI parameters with clinical features: an attempt to define a new strategy in multiple sclerosis. Tourbah A, Stievenart JL, Abanou A, Fontaine B, Cabanis EA, Lyon-Caen O. Federation de Neurologie, Hjpital de la Salpetriere, Paris, France.	Neuroradiology 2001 Sep;43(9):712-20 Abstract quote MRI is the most powerful imaging technique in managing patients with suspected or confirmed multiple sclerosis (MS). However, conventional MRI variables show nonspecific abnormalities weakly correlated with clinical progression of the disease. New techniques, now routinely available, offer better characterisation of the pathophysiology. We combined conventional MRI, including lesion load, contrast enhancement and "black holes" with magnetisation transfer and diffusion-weighted imaging and localised proton MR spectroscopy (MRS) to study their relationship with disability, course and duration of MS. The variables that were the most significantly linked to the course of the disease (relapsing remitting versus secondary progressive) were lesion load, mean overall magnetisation transfer ratio and apparent diffusion coefficient (MGADC), the percentage of ADC in (PADCIMD), and out of (PAD-COMD) modal distribution, and the ratio N-acetylaspartate and creatine-containing compounds on MRS of the centrum semiovale. MGADC and PADCIMD were the independent factors most related to disability and duration of disease. Combining MRI techniques is clinically relevant and feasible for studies of MS and may be applied to other diseases of the central nervous system.
Magnetic resonance imaging in primary progressive multiple sclerosis. Ingle GT, Thompson AJ, Miller DH. NMR Research Unit, Institute of Neurology, London, United Kingdom.	J Rehabil Res Dev 2002 Mar-Apr;39(2):261-71 Abstract quote Ten to fifteen percent of patients with multiple sclerosis (MS) have a condition that is progressive from onset without a preceding relapsing-remitting phase: this is known as primary progressive multiple sclerosis (PPMS). Patients with PPMS tend to be older, often present with motor symptoms and, in contrast to relapsing MS, are as likely to be male as female. The conventional magnetic resonance imaging (MRI) characteristics of PPMS include a tendency to lower lesion loads and lower rate of new lesion formation. In common with relapsing MS, the relation between conventional MRI abnormalities and clinical condition is poor. Studies using newer MRI techniques, such as magnetization transfer imaging (MTI), diffusion-weighted imaging (DWI), magnetic resonance spectroscopy (MRS), and functional MRI (fMRI), have also been carried out. These techniques are sensitive to a wider range of abnormalities within tissue, and their increased pathological specificity may be helpful in clarifying the underlying pathology of the condition.
Assessment of normal-appearing white and gray matter in patients with primary progressive multiple sclerosis: a diffusion-tensor magnetic resonance imaging study. Rovaris M, Bozzali M, Iannucci G, Ghezzi A, Caputo D, Montanari E, Bertolotto A, Bergamaschi R, Capra R, Mancardi GL, Martinelli V, Comi G, Filippi M. Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute and University Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy.	Arch Neurol 2002 Sep;59(9):1406-12 Abstract quote BACKGROUND: Diffusion-tensor magnetic resonance imaging is sensitive to the more destructive aspects of multiple sclerosis (MS) evolution occurring outside and within T2-visible lesions and, as a consequence, holds promise for providing a more complete picture of primary progressive (PP) MS-related tissue damage than conventional magnetic resonance imaging. OBJECTIVE: To improve our understanding of PPMS by assessing the extent of occult pathological features in the normal-appearing white and gray matter of the brain using diffusion-tensor magnetic resonance imaging. METHODS: Ninety-six patients with PPMS, 47 patients with secondary progressive (SP) MS, and 44 healthy control subjects were studied. T2-hyperintense and T1-hypointense lesion volumes were calculated, and the volume of the whole brain tissue was measured. Diffusion-tensor magnetic resonance imaging scans were postprocessed and analyzed to obtain the mean diffusivity and fractional anisotropy histograms from the brain and from the normal-appearing white and gray matter in isolation. RESULTS: The mean T2-hyperintense and T1-hypointense lesion volumes were lower in patients with PPMS than in patients with SPMS, while the mean absolute brain volumes were similar in the 2 groups. The average lesion diffusivity was significantly higher in patients with SPMS than in patients with PPMS (P<.001). Histogram-derived metrics of the brain tissue and normal-appearing white and gray matter were significantly different between patients with PPMS and healthy subjects (range, P =.004 to <.001). Average diffusivity values were significantly higher in patients with SPMS than in patients with PPMS for all the tissues studied (range, P =.001 to <.001). Fractional anisotropy histogram-derived quantities did not significantly differ between the 2 patient groups (range, P =.94 to.03). CONCLUSION: This study confirms that, in patients with PPMS, normal-appearing white and gray matter are not spared by disease-related pathological processes, although they are affected to a lesser degree than in patients with SPMS.
MRI predictors of early conversion to clinically definite MS in the CHAMPS placebo group. CHAMPS Study Group.	Neurology 2002 Oct 8;59(7):998-1005 Abstract quote OBJECTIVE: To assess the ability of baseline MRI characteristics to predict the early development of clinically definite MS (CDMS) and combined CDMS/MRI outcomes in 190 patients with a positive MRI at the time of their first demyelinating event. METHODS: Based on individual and sets of baseline MRI characteristics, the authors evaluated the percentage of patients meeting outcomes of CDMS and various combined CDMS/MRI outcomes by 18 months. They also optimized a cutpoint for dichotomizing each baseline MRI characteristic and evaluated these variables using logistic regression to determine which MRI characteristics best predicted CDMS by 18 months. RESULTS: The presence of two or more gadolinium-enhancing lesions better predicted the development of CDMS and combined CDMS/MRI outcomes by 18 months than any other individual MRI characteristic or set of MRI characteristics. Among patients with two or more gadolinium-enhancing lesions, 52% developed CDMS compared with 24% of patients with fewer than two lesions. For those meeting the criteria of Barkhof et al., 32% of patients developed CDMS compared with 16% of those not meeting these criteria. Irrespective of individual or sets of criteria, however, the majority of patients developed either CDMS or demonstrated disease activity on brain MRI by 18 months. CONCLUSIONS: For patients with positive MRI at the time of their initial neurologic event, both gadolinium-enhancing lesions and the Barkhof criteria are predictors for development of CDMS over a short interval. However, these results, based on a combined CDMS/MRI outcome, suggest that the majority of these patients are already in the earliest stages of MS, regardless of whether any further MRI criteria are met.
