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Biomedical subjects

B G Weinshenker

Publications and source records attributed to B G Weinshenker.

At least 19 recordsLinked to original sources
PubMed2006

Men transmit MS more often to their children vs women: the Carter effect.

OBJECTIVE: Multiple sclerosis (MS) is approximately twice as common among women as men. If men have greater physiologic resistance to MS, they might theoretically require stronger genetic predisposition than women to overcome this resistance. In this circumstance, men would be expected to transmit the disease more often to their children, a phenomenon known as the Carter effect. The authors evaluated whether the Carter effect is present in MS. METHODS: The authors studied 441 children (45 with definite MS) of an affected father or mother (197 families of interest) from 3598 individuals in 206 multiplex pedigrees. The authors compared transmission of MS from affected men with transmission from affected women. RESULTS: Fathers with MS transmitted the disease to their children more often (transmitted: 18, not transmitted: 99) than mothers with MS (transmitted: 27, not transmitted: 296) (p = 0.032; OR: 1.99, 95% CI: 1.05, 3.77). Adjusting for both the sex of the affected child and multiple transmissions from a single affected parent, the sex of the affected parent remained as an independent risk factor for transmission of MS to children, fathers transmitting more often than mothers (p = 0.036; OR: 2.21, 95% CI: 1.05, 4.63). CONCLUSIONS: The authors have demonstrated the Carter effect in multiple sclerosis (MS). These observations may be explained by greater genetic loading in men that leads to relative excess paternal vs maternal transmission. Linkage analysis in genetic studies of MS may be more informative if patrilineal transmission were given additional weighting.

Child↗
PubMed2006

Revised diagnostic criteria for neuromyelitis optica.

BACKGROUND: The authors previously proposed diagnostic criteria for neuromyelitis optica (NMO) that facilitate its distinction from prototypic multiple sclerosis (MS). However, some patients with otherwise typical NMO have additional symptoms not attributable to optic nerve or spinal cord inflammation or have MS-like brain MRI lesions. Furthermore, some patients are misclassified as NMO by the authors' earlier proposed criteria despite having a subsequent course indistinguishable from prototypic MS. A serum autoantibody marker, NMO-IgG, is highly specific for NMO. The authors propose revised NMO diagnostic criteria that incorporate NMO-IgG status. METHODS: Using final clinical diagnosis (NMO or MS) as the reference standard, the authors calculated sensitivity and specificity for each criterion and various combinations using a sample of 96 patients with NMO and 33 with MS. The authors used likelihood ratios and logistic regression analysis to develop the most practical and informative diagnostic model. RESULTS: Fourteen patients with NMO (14.6%) had extra-optic-spinal CNS symptoms. NMO-IgG seropositivity was 76% sensitive and 94% specific for NMO. The best diagnostic combination was 99% sensitive and 90% specific for NMO and consisted of at least two of three elements: longitudinally extensive cord lesion, onset brain MRI nondiagnostic for MS, or NMO-IgG seropositivity. CONCLUSIONS: The authors propose revised diagnostic criteria for definite neuromyelitis optica (NMO) that require optic neuritis, myelitis, and at least two of three supportive criteria: MRI evidence of a contiguous spinal cord lesion 3 or more segments in length, onset brain MRI nondiagnostic for multiple sclerosis, or NMO-IgG seropositivity. CNS involvement beyond the optic nerves and spinal cord is compatible with NMO.

Adolescent↗
PubMed2006

Clinical and MRI features of Japanese patients with multiple sclerosis positive for NMO-IgG.

This study investigates the relation between the serological status of NMO (neuromyelitis optica)-IgG and the clinical and MRI features in Japanese patients with multiple sclerosis. Serum NMO-IgG was tested in 35 Japanese patients diagnosed with multiple sclerosis, including 19 with the optic-spinal form of multiple sclerosis (OSMS), three with the spinal form of multiple sclerosis (SMS), and 13 with the conventional form of multiple sclerosis (CMS), which affects the brain. NMO-IgG was detected in 14 patients, 12 with OSMS and 2 with CMS. In these patients, longitudinally extensive (> 3 vertebral segments) spinal cord lesions (93% v 57%) and permanent, complete blindness (no perception of light) in at least one eye (50% v 0%) were the noticeable features as compared with NMO-IgG-negative OSMS. The two patients having CMS with NMO-IgG had unusual brain lesions, but in other respects had features suggesting OSMS. NMO-IgG was detected in more than half the number of patients with OSMS and in some patients with CMS. This newly discovered serum autoantibody was markedly associated with longitudinally extensive spinal cord lesions and with complete blindness, suggesting severe optic-spinal disease.

