Search

Mortality in patients with multiple sclerosis (MS) is significantly increased compared with the general population. Many questions concerning survival in MS are still unanswered due to the difficulty of comparing information collected at different times and in different geographic areas. The increasing incidence of MS, the improvement in care of the chronically disabled, and different methodologies may explain the lack of coherence among studies' results. Reported times to death from birth and from disease onsetdiagnosis are highly variable. Patients older at onset or with primary progressive course have shorter survival; however, data on sex and mortality are contradictory. Changes in sex ratio in MS over time represent one possible explanation. MS is the main cause of death in ≥50 of patients and the incidence of deaths not due to MS varies among countries. Particularly, suicide is substantially increased in patients with MS, and, despite its varying incidence, mainly due to “cultural bias,” it should be considered an MS-related cause of death. Recent results of the long-term follow-up study of interferon--1b demonstrated a significant reduction of mortality among treated patients. Notwithstanding its long latency, mortality is therefore an unambiguously valid long-term outcome in randomized controlled trials. It usefully combines the net impact of treatment efficacy on longevity and adverse events, which may reduce it.

OBJECTIVES To investigate the relationship among attacks in the first 2 years (early relapses), secondary progression (SP), and late disability in multiple sclerosis (MS). DESIGN Cohort study with follow-up of 28 years. SETTING Referral MS center. PATIENTS Patients (N = 730) with relapsing-remitting MS diagnosed according to Poser criteria, from the database of the London Multiple Sclerosis Clinic, London, Ontario, Canada. MAIN OUTCOME MEASURE Long-term evolution of patients with high (≥3 attacks) and early (within the first 2 years of the disease) frequency of relapses. In the total SP population and in patients grouped by numbers of early relapses, we assessed the predictive effect of latency to progression (time to SP) on times to attain cane requirement (Disability Status Scale score of 6 [DSS 6]) and bedridden status (DSS 8). RESULTS Among the group with frequent early relapses (n = 158), outcomes were variable. Although 103 (65.2%) experienced rapid conversion to SP MS (median duration, 5 years) and rapidly attained DSS 6 and DSS 8 scores (7 and 17 years, respectively), the remainder (n = 55) did not enter the SP phase, despite adverse early relapse features. Among the total SP population, longer latency to progression was associated with lower probability of attaining DSS 6 (odds ratio, 0.76 [95% CI, 0.69-0.84] and 0.44 [95% CI, 0.37-0.52] for 5- and 15-year latency, respectively) and longer times to severe disability. The same association between time to onset of SP and late outcomes was observed even in patients matched by number of early attacks. However, duration of the relapsing-remitting phase did not influence the times from SP onset to DSS levels. CONCLUSIONS Our results indicate dissociation between early inflammatory attacks and onset of the SP phase and further question the validity of relapse frequency as a surrogate marker for late disability. Among the group with frequent early relapses, we observed a large variability of outcomes, ranging from one extreme to the opposite.

To identify rare variants contributing to multiple sclerosis (MS) susceptibility in a family we have previously reported with up to 15 individuals affected across 4 generations.

Migraine with aura (MA) may share some but not all risk factors with other forms of migraine. As common migraine without aura (MO) has been associated with the chromosome 1p36 locus, we tested its involvement in MA by using two-point parametric linkage analysis to analyze 64 multiplex MA families. A logarithm of the odds score of 1.9 was suggestive of chromosome 1p36 linkage to MA. The transmission disequilibrium test analysis was then performed in 79 nuclear families with one MA parent and one MA offspring. We identified the presence of genetic association at chromosome 1p36 with MA (P=0.045, Bonferroni corrected): the locus encoding the 5HT1Dreceptor gene. Although these data suggest that the 1p36 locus may protect against MA, consistent with the role of the 5HT1Dreceptor in migraine treatment with triptan drugs, the study is subject to the limitations associated with studying a small number of affected families. As a result, we contrast evidence suggesting that the chromosome 1p36 locus is strongly MO associated with our finding that 1p36 has a more limited contribution to MA in the families we analyzed. Further work using a genome-wide association study approach in familial typical migraine, consisting of those affected by MO or MA, will serve to further distinguish how and why MA differs from MO.