LABORATORY MARKERS
AUTOANTIBODIES
Autoantibodies in multiple sclerosis patients before and during IFN-beta 1b treatment: are they correlated with the occurrence of autoimmune diseases? Verdun E, Isoardo G, Oggero A, Ferrero B, Ghezzi A, Montanari E, Zaffaroni M, Durelli L; Betaferon Safety Trial (BEST) Study Group. Clinica Neurologica, Dipartimento di Neuroscienze, Universita di Torino, Torino, Italy.	J Interferon Cytokine Res 2002 Feb;22(2):245-55 Abstract quote Autoimmune side effects, namely autoantibody (autoAb) occurrence and thyroid function alteration, have been described during interferon-beta (IFN-beta) treatment for multiple sclerosis (MS). AutoAb occurrence and autoimmune thyroid diseases are also frequently detected in MS patients free of any treatment. The aim of this study was to evaluate the relationship between IFN-beta 1b treatment, autoAb occurrence, and autoimmune diseases in MS. Thyroid and liver function and serum autoAb (antithyroid, antinuclear, anti-liver, anti-kidney microsomes, anti-smooth muscle and parietal cell antigens) occurrence were evaluated in 156 relapsing-remitting MS (RRMS) patients before and every 3 months after starting IFN-beta 1b treatment (8 MIU subcutaneously [s.c.] on alternate days). The probability of having liver or thyroid function alteration or autoAb occurrence was analyzed longitudinally with the generalized estimating equations (GEE) approach. At baseline, 16.1% of patients had autoAb. During treatment, autoAb occurred de novo in 7.2% of patients. GEE analysis showed that the probability of having autoAb at any time during IFN-beta 1b treatment did not change significantly compared with baseline. AutoAb occurring de novo rarely persisted during treatment and significantly less than those already present at baseline. Positivity for autoAb at baseline or during treatment was not correlated with the development of thyroid or liver function alteration during IFN-beta 1b treatment. Our study indicates that IFN-beta treatment is a safe treatment for MS patients, free of risk of autoimmunity and of associated liver or thyroid function alteration.
GENETIC SCREENING
A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis. Akesson E, Oturai A, Berg J, Fredrikson S, Andersen O, Harbo HF, Laaksonen M, Myhr KM, Nyland HI, Ryder LP, Sandberg-Wollheim M, Sorensen PS, Spurkland A, Svejgaard A, Holmans P, Compston A, Hillert J, Sawcer S. University of Cambridge, Neurology unit, Addenbrooke's Hospital, UK.	Genes Immun 2002 Aug;3(5):279-85 Abstract quote Genetic factors influence susceptibility to multiple sclerosis but the responsible genes remain largely undefined, association with MHC class II alleles being the only established genetic feature of the disease. The Nordic countries have a high prevalence of multiple sclerosis, and to further explore the genetic background of the disease, we have carried out a genome-wide screen for linkage in 136 sibling-pairs with multiple sclerosis from Denmark, Finland, Norway and Sweden by typing 399 microsatellite markers. Seventeen regions where the lod score exceeds the nominal 5% significance threshold (0.7) were identified-1q11-24, 2q24-32, 3p26.3, 3q21.1, 4q12, 6p25.3, 6p21-22, 6q21, 9q34.3, 10p15, 10p12-13, 11p15.5, 12q21.3, 16p13.3, 17q25.3, 22q12-13 and Xp22.3. Although none of these regions reaches the level of genome-wide significance, the number observed exceeds the 10 that would be expected by chance alone. Our results significantly add to the growing body of linkage data relating to multiple sclerosis.
HLA MOLECULES
Clinical and MRI disease activity in multiple sclerosis are associated with reciprocal fluctuations in serum and cerebrospinal fluid levels of soluble HLA class I molecules. Fainardi E, Granieri E, Tola MR, Melchiorri L, Vaghi L, Rizzo R, Castellazzi M, Ceruti S, Paolino E, Baricordi OR. Multiple Sclerosis Center, Department of Neurology, University of Ferrara, Arcispedale S. Anna, Corso della Giovecca 203, I-44100, Ferrara, Italy	J Neuroimmunol 2002 Dec;133(1-2):151-159 Abstract quote The goal of our study was to clarify the contribution of soluble human leukocyte antigens class I (sHLA-I) in multiple sclerosis (MS) immune dysregulation. We retrospectively evaluated by ELISA cerebrospinal fluid (CSF) and serum sHLA-I levels in 79 relapsing-remitting (RR), 26 secondary progressive (SP) and 15 primary progressive (PP) MS patients stratified according to clinical and Magnetic Resonance Imaging (MRI) evidence of disease activity. One hundred and nine patients with other inflammatory neurological disorders (OIND), 88 with noninflammatory neurological disorders (NIND) and 82 healthy donors were used as controls. An intrathecal synthesis of sHLA-I detected by a specific index was significantly more consistent in MS than in controls, with more pronounced values in MS patients with relapses and MRI enhancing brain lesions. A decrease in serum sHLA-I concentrations was observed in MS patients with demyelinating attacks, while an increase in CSF levels of sHLA-I was found in MS patients with lesional activity on MRI scans. This association between intrathecal synthesis and reciprocal fluctuations of CSF and serum levels of sHLA-I in clinically and MRI active MS seems to suggest a potential role for CSF and serum levels of sHLA-I as a sensitive marker of immune activation taking place both intrathecally and systemically in MS.