Adult↗
PubMed2005

A randomized controlled crossover trial of aspirin for fatigue in multiple sclerosis.

Pharmacotherapeutic options for multiple sclerosis (MS)-related fatigue are limited. Thirty patients were randomly assigned to aspirin (ASA) 1,300 mg/day or placebo in a double-blind crossover study. Results favored ASA for the main clinical outcomes: Modified Fatigue Impact Scale scores (p = 0.043) and treatment preference (p = 0.012). There were no significant adverse effects. The results warrant further study and support a role for ASA-influenced mechanisms, perhaps immunologic, in the generation of MS-related chronic fatigue.

Administration, Oral↗
PubMed2005

IFNG polymorphisms are associated with gender differences in susceptibility to multiple sclerosis.

Interferon-gamma (IFNgamma) treatment is deleterious in multiple sclerosis (MS). MS occurs twice as frequently in women as in men. IFNgamma expression varies by gender. We studied a population-based sample of US MS patients and ethnicity-matched controls and independent Northern Irish and Belgian hospital-based patients and controls for association with MS, stratified by gender, of an intron 1 microsatellite [I1(761)*CAn], a single nucleotide polymorphism 3' of IFNG [3'(325)*G --> A] and three flanking microsatellite markers spanning a 118 kb region around IFNG. Men carriers of the 3'(325)*A allele have increased susceptibility to MS compared to noncarriers in the USA (P=0.044; OR: 2.58, 95% CI: 0.97-8.08) and Northern Ireland (P=0.019; OR: 2.37, 95% CI: 1.10-5.13). There is a nonsignificant trend in the same direction in Belgian men (P=0.299; OR: 1.50, 95% CI: 0.71-3.26). Men carriers of I1(761)*CA13, which is in strong linkage disequilibrium with the 3'(325)*A, have increased susceptibility (P=0.050; OR: 2.22, 95% CI: 0.98-5.40), while men carriers of I1(761)*CA12 have decreased susceptibility (P=0.022; OR: 0.46, 95% CI: 0.23-0.90) to MS in the USA. Similar associations were reported in Sardinia between the I1(761)*CA12 allele and reduced risk of MS in men. Flanking markers were not associated with MS susceptibility. Polymorphisms of IFNG may contribute to differences in susceptibility to MS between men and women.

3' Flanking Region↗
PubMed2005

Clinical course, pathological correlations, and outcome of biopsy proved inflammatory demyelinating disease.

BACKGROUND: A pathological classification has been developed of early active multiple sclerosis (MS) lesions that reveals four patterns of tissue injury: I-T cell/macrophage associated; II-antibody/complement associated; III-distal oligodendrogliopathy, and IV-oligodendrocyte degeneration in the periplaque white matter. Mechanisms of demyelination in early MS may differ among the subgroups. Previous studies on biopsied MS have lacked clinicopathological correlation and follow up. Critics argue that observations are not generalisable to prototypic MS. OBJECTIVE: To describe the clinicopathological characteristics of the MS Lesion Project biopsy cohort. METHODS: Clinical characteristics and disability of patients with pathologically confirmed inflammatory demyelinating disease (excluding ADEM) classified immunopathologically (n = 91) and patients from the Olmsted County MS prevalence cohort (n = 218) were determined. RESULTS: Most patients who underwent biopsy and had pathologically proved demyelinating disease ultimately developed definite (n = 70) or probable (n = 12) MS (median follow up 4.4 years). Most had a relapsing remitting course and 73% were ambulatory (EDSS < or =4) at last follow up. Nine patients remained classified as having an isolated demyelinating syndrome at last follow up. Patients with different immunopathological patterns had similar clinical characteristics. Although presenting symptoms and sex ratios differed, the clinical course in biopsy patients was similar to the prevalence cohort. Median EDSS was <4.0 in both cohorts when matched for disease duration, sex, and age. CONCLUSIONS: Most patients undergoing biopsy, who had pathologically confirmed demyelinating disease, were likely to develop MS and remain ambulatory after a median disease duration of 4.4 years. The immunopathological patterns lacked specific clinical correlations and were not related to the timing of the biopsy. These data suggest that pathogenic implications derived largely from MS biopsy studies may be extrapolated to the general MS population.

