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Biomedical subjects

Brian G Weinshenker

Publications and source records attributed to Brian G Weinshenker.

At least 19 recordsLinked to original sources
PubMed2006

Multiple sclerosis, brain radiotherapy, and risk of neurotoxicity: the Mayo Clinic experience.

PURPOSE: The aim of this study was a retrospective assessment of neurotoxicity in patients with multiple sclerosis (MS) receiving external beam radiotherapy (EBRT) to the brain. METHODS AND MATERIALS: We studied 15 consecutively treated patients with MS who received brain EBRT. Neurologic toxicity was assessed with the Common Toxicity Criteria v.3.0. RESULTS: Median follow-up for the 5 living patients was 6.0 years (range, 3.3-27.4 years). No exacerbation of MS occurred in any patient during EBRT. Five patients had Grade 4 neurologic toxicity and 1 had possible Grade 5 toxicity. Kaplan-Meier estimated risk of neurotoxicity greater than Grade 4 at 5 years was 57% (95% confidence interval, 27%-82%). Toxicity occurred at 37.5 to 54.0 Gy at a median of 1.0 year (range, 0.2-4.3 years) after EBRT. Univariate analysis showed an association between opposed-field irradiation of the temporal lobes, central white matter, and brainstem and increased risk of neurotoxicity (p < 0.04). Three of 6 cases of toxicity occurred in patients treated before 1986. CONCLUSIONS: External beam radiotherapy of the brain in patients with MS may be associated with an increased risk of neurotoxicity compared with patients without demyelinating illnesses. However, this risk is associated with treatment techniques that may not be comparable to modern, conformal radiotherapy.

Adolescent↗
PubMed2006

Brain abnormalities in neuromyelitis optica.

BACKGROUND: Neuromyelitis optica (NMO) is a severe demyelinating disease defined principally by its tendency to selectively affect optic nerves and the spinal cord causing recurrent attacks of blindness and paralysis. Contemporary diagnostic criteria require absence of clinical disease outside the optic nerve or spinal cord. We have, however, frequently encountered patients with a well-established diagnosis of NMO in whom either asymptomatic or symptomatic brain lesions develop suggesting that the diagnostic criteria for NMO should be revised. OBJECTIVE: To describe the magnetic resonance image (MRI) brain findings in NMO. DESIGN: Observational, retrospective case series. Patients We ascertained patients through a clinical biospecimens database of individuals with definite or suspected NMO. We included patients who (1) satisfied the 1999 criteria of Wingerchuk et al for NMO except for the absolute criterion of lacking symptoms beyond the optic nerve and spinal cord and the supportive criterion of having a normal brain MRI at onset; (2) had MRI evidence of a spinal cord lesion extending 3 vertebral segments or more (the most specific nonserological feature to differentiate NMO from MS); and (3) were evaluated neurologically and by brain MRI at the Mayo Clinic. MAIN OUTCOME MEASURES: Magnetic resonance images were classified as normal or as abnormal with either nonspecific, multiple sclerosis-like or atypical abnormalities. We evaluated whether brain lesions were symptomatic and analyzed the neuropathologic features of a single brain biopsy specimen. RESULTS: Sixty patients (53 women [88%]) fulfilled these inclusion criteria. The mean +/- SD age at onset was 37.2 +/- 18.4 years and the mean +/- SD duration of follow-up was 6.0 +/- 5.6 years. Neuromyelitis optica-IgG was detected in 41 patients (68%). Brain MRI lesions were detected in 36 patients (60%). Most were nonspecific, but 6 patients (10%) had multiple sclerosis-like lesions, usually asymptomatic. Another 5 patients (8%), mostly children, had diencephalic, brainstem or cerebral lesions, atypical for multiple sclerosis. When present, symptoms of brain involvement were subtle, except in 1 patient who was comatose and had large cerebral lesions. CONCLUSIONS: Asymptomatic brain lesions are common in NMO, and symptomatic brain lesions do not exclude the diagnosis of NMO. These observations justify revision of diagnostic criteria for NMO to allow for brain involvement.

Adult↗
PubMed2006

Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression.

BACKGROUND: Neuromyelitis optica (NMO)-IgG is a specific autoantibody marker for NMO. It binds selectively to aquaporin 4 (AQP4), which is highly concentrated in astrocytic foot processes at the blood-brain barrier and is not restricted to optic nerve and spinal cord. Although it is conventionally believed that the brain is spared, brain imaging abnormalities are not uncommon in patients with NMO. OBJECTIVE: To investigate the location of brain lesions that are distinctive for NMO with respect to the localization of AQP4 in mammalian brain. DESIGN: Observational, retrospective case series. SETTING: Clinical serologic cohort of patients tested for NMO-IgG for whom brain MRI images were available. PATIENTS: We identified 120 patients seropositive for NMO-IgG for whom brain magnetic resonance images were available. MAIN OUTCOME MEASURE: Magnetic resonance imaging abnormalities. RESULTS: In 8 patients we observed recurring and distinctive magnetic resonance imaging abnormalities in the hypothalamic and periventricular areas that corresponded to brain regions of high AQP4 expression. CONCLUSION: The distribution of NMO-characteristic brain lesions corresponds to sites of high AQP4 expression.

Adolescent↗
PubMed2006

Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis.