OLIGOCLONAL BANDS
Cerebrospinal Fluid Oligoclonal Bands in the Diagnosis of Multiple Sclerosis Isoelectric Focusing With IgG Immunoblotting Compared With High-Resolution Agarose Gel Electrophoresis and Cerebrospinal Fluid IgG Index Alexandre S. Fortini, MD, Elizabeth L. Sanders, Brian G. Weinshenker, MD, and Jerry A. Katzmann, PhD	Am J Clin Pathol 2003;120:672-675 Abstract quote Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. We compared the diagnostic performance of isoelectric focusing (IEF) combined with IgG immunoblotting to high-resolution agarose gel electrophoresis for the detection of intrathecal synthesis of IgG due to the MS disease process. In 20 patients with definite MS, IEF and high-resolution agarose gel electrophoresis had sensitivities of 90% and 60%, respectively. In the 51 patients with no evidence of MS, the methods had specificities of 94% and 96%, respectively. With a prevalence of 15% in this test population, IEF and high-resolution agarose gel electrophoresis had positive predictive values of 73% and 73% and negative predictive values of 98% and 93%, respectively. The IEF method improves the sensitivity and the negative predictive value of the oligoclonal-banding assay, the IEF gels are easier to interpret, and the IEF assay requires a smaller cerebrospinal fluid volume.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS. Royal College of Physicians, London, United Kingdom.	Ann Neurol 2001 Jul;50(1):121-7 Abstract quote The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with dinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including "monosymptomatic" disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as "clinically definite" and "probable MS" are no longer recommended. The outcome of a diagnostic evaluation is either MS, "possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "not MS."
VARIANTS
ACUTE DEMYLINATING OPTIC NEURITIS
Acute demyelinating optic neuritis. Foroozan R, Buono LM, Savino PJ, Sergott RC.	Curr Opin Ophthalmol 2002 Dec;13(6):375-80 Abstract quote Acute demyelinating optic neuritis associated with multiple sclerosis (MS) is the most common cause of inflammation of the optic nerve. The Optic Neuritis Treatment Trial (ONTT) has provided important clinical data on the use of corticosteroids, and demonstrated that patients with characteristic inflammatory lesions within the brain on magnetic resonance imaging had a greater chance of developing clinically definite MS (CDMS). The current approach to patients with optic neuritis has been modified by the results of the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS). Patients with an initial clinical episode of demyelination (optic neuritis, incomplete transverse myelitis, or brain-stem/cerebellar syndrome) and at least two characteristic demyelinating lesions within the brain were randomized to receive interferon beta-1a or placebo after initial treatment with intravenous corticosteroids. At the 3-year point patients treated with interferon beta-1a showed a 50% less risk of CDMS. The results of this study have set the standard for patients with a first bout of demyelinating optic neuritis.
FAMILIAL
The natural history of multiple sclerosis: a geographically based study: 8: familial multiple sclerosis. Ebers GC, Koopman WJ, Hader W, Sadovnick AD, Kremenchutzky M, Mandalfino P, Wingerchuk DM, Baskerville J, Rice GP. Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada.	Brain 2000 Mar;123 Pt 3:641-9 Abstract quote We have examined the demographics and long-term outcome of 1044 patients with sporadic and familial multiple sclerosis in a population-based cohort from London, Ontario. The mean follow-up was 25 years in duration, and by this time most patients had reached the unambiguous endpoint scores of the Kurtzke disability status scale (DSS), DSS 6, 8 or 10. An affected family member was identified in 19.8% of the total population, and this subgroup was further divided arbitrarily into the following three groups by the type and number of relatives affected: (i) first degree only; (ii) first degree plus others; (iii) second or third degree. The outcome in these groups was compared with that for those patients who, at a mean 25 year follow-up, had no relatives known to be affected. Familial cases closely resembled those remaining sporadic in both demographics and outcome, although onset in the most heavily loaded families was earlier and male/female ratio was greater. The times to DSS 6, 8 and 10 did not differ significantly when sporadic, familial and familial subgroups were compared. These results provide no clinical support for viewing familial multiple sclerosis as distinct from the sporadic form. The observed recurrence rate for siblings in a strictly defined epidemiological sample was 3.5%, much as projected. These results validate the recurrence risks which have previously been derived from age-corrected data for these first-degree relatives.
Multiple sclerosis in sibling pairs: an analysis of 250 families. Chataway J, Mander A, Robertson N, Sawcer S, Deans J, Fraser M, Broadley S, Clayton D, Compston A. University of Cambridge Neurology Unit, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, UK	J Neurol Neurosurg Psychiatry 2001 Dec;71(6):757-61 Abstract quote OBJECTIVES: To assess the potential contribution of genetic factors to clinical phenotype in multiple sclerosis. METHODS: Using a cohort of 262 pairs of coaffected siblings from 250 families with multiple sclerosis, intersibling concordance analysis was used to explore underlying genetic mechanisms in disease pathogenesis by assessing parameters of disease course, clinical presentation, age and year of onset, and measures of disability and handicap. RESULTS: Adjusted intraclass correlation coefficients were not significant for either age of onset or for year of first symptom. One third of sibling pairs were concordant for presenting symptom (81/262), a result that was non-significant. However, course type was identical in 50% of the sibling pairs (kappa=0.17 (95% confidence interval (95% CI) 0.08 to 0.26)) indicating a significant result. Severity of the disease at assessment, using the Kurtzke and CAMBS scales, demonstrated that whereas there was no agreement for relapse rate in the previous year within the sibship, there was significant concordance for measures of disability (kappa=0.11 (95% CI 0.04 to 0.19)), progression (kappa=0.09 (95% CI 0.01 to 0.18)) and handicap (kappa=0.08 (95% CI 0.02 to 0.14)). CONCLUSIONS: Within a sibship, the clinical presentation tends to be different. However, once established, concordance is more likely to be seen for the ultimate course, leading in the end to similar disability and handicap scores. These results are consistent with the hypothesis that genes influence both disease susceptibility and evolution in multiple sclerosis.
PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS
Course and prognosis of chronic progressive multiple sclerosis. Results of an epidemiological study. Minderhoud JM, van der Hoeven JH, Prange AJ. Department of Neurology, University Hospital, Groningen, The Netherlands.	Acta Neurol Scand 1988 Jul;78(1):10-5 Abstract quote In studies on the natural course of multiple sclerosis (MS), several forms of the disease are distinguished. The most important are the relapsing remitting and the chronic progressive forms. The relationship between these remains unclear. In a prospective epidemiological survey we studied the course of MS using the year in which the chronic-progressive phase started as a landmark. The reliability of this "year of progression" was examined in an observer agreement study. Data were acquired from 342 patients. Progression of the handicap was most rapid in case of a secondary progressive course, female sex, high relapse rate in the preceding remitting phase and "year of progression" at a higher age. Survival after the "year of progression" was lowest in the secondary progressive group. Determining the "year of progression" seems to be significant for the prognosis.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
Patterns of oligodendroglia pathology in multiple sclerosis. Ozawa K, Suchanek G, Breitschopf H, Bruck W, Budka H, Jellinger K, Lassmann H. Research Unit for Experimental Neuropathology, Austrian Academy of Sciences, Wien.	Brain 1994 Dec;117 ( Pt 6):1311-22 Abstract quote Patterns of inflammation, demyelination and oligodendrocyte pathology were studied in acute multiple sclerosis and during early and late exacerbations of chronic multiple sclerosis. Cells within lesions were identified by immunocytochemistry with markers for T lymphocytes, macrophages, oligodendrocytes and astrocytes. In addition, in situ hybridization for proteolipid protein mRNA was used to identify myelinating and myelin supporting oligodendrocytes. Degenerating cells in the lesions were detected by DNA fragmentation in cell nuclei. The inflammatory reaction in all three types of multiple sclerosis lesions was shown to be dominated by T lymphocytes and macrophages. In late chronic multiple sclerosis lesions, a significant increase in the number of immunoglobulin producing plasma cells was found in infiltrates as compared with acute and early multiple sclerosis lesions. In all three types of multiple sclerosis, confluent plaques of demyelination were found to be present. In acute multiple sclerosis, demyelination was found to be associated with extensive destruction of other tissue elements, including oligodendrocytes, astrocytes and axons, but even in these destructive lesions a considerable number of oligodendrocytes was preserved and at disposal therefore, for rapid remyelination. During early exacerbations of chronic multiple sclerosis, selective demyelination was associated with almost complete preservation of oligodendrocytes in the majority of cases. Correspondingly, a high number of remyelinating lesions was present at that stage of disease. In lesions developing late after onset of multiple sclerosis, demyelination generally accompanied extensive destruction and loss of oligodendrocytes. In these lesions, remyelination was sparse and restricted to lesional borders. The observed patterns of cell death suggest that in some cases oligodendrocytes, in others myelin sheaths are the primary target of the destructive process. Our data indicate that the type and amount of inflammation, de- and remyelination, and of tissue damage vary between different forms of multiple sclerosis and between different stages of the disease, possibly reflecting different pathogenic mechanisms in a disease spectrum.
Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis. Lucchinetti CF, Bruck W, Rodriguez M, Lassmann H. Department of Neurology; Mayo Clinic Foundation; Rochester, Minnesota, USA	Brain Pathol 1996 Jul;6(3):259-74 Abstract quote Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. The hallmark of its pathology is the demyelinated plaque with reactive glial scar formation. However, a detailed analysis of the patterns of demyelination, oligodendroglia cell pathology and the reaction of other tissue components suggests that the pathogenesis of myelin destruction in this disease may be heterogeneous. In this review we present a new classification scheme of lesional activity on the basis of the molecular composition of myelin degradation products in macrophages. When these criteria are used, different patterns of demyelination can be distinguished, including demyelination with relative preservation of oligodendrocytes, myelin destruction with concomitant and complete destruction of oligodendrocytes or primary destruction or disturbance of myelinating cells with secondary demyelination. Furthermore, in some cases a primary selective demyelination may be followed by a secondary oligodendrocyte loss in the established lesions. Finally, some extraordinarily severe conditions may result in destructive lesions with loss of myelin, oligodendrocytes, axons and astrocytes. This heterogeneity of plaque pathology is discussed in the context of recent experimental models of inflammatory demyelination, which show that different immunological pathways may lead to the formation of demyelinated plaques that reveal the diverse structural aspects described above. Our data indicate, that the demyelinated plaques of multiple sclerosis may reflect a common pathological end point of a variety of different immunological mechanisms of myelin destruction in this disease.
Axonal transection in the lesions of multiple sclerosis. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, OH 44195, USA.	N Engl J Med 1998 Jan 29;338(5):278-85 Abstract quote BACKGROUND: Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and is the most common cause of neurologic disability in young adults. Despite antiinflammatory or immunosuppressive therapy, most patients have progressive neurologic deterioration that may reflect axonal loss. We conducted pathological studies of brain tissues to define the changes in axons in patients with multiple sclerosis. METHODS: Brain tissue was obtained at autopsy from 11 patients with multiple sclerosis and 4 subjects without brain disease. Fourteen active multiple-sclerosis lesions, 33 chronic active lesions, and samples of normal-appearing white matter were examined for demyelination, inflammation, and axonal pathologic changes by immunohistochemistry and confocal microscopy. Axonal transection, identified by the presence of terminal axonal ovoids, was detected in all 47 lesions and quantified in 18 lesions. RESULTS: Transected axons were a consistent feature of the lesions of multiple sclerosis, and their frequency was related to the degree of inflammation within the lesion. The number of transected axons per cubic millimeter of tissue averaged 11,236 in active lesions, 3138 at the hypocellular edges of chronic active lesions, 875 in the hypocellular centers of chronic active lesions, and less than 1 in normal-appearing white matter from the control brains. CONCLUSIONS: Transected axons are common in the lesions of multiple sclerosis, and axonal transection may be the pathologic correlate of the irreversible neurologic impairment in this disease.