Adolescent↗
PubMed2004

Association of APOE polymorphisms with disease severity in MS is limited to women.

The authors studied the association of an exon 4 (E4*epsilon2/3/4) and three promoter polymorphisms of APOE with disease course and severity stratified by gender in 221 patients with multiple sclerosis from two overlapping population-based prevalence cohorts. Women carriers of the E4*epsilon2 allele took longer to attain an Expanded Disability Status Scale score of 6 (p = 0.015) and had more favorable ranked severity scores than noncarriers (p = 0.009). There was no association in men. Alleles epsilon3 or epsilon4 and promoter polymorphisms were not associated with disease course or severity.

Adult↗
PubMed2004

Change in MS-related disability in a population-based cohort: a 10-year follow-up study.

OBJECTIVE: S: To study the change in disability over 10 years in individual patients constituting the 1991 Olmsted County, MN, multiple sclerosis (MS) prevalence cohort. METHODS: The authors reassessed this 1991 cohort in 2001. The authors determined the Expanded Disability Status Scale scores (EDSS) for each patient still alive, and within the year prior to death for those who died. The authors analyzed determinants of potential prognostic significance on change in disability. RESULTS: Follow-up information was available for 161 of 162 patients in the 1991 cohort. Only 15% had received immunomodulatory therapy. The mean change in EDSS for the entire cohort over 10 years was 1 point and 20% worsened by >or=2 points. For patients with EDSS <3 in 1991 (n = 66), 83% were ambulatory without a cane 10 years later. For patients with EDSS of 3 through 5 in 1991 (n = 33), 51% required a cane to ambulate (48%) or worse (3%). For patients with EDSS 6 to 7 in 1991 (n = 39), 51% required a wheelchair or worse in 2001. Gait impairment at onset, progressive disease, or longer duration of disease were associated with more worsening of disability (p < 0.002). The 10-year survival was decreased compared with the Minnesota white population for both men and women. CONCLUSIONS: Although survival was reduced and 30% of patients progressed to needing a cane or wheelchair or worse over the 10-year follow-up period, most remained stable or minimally progressed. Patients within the EDSS 3.0 through 5.0 range are at moderate risk of developing important gait limitations over the 10-year period. The authors did not identify factors strongly predictive of worsening disability in this study.

Adult↗
PubMed2004

Mechanical ventilation and tracheostomy in multiple sclerosis.

Decisions on ventilatory support (VS) in multiple sclerosis (MS) are complex. All patients with MS requiring mechanical ventilation or tracheostomy since 1969 (22) at Mayo Clinic were reviewed. Seventeen had progressive (PMS; 11 secondary and six primary progressive) and one had relapsing remitting MS (RRMS). Four had neuromyelitis optica (NMO). Of those with PMS, all but two required a wheelchair or were bedbound before VS and survived a median of 22 months; 14 were mechanically ventilated and seven underwent subsequent lifelong tracheostomy; three had tracheostomy only. The indications (usually multiple) for VS in PMS patients were aspiration pneumonia, poor ventilation because of mucous plugging, mechanical failure, and airway control/protection for seizures and coma. The RRMS patient required mechanical ventilation for 10 days, with subsequent short-term tracheostomy during a brainstem exacerbation. Of the four patients with NMO one made a dramatic recovery after plasmapheresis. Compared with PMS, the NMO group had a shorter time from disease onset to VS, a longer duration of ventilation, and the three patients not treated with plasma exchange or steroids did worse. The prognosis for independent ventilation (+/- tracheostomy) was worst for patients with NMO, except for one patient who received plasma exchange, and better then expected for PMS, despite poor preventilation functional status.

Adolescent↗
PubMed2003

Contrasting effects of IFNbeta and IVIG in children with central and peripheral demyelination.

Reported are three children with MS who responded dramatically to interferon-beta (IFNbeta) therapy. While on immunomodulatory therapy, they developed chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) that responded to IV immunoglobulin (IVIG) administration. These cases emphasize two interesting observations: 1) IFNbeta treatment did not prevent development of CIDP; 2) CIDP in the context of MS responded to IVIG, even though IVIG had no therapeutic effect on the central demyelinating disease.

Autoimmune Diseases of the Nervous System↗
PubMed2002

Plasma exchange for severe attacks of CNS demyelination: predictors of response.