OBJECTIVE To determine whether multiple sclerosis (MS) and infectious mononucleosis (IM) share common HLA associations. DESIGN A prospective cohort study was conducted from October 1, 1999, through September 30, 2003. SETTING University of Edinburgh Richard Verney Health Centre, Edinburgh, Scotland. PATIENTS Participants included 179 individuals who underwent asymptomatic Epstein-Barr virus seroconversion and 175 patients who developed IM. INTERVENTION Genotyping for 5 classical HLA loci (HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1). MAIN OUTCOME MEASURE Diagnosis of IM and allele frequency. RESULTS Allelic analysis showed that HLA-DRB1*01:01 was significantly associated with the development of IM (odds ratio, 3.2; P < .001). Patients with IM and HLA-DRB1*01:01 had a lower Epstein-Barr virus viral load compared with those without the allele (median, 783 vs 7366 copies/106 peripheral blood mononuclear cells; P = .03). CONCLUSION HLA-DRB1*01:01 is protective against developing MS; thus, a common genetic basis between IM and MS is not supported.Arch Neurol. 2011;68(4):469-472--

Multiple sclerosis (MS) has a remarkable geographic distribution inversely paralleling that of regional ultraviolet radiation, supporting the hypothesis that vitamin D plays a central role in the disease etiology. The major histocompatibility complex exerts the largest genetic contribution to MS susceptibility, but much risk remains unexplained and direct gene-environment interaction is a strong candidate for this additional risk. Such interactions may hold the key for disease prevention.

Multiple sclerosis (MS) is a common, complex neurological disease. Epidemiological data implicate both genetic and environmental factors in the etiology of MS, with various factors interacting with one another. Environmental exposures might occur long before the disease becomes clinically evident, as suggested by the wide range in onset age. In this Review, we examine the key time periods during which the environment might contribute to MS susceptibility, as well as the potential environmental factors involved. Understanding the nature of environmental influences in MS is highly relevant to the development of public health measures that are aimed at preventing this debilitating disease.

Multiple sclerosis and type 1 diabetes mellitus are seemingly very different autoimmune diseases. However, this Review discusses recent studies in genetics, epidemiology and immunology that have uncovered many features common to both disorders. Overlaps between T1DM and MS might lead to similar strategies in preventing and treating these debilitating conditions.

This Review summarizes the natural history studies on multiple sclerosis (MS) that have evaluated prognostic factors. Reassessment of prognostic factors is warranted, as our ability to offer patients a reliable prognosis is limited, yet we rely on this knowledge to appropriately design clinical trials and interpret their results. The selection criteria for studies to review included a geographical referral base, duration of at least 9 years, prospective design, and populations of at least 100 patients with MS. For all forms of MS combined, negative prognostic factors included progressive disease, and disability at 2 and 5 years. In relapsing–remitting MS (RRMS) and secondary progressive MS (SPMS) combined, negative prognostic factors were the onset of progression, a higher relapse rate, greater disability in the first 5 years, a shorter interval to the second relapse, and the involvement of more systems. Additional negative factors include a shorter time to progression in SPMS and a faster rate of disability in the first 2 and 5 years in primary progressive MS (PPMS). Onset of progression, relapse rate and disability in the initial 5 years could be fruitful therapeutic targets; however, longer-term clinical trials will be required to justify these end points.

Multiple sclerosis (MS) is the most common neurological disease affecting young adults. The cause is unknown, but detailed epidemiological and genetic studies have shown a clear inherited component. We review here some of the recent findings of MS genetics with a particular focus on genes of the major histocompatibility complex (MHC).