Morphometric analysis of axons in the minute multiple sclerosis lesions and shadow plaques in patients with multiple sclerosis. Nowacki P, Potemkowski A, Korwin-Piotrowska T, Nocon D. Department of Neurology, Pomeranian Medical Academy, Szczecin, Poland.	Folia Neuropathol 2000;38(3):104-10 Abstract quote The objective of the present study was to quantitatively detect axons in the minute multiple sclerosis (MS) lesions and in shadow plaques, taking into consideration the relapsing-remitting(R-R) and secondary progressive(SP) stages of MS. The brain tissue of 12 patients deceased due to MS was investigated. An image-computerized analysis was made for measurements of axons. Based on the findings we concluded that damage to axons appears in both the minute MS lesions and in shadow plaques. Demyelination and ineffective (too late or too slow) remyelination seemed to be very important factors in axonal damage. Irreversible damage to axons may appear in both the secondary progressive and relapsing-remitting stages of MS, causing permanent neurological deficits, irrespective of the duration of the disease.
VARIANTS

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
ACTIVITIES OF DAILY LIVING
The reliability and validity of the Nottingham Extended Activities of Daily Living Scale in patients with multiple sclerosis. Nicholl CR, Lincoln NB, Playford ED. School of Psychology, University of Nottingham, UK.	Mult Scler 2002 Oct;8(5):372-6 Abstract quote OBJECTIVE: To investigate whether the Nottingham Extended Activities of Daily Living Scale (EADL) is reliable and valid for the assessment of disability in patients with multiple sclerosis (MS). DESIGN: Questionnaire measures were administered on two occasions four months apart. SUBJECTS: A total of 240 patients recruited through a randomized controlled trial of cognitive assessment and treatment in MS. Measures: The Nottingham EADL, Guys Neurological Disability Scale (GNDS) and SF-36 quality of life scale. RESULTS: The EADL items did not form a Guttman Scale (CR 0.8, CS 0.3). The EADL and its four subscales all had high internal consistency (alpha 0.72-0.94). Test-retest reliability was satisfactory (r(s) 0.81-0.90) with a mean difference in scores on the two occasions of 0.29. Factor analysis generally supported the subscale structure. There were significant but weak correlations with quality of life measures. CONCLUSIONS: The EADL shows promise for the assessment of disability in MS, but the range of items needs to be extended. Further evaluation of the scale seems warranted.
CYTOKINES
Analysis of immunoregulatory T-helper cell subsets in patients with multiple sclerosis: relapsing-progressive course correlates with enhanced T(H1), relapsing-remitting course with enhanced T(H0) reactivity. Barth H, Klein K, Bortlein A, Guseo A, Berg PA, Wietholter H, Klein R. Medizinische Klinik, Innere Medizin II, Universitat Tubingen, Otfried-Muller-Str. 10, 72076, Tubingen, Germany	J Neuroimmunol 2002 Dec;133(1-2):175-183 Abstract quote In this study, we analysed the recall antigen-induced cytokine production by peripheral blood mononuclear cells (PBMC) from 31 patients with multiple sclerosis (MS) with a relapsing-remitting (rr) and a relapsing-progressive (rp) course and from 40 healthy controls. Cells were stimulated with purified protein derivative (PPD; type 1 response) and tetanus toxoid (TT; type 2 response). Cytokines were determined in the supernatants by ELISA. One of the interesting findings was that healthy controls showed more frequently an IL-5 production after incubation with TT than MS-patients (68% vs.37%; p<0.01), while the type 1 reactivity was only slightly enhanced in MS patients as compared to the controls. However, within the MS patients, there was a significant difference in the incidence of the type 1 reactivity comparing patients with an rp and an rr course (60% vs. 24%; p<0.05). Furthermore, the frequency of a type 0 profile (simultaneous PPD-induced IFN-gamma and TT-induced IL-5 production) was fourfold higher in rr than in the rp patients (43% vs. 10%, p<0.05). In vitro analysis of cytokine profiles in MS could therefore be an interesting approach to evaluate the prognosis of MS (rr vs. rp) already at the beginning of the disease. Thus, it seems that the presence of a type 0 profile is a valid indicator for a favorable course, while a type 1 profile is rather associated with rp MS.
HLA
HLA-DRB1 and disease outcome in multiple sclerosis. Weatherby SJ, Thomson W, Pepper L, Donn R, Worthington J, Mann CL, Davies MB, Fryer AA, Boggild MD, Young CA, Jones PW, Strange RC, Ollier WE, Hawkins CP. Keele Multiple Sclerosis Research Group, Postgraduate Medical School, Royal Infirmary, Stoke-on-Trent, UK.	J Neurol 2001 Apr;248(4):304-10 Abstract quote The association between susceptibility to multiple sclerosis (MS) and the class II MHC allele HLA-DRB1*15 is well established although a possible relationship between this allele and outcome in MS is less clear. HLA-DRB1 typing was performed on 375 unrelated white patients with clinically definite MS and on 367 healthy controls. Putative associations of the gene with outcome were examined by dividing patients into two groups: those with an EDSS of 0-5.5 (mild/moderate disease) and those with an EDSS of 6-10 (severe disease). In order to minimise the effects of disease variability patients with a disease duration of at least 10 years or 15 years were examined. As subsidiary HLA-DRB1*03 and HLA-DRB1*04 associations have been previously reported, the effect of these alleles was also examined. As expected, HLA-DRB1*15 was found more frequently in patients than in controls (P < 0.000001). HLA-DRB1*15 positive patients had a significantly earlier age at onset than HLA-DRB1*15 negative patients. No significant associations were noted between HLA-DRB1*15 and outcome in the total patient group or in patients with a disease duration of 10 years or longer. In patients with a disease duration of at least 15 years HLA-DRB1*15 negative status was associated with a worse prognosis, although this did not remain significant after correction for multiple testing. It is thus likely that the contribution of HLA in MS is primarily towards onset and initial triggering mechanisms rather than influencing disease progression, chronicity and severity.