The authors reviewed 59 consecutive patients treated with plasma exchange (PE) for acute, severe attacks of CNS demyelination at Mayo Clinic from January 1984 through June 2000. Most patients had relapsing-remitting MS (n = 22, 37.3%), neuromyelitis optica (NMO) (n = 10, 16.9%), and acute disseminated encephalomyelitis (n = 10, 16.9%). PE was followed by moderate or marked functional improvement in 44.1% of treated patients. Male sex (p = 0.021), preserved reflexes (p = 0.019), and early initiation of treatment (p = 0.009) were associated with moderate or marked improvement. Successfully treated patients improved rapidly following PE, and improvement was sustained.

Adolescent↗
PubMed2001

Genetic variation in the transforming growth factor beta1 gene in multiple sclerosis.

Transforming growth factor beta1 (TGFbeta1) is a Th2 cytokine encoded on chromosome 19q13, a region possibly linked to multiple sclerosis (MS). TGFbeta1 exerts favorable effects on experimental allergic encephalomyelitis. We performed a comprehensive search for genetic variants in this gene in 122 population-based sporadic cases of MS. We detected six variants, including three missense variants. We tested for association of the variants with susceptibility and course of MS and for linkage and transmission disequilibrium in a family series consisting of 395 samples in 59 pedigrees. Genetic variation in TGFB1 does not appear to contribute in a major way to susceptibility to MS.

Adult↗
PubMed2001

A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis.

OBJECTIVE: To determine whether IV immunoglobulin (IVIg) reverses chronic visual impairment in MS patients with optic neuritis (ON). METHODS: In this double-blind, placebo-controlled Phase II trial, 55 patients with persistent acuity loss after ON were randomized to receive either IVIg 0.4 g/kg daily for 5 days followed by three single infusions monthly for 3 months, or placebo. RESULTS: The trial was terminated by the National Eye Institute because of negative results when 55 of the planned 60 patients had been enrolled. Fifty-two patients completed the scheduled infusions, and 53 patients completed 12 months of follow-up. Analysis of this data indicated that a difference between treatment groups was not observed for the primary outcome measure, improvement in logMAR visual scores at 6 months (p = 0.766). Exploratory secondary analyses suggested that IVIg treatment was associated with improvement in visual function (including logMAR visual scores at 6 months and visual fields at 6 and 12 months) in patients with clinically stable MS during the trial. CONCLUSIONS: IVIg administration does not reverse persistent visual loss from ON to a degree that merits general use.

Adult↗
PubMed2001

Plasma exchange for severe attacks of inflammatory demyelinating diseases of the central nervous system.

Plasma exchange has not been widely accepted as a treatment for multiple sclerosis. However, several uncontrolled studies have suggested that patients with severe attacks of MS and other inflammatory demyelinating disease may improve rapidly after plasma exchange treatment. We recently completed a randomized, sham-controlled, crossover clinical trial of plasma exchange in 22 patients with idiopathic inflammatory demyelinating diseases of the central nervous system. Twelve had MS and ten had other inflammatory demyelinating disease syndromes. Forty-two percent of patients experienced moderate or greater recovery over 2 weeks of active treatment administered every other day while only 6% of patients experienced similar improvement while receiving sham treatment. Three patients who failed the sham treatment subsequently improved rapidly after crossover to active treatment; no patient who failed active treatment improved after crossover to sham. This study illustrates the importance of designing randomized clinical trials based on the treatment regimen and patient population studied in the uncontrolled reports that suggested treatment efficacy. Plasma exchange should be considered for patients with idiopathic inflammatory demyelinating disease syndromes when they have failed corticosteroid therapy.

Demyelinating Autoimmune Diseases, CNS↗
PubMed2001

VAPSE-based analysis: a two-phased candidate gene approach for elucidating genetic predisposition to complex disorders.

The extraordinary success of linkage analysis in diseases with Mendelian inheritance has not extended readily to the genetics of common complex diseases. VAPSE-based analysis is a type of candidate gene approach that represents an alternative strategy by which genetic mechanisms can be defined despite the presence of substantial genetic heterogeneity. Recent advances in mutation screening and statistical methodology have enhanced substantially the efficiency and power of this approach. The "bread and butter" of VAPSE-based analysis is genotype-to-phenotype searches in large populations with computerized medical records.

Alzheimer Disease↗