The complexity of multiple sclerosis MS genetics has made the search for novel genes using traditional sharing methods problematic. In order to minimize the genetic heterogeneity present in the MS population we have screened the Canadian MS population for individuals belonging to the Hutterite Brethren. Seven Hutterites with clinically definite MS were ascertained and are related to a common founder by eight generations. Six of the 7 affected individuals and 21 of their unaffected family members total  27 were genotyped for 807 markers. Haplotypes were then inspected for sharing among the six MS patients. There were three haplotypes shared among all six MS patients. The haplotypes were located at 2q3435, 4q3132, and 17p13. An additional 15 haplotypes were shared among five of the six Hutterites MS patients. The HLA Class II region was one of the highlighted regions; however, the shared MHC haplotype bore the DRB104 allele and not the MSassociated DRB115 allele providing further evidence of the complexity of the MHC. Additional genotyping to refine the haplotypes followed by screening for potential variants may lead to the identification of a novel MS susceptibility genes in this unique population. © 2007 WileyLiss, Inc.

OBJECTIVE To investigate the parental relationship of patients with multiple sclerosis (MS) from an extended pedigree with extensive genealogical information up to the middle of the 18th century. DESIGN Multiple sclerosis is a complex disease resulting from genetic and environmental factors. Parent-of-origin effect, a phenomenon when the same allele may express differently depending on the sex of the transmitting parent, may influence the risk for MS. We investigated parental relationships between patients with MS using extensive genealogical information available from the Genetic Research in Isolated Populations program. We compared the average kinship of the parents of MS patients. We further explored the distribution of shortest genealogical links between parents of MS patients. SUBJECTS Twenty-four MS patients from the isolated population who could be linked within a large complex pedigree, including 2471 people in total. RESULTS The results consistently indicate a higher prevalence of maternal transmission of MS. The kinship between mothers of patients was 3.8 times higher than that between fathers (bootstrap P = .01). Among the 814 shortest connections between parents, 333 were maternal (40.9%, vs 25.0% expected), 98 were paternal (12.0%, vs 25.0% expected), and 383 were maternal-paternal (47.1%, vs 50.0% expected) (P < .001). CONCLUSIONS Mothers of MS patients were more closely related than their fathers. This skewed relationship shows evidence for a maternal effect in MS. The most likely explanation is a gene-environment effect that takes place in utero.arch neurol. 2008;65(3):345-348--

We review current thinking on the aetiology of multiple sclerosis, how genetic susceptibility interacts with environmental risk factors at the population level, multiple sclerosis-associated risk factors and contemporary causation theory.

The differences between right (RH) and left (LH) handers reported in the literature on fine motor tasks, has traditionally been interpreted relative to purported functioning of the cerebral hemispheres. However, conclusive evidence for performance differences which are intrinsic to handedness per se is difficult to obtain unless left and right handers are compared who are similar in their genetic and environmental background. The present study therefore, employed a monozygotic (MZ) twin design which minimizes differences in genetic variation between the two groups. Forty female monozygotic twins (20 pairs) were selected on the basis of discordance of writing hand. Their laterality preferences were assessed and they were tested for differences on hand performance tasks (dot filling, finger tapping, and peg moving). The results revealed that on the hand and foot preference inventories, the right-handers were more strongly lateralized than their left-handed sisters, and that the left-handers had greater variation in their laterality scores. There were substantial correlations between preference and performance scores. The analyses not only revealed the obvious strong main effects of writing hand on performance tasks, but interaction effects of handedness on the peg-moving task. The dot filling task differentiated the writing versus non-writing hand considerably better than either of the other two performance tasks. However, no evidence was found to indicate that twins who wrote with their left hands showed poorer performance than their right-handed twin sisters.

Four published genome screens have identified a number of markers with increased sharing in multiple sclerosis (MS) families, although none has reached statistical significance. One hundred and five markers previously identified as showing increased sharing in Canadian, British, Finnish, and American genome screens were genotyped in 219 sibling pairs ascertained from the database of the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). No markers examined met criteria for significant linkage. Markers located at 5p14 and 17q22 were analyzed in a total of 333 sibling pairs and attained mlod scores of 2.27 and 1.14, respectively. The known HLA Class II DRB1 association with MS was confirmed (P<0.0001). Significant transmission disequilibrium was also observed for D17S789 at 17q22 (P=0.0015). This study highlights the difficulty of searching for genes with only mild-to-moderate effects on susceptibility, although large effects of specific loci may still be present in individual families. Future progress in the genetics of this complex trait may be helped by (1) focussing on more ethnically homogeneous samples, (2) using an increased number of MS families, and (3) using transmission disequilibrium analysis in candidate regions rather than the affected relative pair linkage analysis.