NAA
Relapsing-remitting multiple sclerosis and whole-brain N-acetylaspartate measurement: evidence for different clinical cohorts initial observations. Gonen O, Moriarty DM, Li BS, Babb JS, He J, Listerud J, Jacobs D, Markowitz CE, Grossman RI. Department of Radiology, New York University School of Medicine, 560 First Ave, New York, NY 10016, USA.	Radiology 2002 Oct;225(1):261-8 Abstract quote PURPOSE: To quantify the rate of concentration decline of neuronal marker N-acetylaspartate (NAA) in the entire brain of patients with relapsing-remitting multiple sclerosis (MS) in relation to healthy age-matched control subjects. MATERIALS AND METHODS: Whole-brain NAA (WBNAA) concentration was quantified in 49 patients with relapsing-remitting MS by using magnetic resonance (MR) imaging and proton MR spectroscopy. It was statistically analyzed by using Spearman rank correlation coefficients to test the intragroup relationship between WBNAA and Expanded Disability Status Scale (EDSS) score and Mann-Whitney analyses to test for differences between subgroups' EDSS scores versus previously published WBNAA values for healthy subjects, disease duration, and age. RESULTS: Analyses indicated three subgroups of WBNAA dynamics: Ten patients' conditions were "stable," exhibiting an insignificant change of about 0% (0.02/14.37) per year of clinically definite disease duration (P =.54); 27 patients showed "moderate" decline, -2.8% (-0.34/12.18) per year (P <.01); and 12 patients experienced "rapid" decline, -27.9% (-3.39/12.14) per year (P <.01). No correlation was found between WBNAA deficit, EDSS score, and age. CONCLUSION: Ascertaining an individual's NAA concentration dynamics might enable early forecast of disease course, reflect disease severity and thus influence treatment decisions, and improve clinical trial efficiency by allowing selection of candidates on the basis of WBNAA dynamics in addition to clinical status.
SURVIVAL
The natural history of multiple sclerosis: a geographically based study. 7. Progressive-relapsing and relapsing-progressive multiple sclerosis: a re-evaluation. Kremenchutzky M, Cottrell D, Rice G, Hader W, Baskerville J, Koopman W, Ebers GC. Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada.	Brain 1999 Oct;122 ( Pt 10):1941-50 Abstract quote Classifications of multiple sclerosis subtypes have been largely based on clinical phenomenology. Nevertheless, definitions of relapse, remission and progression have been imprecise. Recently an international consensus group, as part of a reclassification of disease subtypes, recommended dropping the term 'relapsing-progressive' (RP) and retaining the term 'progressive-relapsing' (PR) multiple sclerosis. The term 'RP' multiple sclerosis had been applied when the early course combined both relapses and progression and was believed to identify some patients with a worse than average outcome. The PR group consisted of patients with primary progressive disease who later in their course developed relapses. Since the terminology has been largely arbitrary, we have evaluated the validity of the terms 'RP' and 'PR' multiple sclerosis in the context of long-term outcome within a large population-based cohort of progressive multiple sclerosis patients seen at the London Multiple Sclerosis Clinic (Canada) between 1972 and 1984. Mean follow-up of the entire cohort was 25 years. Designation of RP multiple sclerosis did identify a more rapidly progressive subgroup. To realign these natural history data with consensus recommendations, these patients were reassigned to secondary progressive (SP) or to primary progressive (PP) multiple sclerosis, with progression defined as at least 1 year of progressive deterioration. PP multiple sclerosis patients with relapses after a year were designated as having PR multiple sclerosis. Relapses in primary progressive multiple sclerosis occurred in 27.8% of patients at some point even two to three decades after onset. In general these relapses were mild and remitting, but served to blur the distinction between progressive and relapsing-remitting disease. The long-term outcomes of time to Kurtzke disability scores (DSS) of 3, 6, 8 and 10 were compared among the progressive subtypes. Times to these disability end-points and to death were not different between PR and PP multiple sclerosis. Survival curves for progressive patients have been amended to incorporate the reassignment of PR multiple sclerosis patients into the PP group and the RP multiple sclerosis patients into the PP and SP subgroups. The time to reach DDS 3, 6, 8 and 10 for a population-based cohort of primary and secondary progressive patients resulting from the elimination of the categories of RP multiple sclerosis and PR multiple sclerosis has been established. These results provide justification for retaining only PP and SP multiple sclerosis as the subgroups of progressive disease.
One year follow up study of primary and transitional progressive multiple sclerosis. Stevenson VL, Miller DH, Leary SM, Rovaris M, Barkhof F, Brochet B, Dousset V, Filippi M, Hintzen R, Montalban X, Polman CH, Rovira A, de Sa J, Thompson AJ. NMR Research Unit, Institute of Neurology, Queen Square, London WC1 N3BG, UK.	J Neurol Neurosurg Psychiatry 2000 Jun;68(6):713-8 Abstract quote OBJECTIVE: To document clinical and magnetic resonance imaging (MRI) characteristics of a large cohort of primary and transitional progressive multiple sclerosis (PP and TP MS) patients over one year. INTRODUCTION: Patients with PP or TP MS have been shown to have low brain T2 and T1 lesion loads and slow rates of new lesion formation with minimal gadolinium enhancement, despite their accumulating disability. Serial evaluation of these patients is needed to elucidate the pathological processes responsible for disease progression and to identify clinical and MRI measures which can monitor these processes in treatment trials. METHOD: Patients, recruited from six European centres, underwent two assessments on the expanded disability status scale (EDSS) and MRI of the brain and spinal cord, 1 year apart. RESULTS: Of the 167 patients studied (137 with PP MS and 30 with TP MS), 41 (25%; 35 PP and six TP) showed a one step increase in the EDSS. The mean number of new brain lesions seen was 0.88 in the PP group and 0.47 in the TP MS group. Both groups demonstrated change in T2 lesion load over the year (p< or =0.002), with median percentage changes of 7.3% in the PP group and 10. 8% in the TP MS group. The PP group also showed a significant change in T1 load (p< 0.001, median change 12.6%). The number of new cord lesions seen was small (mean of 0.14 in the PP group and no new cord lesions in the TP group). Both groups demonstrated a decrease in cord cross sectional area (p< 0.001, median changes; PP 3.8%, TP 4. 9%), but only the PP group showed evidence of significant brain atrophy (p<0.001, 0.95%). CONCLUSION: Although the monitoring of disease progression in this patient group is difficult, this study demonstrates changes in both lesion load and atrophy, which, if shown to correlate with clinical change over a longer time will facilitate therapeutic trial design.
Survival of multiple sclerosis patients in the Belgrade population. Pekmezovic T, Jarebinski M, Drulovic J, Stojsavljevic N, Levic Z. Institute of Epidemiology, School of Medicine, University of Belgrade, Belgrade, Yugoslavia.	Neuroepidemiology 2002 Sep-Oct;21(5):235-40 Abstract quote The aim of this study was to estimate survival rates of multiple sclerosis (MS) patients in the Belgrade population, Yugoslavia, and furthermore, to determine the prognostic value of some demographic and clinical variables for survival. The cumulative survival probability was calculated by the Kaplan-Meier method. The prognostic value of different variables was assessed by univariate and multivariate analyses using the Cox regression model. In the Belgrade population, the cumulative 25-year survival probability of MS patients and the mean survival time from MS onset were 73.2% and 38 years, respectively. The univariate analysis showed that survival was significantly related to sex, age at onset, course of disease and monoregional initial symptoms. A multivariate model demonstrated that a relapsing-remitting course of MS and monoregional onset were predictors of a better prognosis. The presence of motor symptoms at the onset was found to be an independent predictor of a poorer outcome of MS.
TREATMENT
CORTICOSTEROIDS
Monthly corticosteroids decrease neutralizing antibodies to IFNbeta1 b: a randomized trial in multiple sclerosis. Pozzilli C, Antonini G, Bagnato F, Mainero C, Tomassini V, Onesti E, Fantozzi R, Galgani S, Pasqualetti P, Millefiorini E, Spadaro M, Dahlke F, Gasperini C. Department of Neurological Sciences, University La Sapienza, Rome, Italy.	J Neurol 2002 Jan;249(1):50-6 Abstract quote Neutralizing antibodies (NAB) to interferon beta (IFNbeta) occur in some multiple sclerosis (MS) patients, particularly during the first year of treatment. The presence of NAB may be associated with an attenuation of the therapeutic effect. The aim of this study was to compare the frequency of NAB occurrence in patients treated with IFNbeta-1 b with that in patients treated with IFNbeta-1 b combined with monthly pulses of intravenous methylprednisolone (MP). One hundred and sixty-one patients with relapsing-remitting MS were randomized in two treatment arms: 8 MIU of IFNbeta- 1 b subcutaneously injected every other day either alone or in combination with 1000 mg of monthly intravenous MP. NAB were evaluated at baseline and at months 3,6,9,12 and 15 by the MxA assay in a specialized laboratory. Positivity was defined as a titer of > or = 20 neutralizing units according to two different definitions: I) one or more non-consecutive positive samples, II) at least two consecutive positive samples. NAB (definition I) were observed in 26.8% of patients in the IFNbeta-1 b alone arm and in 12.1% of patients in the combination therapy arm (p = 0.05 by the chi-square test), which corresponds to a relative reduction of 54.9%, whereas according to definition II, these figures dropped to 22.5 % for the IFNbeta-1 b alone arm, and 10.6% for the combination therapy arm (relative reduction 52.9%, p = 0.10, NS). A higher probability of remaining in the NAB-free status was observed in patients treated with the combination therapy (p = 0.031 for definition I and p = 0.o49 for definition II, by the Wilcoxon-Gehan test). Methylprednisilone combined with IFNbeta-1 b reduces the incidence of neutralizing bodies to in terferon-beta during the first year of treatment in MS patients.
INTERFERON BETA 1A
The controlled high risk Avonex multiple sclerosis trial (CHAMPS Study). Galetta SL. Department of Neurology, University of Pennsylvania, Philadelphia 19104, USA.	J Neuroophthalmol 2001 Dec;21(4):292-5 Abstract quote The Controlled High Risk Avonex Multiple Sclerosis Study (CHAMPS) tested whether interferon beta la (Avonex) treatment would benefit patients who had experienced a first acute demyelinating event involving the optic nerve, brain stem/cerebellum, or spinal cord, and who displayed MRI brain signal abnormalities that have previously predicted a high likelihood of future MS-like events. The study randomized 383 patients into an Avonex-treated and a placebo-treated group; both groups received intravenous methylprednisolone 1 gm/d followed by prednisone 1 mg/kg for 11 days. The Avonex-treated group demonstrated a 44% reduction in the 3-year cumulative probability of developing clinically definite multiple sclerosis (rate ratio 0.56, 95% confidence interval 0.38 to 0.8; P = 0.002). At 18 months, treatment with Avonex was associated with a significant reduction of new T2 lesions, gadolinium enhanced lesions and T2 lesion volume. Among placebo-treated patients, 82% had developed a new subclinical MRI signal abnormality by the eighteenth month after study entry. Treatment benefit was observed irrespective of the qualifying event. The findings of this study support the efficacy of Avonex therapy in significantly reducing the 3-year likelihood of future neurologic events and worsening of the brain MRI in patients with a first acute CNS demyelinating event.