To determine the prevalence and nature of pain in multiple sclerosis, we evaluated by questionnaire, interview, and chart review 159 patients residing in Middlesex County and followed in the MS Clinic at University Hospital, London, Ontario, Canada. Eighty-eight patients (55) had either an acute or chronic pain syndrome at some time during their disease. Fifteen patients (9) with acute pain syndromes had episodes of paroxysmal tic-like pain diagnosed in seven as trigeminal neuralgia. Chronic pain syndromes, present for a mean duration of 4.9 years, occurred in 76 patients (48) and included dysesthetic extremity pain (29), back pain (14), painful leg spasms (13), and abdominal pain (2). MS patients with pain were similar to the pain-free group in mean age of onset (34.0 versus 31.9 years), average duration of disease (13.3 versus 12.1 years), spinal cord involvement (97 for each group), and mean rating on Kurtzke Disability Status Scale (4.2 versus 3.5). They differed in sex ratio with a higher female-to-male ratio in the pain group (3:1 versus 1.4:1). Chronic pain is a common feature of well-established MS and is usually associated with a myelopathy. Therapy must be individualized for each specific pain syndrome.

Thomsen's disease (autosomal dominant myotonia congenita) has recently been linked to chromosome 7q35 in the region of the human skeletal muscle chloride channel gene (HUMCLC). Single strand conformation polymorphism analysis (SSCP) was used to screen DNA from members of four unrelated pedigrees with this disorder for mutations in HUMCLC. Abnormal bands were detected in all affected, but no unaffected individuals in three of the families. Direct sequencing revealed a G to A transition that results in the substitution of a glutamic acid for a glycine residue located between the third and fourth predicted membrane spanning segments. This glycine residue is conserved in all known members of this class of chloride channel proteins. These findings establish HUMCLC as the Thomsen's disease gene.

Sixty-two experienced multiple sclerosis (MS) investigators attending a research workshop were asked their opinions about clinical trial design, outcome measures, and treatment. Respondents favored repeated clinical observations of neurologic function (eg, Expanded Disability Status Scale or Ambulation Index) over the opinion of a blinded physician and changes on magnetic resonance imaging. There was agreement that stable MS should not be treated with immunosuppressives. Corticosteroids were rated the most effective treatment for recent disease activity. Total lymphoid irradiation and immunosuppressives were judged more potent for the long-term management of progressive disease. No treatment, however, received the support of more than 11 of the respondents for being of “considerable efficacy” in the long-term management of MS. Most favored a placebo-con trolled design in future trials. In order to judge the acceptability of current trial design, participants were asked to act as patient surrogates and to indicate whether they would agree to participate in 4 randomized trials for which they would be eligible. The majority consented to participate in the 3 major trials currently under way, and most refused to enroll in the 1 trial that had never been initiated.

Background: Monozygotic (MZ) twinning is a poorly understood phenomenon that may result in subtle biologic differences between twins, despite their identical inheritance. These differences may in part account for discordant expression of disease in MZ twin pairs. Due to their stochastic nature, differences in X chromosome inactivation patterns are one source of such variation in female MZ twins. Materials and Methods: We investigated X chromosome inactivation patterns in the blood of 41 MZ twin pairs based on methylation of the androgen receptor gene using a Hpa II-PCR assay. Twenty-six female MZ twin pairs with autoimmune disease (rheumatoid arthritis or multiple sclerosis) were studied. In addition, we studied 15 newborn female MZ twin pairs who were characterized at birth with respect to the anatomy of chorionic membranes (dichorionic versus monochorionic). Results: We found a strong correlation between dichorionic fetal anatomy and differences in X chromosome inactivation patterns between members of an MZ twin pair. In contrast, all monochorionic twin pairs had closely correlated patterns of X chromosome inactivation. X chromosome inactivation patterns did not distinguish between MZ twin pairs who were concordant or discordant for autoimmune disease. Conclusions: The highly similar patterns of X chromosome inactivation among monochorionic twin pairs may result from their shared placental blood supply during intrauterine life. Alternatively, these patterns may indicate that X chromosome inactivation occurs before the twinning event in this anatomic subgroup of MZ twins. The data further suggest that these factors do not make a major contribution to the high discordance rates for autoimmune disease in MZ twin pairs.

• Three patients with focal brain-stem oculomotor disturbances (nuclear sixth nerve syndrome, sixth nerve palsy, bilateral internuclear ophthalmoplegia) as a consequence of multiple sclerosis have been studied with high-volume delayed computed tomography and high-field magnetic resonance imaging. In all of them, high-volume delayed computed tomography was inconclusive in the brain stem, but magnetic resonance imaging showed an area of prolonged T1 and/or T2 in the region appropriate to the oculomotor findings. Magnetic resonance imaging is the imaging technique of choice of small plaques in the brain stem. It can considerably aid clinicotopographic correlation in multiple sclerosis.

The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait1–3. Risks for first degree relatives are increased some 20 fold over the general population4. Twin studies have shown monozygotic concordance rates of 25–30% compared to 4% for dizygotic twins and siblings5,6. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences3,7–9. Studies of candidate genes have been largely unrewarding10–12. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 – DS1). A locus of λ>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of > 1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (nonsignificant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 λ2=10.8, adjusted P<0.01)(DS2 and DS3 λ2= 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.

When multiple sclerosis (MS) presents late in life (after the age of 50), it frequently gives diagnostic difficulty. In a large MS clinic population (N 838), 9.4 of the patients had late onset of MS. Slow deterioration of motor function characterized the initial symptoms and subsequent course of this group of older patients. Progression of disability was more rapid than in younger patients. Evoked response studies and CSF electrophoresis were of high diagnostic yield in the older patient group. Reasons for the differing clinical features in the late-onset patients are discussed. We suggest that the age-of-onset criterion for MS be raised to 60 in adequately investigated cases.

We carried out a randomized, double-blind, placebo-controlled trial of hyperbaric oxygen therapy (HBO) in patients with chronic stable MS. Eighty-two patients were treated in a multiplace hyperbaric chamber with gas supplied by mask. Forty-one patients received 20 consecutive daily treatments of 100 O2followed by 7 “booster” treatments in the next 6 months; 41 control patients received “air” (12.5 O2at 1.75 atmospheres absolute). There was no significant difference in treatment and control groups in the Extended Kurtzke Disability scores, Kurtzke Functional scores, magnetic resonance imaging, or evoked potentials after the initial 20 treatments or after the boosters. HBO is not effective in treating chronic stable MS.

A case-controlled epidemiologic study of multiple sclerosis (MS) was carried out in London, Ontario, and its surrounding Middlesex County for the period 1974–1983. The prevalence rates for clinically definite/probable MS on January 1, 1984 were 94/100,000 for the city and 91/100,000 for the county. The estimated annual incidence rate for the decade 1974–83 was 3.4/100,000. The female-to-male sex ratio was 2.5:1. A familial history of MS was recorded in 14.4 of close relatives and a total of 17 when distant relatives are included. The MS group is predominantly of British (70) and European (23) origin. The urban-rural residence pattern analysis indicates no significant regional influence on the risk of developing MS.

MS is believed to be a complex trait determined by genetic and nongenetic factors. Data suggest that MS susceptibility and age at onset are each, at least to some extent, under genetic control. The present study carefully examined five covariates (sex of the index case, sex of the sibling, birth cohort of the sibling [≤1919, 1920 to 1939, ≥1940], age of MS onset in the index patient (≤20 years, 21 to 30 years, 31 to 40 years, >40 years), and MS disease status of the parents [i.e., MS present in one parent or no parent with MS]) that may influence the familial risk of MS in a large cohort of 1,896 MS patients and 8,878 of their first-degree relatives. Of these, sex of the sibling, parental MS status, and index patient onset age were the important factors influencing MS risks to siblings. The results of this study are (1) the index-patient-onset-age effect suggests that individuals with a greater genetic loading (i.e., a greater contribution of susceptibility alleles) have an earlier age at onset and (2) genetic loading is substantially increased in individuals with an affected parent. These data are important both for genetic counseling and gene identification studies.