A prospective, open-label treatment trial to compare the effect of IFNbeta-1a (Avonex), IFNbeta-1b (Betaseron), and glatiramer acetate (Copaxone) on the relapse rate in relapsing--remitting multiple sclerosis: results after 18 months of therapy. Khan OA, Tselis AC, Kamholz JA, Garbern JY, Lewis RA, Lisak RP. Multiple Sclerosis Center, Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.	Mult Scler 2001 Dec;7(6):349-53 Abstract quote We previously reported results of a 12 month prospective, non-randomized, open-label treatment trial of immunomodulatory therapy in patients with relapsing-remitting multiple sclerosis (RRMS). We now report the results after 18 months of follow-up. Our primary objective was to compare the effect of IFNbeta-1a (Avonex), IFNbeta-1b (Betaseron), and Glatiramer Acetate (GA, Copaxone) to no treatment on the relapse rate in patients with RRMS. One hundred and fifty-six consecutive patients with clinically definite RRMS with a Kurtzke scale (EDSS) score of 4 or less were followed for 18 months. Prior 2-year relapse history and available chart information was carefully reviewed at the time of enrollment Thirty-three of 156 elected no treatment at enrollment; 40 elected IFNbeta-1a, 41 IFNbeta-1b, and 42 chose GA. There were no statistically significant differences among the four groups at enrollment. After 18 months of treatment 122 patients remained in their original treatment group. Compared to the untreated group (1.02), mean annualized number of relapses was significantly reduced only in the GA (0.49, P>0.0001) and IFNbeta-1b groups (0.55, P=0.001) in contrast to the IFNbeta-1a treated patients (0.81, P=0.106) who did not show a significant reduction. Despite limitations of the study design, the results provide helpful clinical information regarding the relative efficacy of each therapy in mildly affected treatment naive RRMS patients.
Randomized, double-blind, placebo-controlled study of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis: a categorical disability trend analysis. Liu C, Blumhardt LD. Faculty of Medicine, University Hospital, Queen's Medical Centre, Nottingham, UK.	Mult Scler 2002 Feb;8(1):10-4 Abstract quote The treatment effects of recent immunomodulatory therapies on disease progression in relapsing-remitting multiple sclerosis (MS) have been mostly established from 'confirmed progression' endpoints. However, the reliability of this outcome measure is poor and a significant proportion of patients may be erroneously classified. We previously proposed the area under disability/time curves to quantify in-trial disability changes, but although these have advantages, they lack information on the direction of change. We have therefore performed disease trend analyses and categorical classifications using serial Expanded Disability Status Scale (EDSS) scores from the 533 complete datasets in a double-blind, randomized, placebo-controlled, phase III trial of subcutaneous interferon beta-1a (IFNbeta-1a) (PRISMS study). We found significant treatment benefits for IFNbeta-1a on in-trial disability course (P=0.002). Therapeutic advantages remained when relapse-related assessments were excluded (P=0.018). Post hoc analyses demonstrated that IFNbeta-1a was mainly effective in both increasing the proportion of patients with a 'stable' course and reducing those with prolonged, disabling deteriorations. Baseline disease duration and EDSS levels, but not MRI lesion load, predicted the subsequent disability trends. Mean 'numbers needed to treat' (NNTs) to obtain preferred disability courses were reduced in patients with shorter disease duration. These results have important implications for the targeting of immunomodulatory therapies in MS.
Assessment of different treatment failure criteria in a cohort of relapsing-remitting multiple sclerosis patients treated with interferon beta: implications for clinical trials. Rio J, Nos C, Tintore M, Borras C, Galan I, Comabella M, Montalban X. Unitat de Neuroimmunologia Clinica., Hospital Universitari Vall d'Hebron, Barcelona, Spain.	Ann Neurol 2002 Oct;52(4):400-6 Abstract quote Clinical trials with interferons in relapsing-remitting multiple sclerosis have shown a modest effect on disability using fixed definitions of treatment failure to measure disease progression. However, in the course of the disease, treatment failure may be influenced by interrater variability and frequent remissions. Thus, the purpose of this study was to assess the clinical usefulness of different treatment failure criteria in a cohort of relapsing-remitting multiple sclerosis patients treated with interferon beta. We studied 252 patients with a follow-up of more than 2 years. We used four different criteria of treatment failure with increasing stringency (1 Expanded Disability Status Scale [EDSS] point increase confirmed at 3 months, 1 EDSS point increase confirmed at 6 months, 1.5 EDSS points increase confirmed at 3 months, and 1.5 EDSS points increase confirmed at 6 months). We divided treatment failure into permanent treatment failure and transient treatment failure. We considered permanent treatment failure when treatment failure was confirmed on the last two scheduled visits and transient treatment failure when treatment failure was not confirmed on these visits at different time points (9, 12, 18, and 24 months). We calculated the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the different criteria of treatment failure to identify patients who achieved a high degree of disability after 4 years of follow-up. Regardless of the stringency of treatment failure definitions, a variable proportion of patients with treatment failure had transient treatment failure depending on the criterion applied. Patients with transient treatment failure had a significantly lower EDSS at entry compared with those with permanent treatment failure or no treatment failure. The number of relapses in patients with transient treatment failure did not differ from that of patients with permanent treatment failure. The criterion of confirmed 1 EDSS point increase at 6 months showed the best sensitivity (76.5%), with satisfactory specificity (89%). Our study shows that a large proportion of patients treated with interferon experience transient treatment failure that may affect outcome interpretation in clinical trials. Using a more strict criterion, as extending time to confirmation of EDSS deterioration, and longer follow-up may reduce this proportion of patients with transient treatment failure and improve the validity of the results attained in clinical trials.

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