It is likely that both environmental and genetic factors interact to determine a person’s susceptibility to MS.

The possible role of inherited factors influencing the development of multiple sclerosis (MS) has been suspected for almost a century, but concepts of genetic and environmental interactions have evolved only recently. Existing family and twin data on MS are consistent with the notion that the study of MS susceptibility will parallel the findings in experimental models of spontaneous autoimmunity. Also, at least two genes (and almost certainly several genes) will be found to influence susceptibility and to interact with each other and with environmental triggers or agents in as yet unknown ways.

OBJECTIVE: To assess the evidence for a genetic basis to magic. Design Literature review. Setting Harry Potter novels of J K Rowling. Participants Muggles, witches, wizards, and squibs. Interventions Limited. MAIN OUTCOME MEASURES: Family and twin studies, magical ability, and specific magical skills. RESULTS: Magic shows strong evidence of heritability, with familial aggregation and concordance in twins. Evidence suggests magical ability to be a quantitative trait. Specific magical skills, notably being able to speak to snakes, predict the future, and change hair colour, all seem heritable. CONCLUSIONS: A multilocus model with a dominant gene for magic might exist, controlled epistatically by one or more loci, possibly recessive in nature. Magical enhancers regulating gene expressionmay be involved, combined with mutations at specific genes implicated in speech and hair colour such as FOXP2 and MCR1.

• A population-based study of pairs of relatives (siblings, second- and third-degree) concordant for multiple sclerosis did not show an excess of like-sexed pairs. In addition, data on human lymphocyte antigen typing for sibling pairs concordant for multiple sclerosis did not find an increase in haplotype sharing for like-sexed pairs. These data do not support the notion that sex-related factors influence multiple-sclerosis susceptibility in families.

A 34-year-old man sustained two middle cerebral artery strokes, one episode of amaurosis fugax, and several vertebro-basilar transient ischemic attacks over a decade. No other cause for this stroke syndrome was found except for cardiomyopathy probably caused by amyloidosis.

• A 58-year-old woman had progressive visual failure in her left eye over a twoyear period. Radiological investigation, including tomography and computerized tomographic (CT) scanning, did not result in a diagnosis. When no useful vision remained, surgical exploration disclosed an optic sheath meningioma. Complete recovery followed removal of the tumor.

We measured eye rotations in three planes in a patient with acquired, torsional nystagmus. This nystagmus had linear or increasing-velocity waveforms, was increased after active pitch rotations of the head, and was suppressed by convergence. Magnetic resonance imaging demonstrated a midpontine lesion that was probably a venous angioma. We postulate that torsional nystagmus in this patient was due to disruption of central vestibular connections.

Pespite many studies on the rate of conversion of optic neuritis (ON) to multiple sclerosis (MS) the subject remains controversial. There are hardly two studies that have treated the problem in quite the same manner, reflecting the fact that many variables affect the calculated outcome, some beyond the control of individual investigators. Most investigators accept a close relationship since many patients with clinically definite MS have an ON at some point in the course of their disease and many patients with ON have converted to clinically definite MS in follow-up. Frequencies of conversion ranging from 13% to 85% have been reported in the literature.1,2 The longest follow-ups have been in some of the studies with the lowest conversion rates and this has led to isolated ON enjoying a diagnostic status approaching that of a specific disease despite the fact that ON is not a clinical pathologic entity. No

• Eight patients with trigeminal neuralgia secondary to multiple sclerosis have been treated with percutaneous trigeminal radiofrequency rhizotomy after failure of medical therapy. Excellent results were obtained with this procedure, which seems ideally suited to these patients who tolerate carbamazepine poorly.