OBJECTIVE: We investigated whether neuromyelitis optica (NMO) IgG seropositivity at the initial presentation of longitudinally extensive transverse myelitis (LETM) predicts relapse of myelitis or development of optic neuritis. METHODS: Prospective study of patients with initial LETM who were tested for the presence of NMO-IgG. RESULTS: Eleven of 29 patients (37.9%) were seropositive after a first attack of LETM spanning three or more vertebral segments on magnetic resonance imaging. Of 23 patients followed up for 1 year, none of 14 who were seronegative experienced a relapse or developed optic neuritis. Of 9 seropositive patients, 5 developed a second event: 4 of 9 (44%) developed recurrent transverse myelitis and 1 of 9 (11%) developed optic neuritis (p = 0.004). INTERPRETATION: LETM represents an inaugural or limited form of NMO in a high proportion of patients. The 40% of patients who are seropositive for NMO-IgG are at high risk for relapse.

Adult↗
PubMed2006

NMO-IgG: a specific biomarker for neuromyelitis optica.

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that principally targets the optic nerves and spinal cord and often leads to severe disability and occasionally life threatening respiratory failure. Although its clinical manifestations overlap with those of multiple sclerosis (MS), in established cases these two conditions can be distinguished on the basis of clinical, radiological, and routine spinal fluid studies. The diagnosis in early cases or limited forms of NMO is difficult. We recently discovered a unique IgG autoantibody (NMO-IgG) that is highly specific to patients with NMO and thus a valuable diagnostic aid. Its antigen, aquaporin-4 (AQP4), is the central nervous system's predominant water channel protein. This antibody has not yet been proven to be pathogenic, but several facts suggest that it might be, including the similarity of the immunohistochemical pattern of NMO-(AQP4) IgG binding to mouse CNS tissues to the pattern of immune complex deposition in autopsied patients' spinal cord tissue. The spectrum of diseases identified by NMO-IgG is broader than has previously been recognized clinically and includes incomplete forms of NMO, such as recurrent transverse myelitis without optic neuritis and recurrent optic neuritis without myelitis.

Autoantibodies↗
PubMed2005

CCR5Delta32 polymorphism effects on CCR5 expression, patterns of immunopathology and disease course in multiple sclerosis.

Four distinct patterns of tissue injury have been described in multiple sclerosis (MS) lesions. Infiltrating monocytes in lesions of all patterns co-express CCR1 and CCR5. However, in pattern II lesions, the number of CCR1 cells is decreased, while the number of CCR5 expressing cells is increased in late active versus early active regions. In contrast, CCR1 and CCR5 cells were equal in all regions of pattern III lesions. These suggest distinct inflammatory microenvironments in pattern II and III lesions and support MS pathological heterogeneity. A deletion in CCR5 (CCR5*Delta32), which encodes a truncated, non-functional protein, has been associated with late onset of MS and a favorable prognosis. We studied the association of CCR5*Delta32 with the course and severity of MS in 221 patients from a population-based cohort in Olmsted County, MN, and with patterns of immunopathology in 94 patients with biopsy-derived, pathologically confirmed demyelinating disease participating in the MS Lesion Project. The frequency of the genotypes in 221 patients from Olmsted County, MN, was 167 (75.6%) wild type, 52 (23.5%) heterozygotes, and 2 (0.9%) homozygotes. There was no association of carrier status for the CCR5*Delta32 mutation with disease severity as analyzed using the disease severity score (ranking of EDSS/duration stratified by duration), age of onset, gender or disease course (bout onset versus primary progressive). Due to low frequency of homozygotes no conclusion can be made regarding their relation to heterozygosity or wild-type status. The frequency of genotypes in the 94 biopsies was 77 (81.9%) wild type, 15 (16.0%) heterozygotes and 2 (2.1%) homozygotes. Carrier status for the CCR5*Delta32 mutation was not associated with patterns of immunopathology in MS. Despite similar numbers of T-lymphocytes, there were no CCR5+ T-cells nor was CCR5 expressed in the CNS of a homozygous CCR5*Delta32 MS patient, and heterozygous patients had reduced CCR5 expression compared to wild type patients. CCR5*Delta32 has a dose effect on CCR5 expression in the CNS, but is neither necessary for development of MS, nor CD3+ T cell recruitment into the CNS. Furthermore it does not segregate with patterns of immunopathology in MS. We did not find an association between CCR5*Delta32 mutation and disease severity and age of onset in MS.

Adult↗
PubMed2005

Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria".

New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.

Humans↗
PubMed2005

Neuromyelitis Optica.

Neuromyelitis optica (Devic's syndrome) is an uncommon, idiopathic, demyelinating syndrome of the central nervous system that preferentially affects the optic nerves and spinal cord. It frequently is misdiagnosed as severe multiple sclerosis, but usually is readily distinguished from multiple sclerosis in fully developed cases because of its severity, typical magnetic resonance imaging (MRI) findings (normal brain MRI; longitudinally extensive lesions on spinal cord MRI), and cerebrospinal fluid analysis (polymorphonuclear pleocytosis and absence of oligoclonal banding). A serum autoantibody marker, NMO-IgG, is highly specific for the disorder. Most patients have relapsing disease, and natural history studies confirm early and severe disability. We treat acute myelitis and optic neuritis exacerbations with parenteral corticosteroids and use rescue plasmapheresis for severe, refractory attacks. Immunomodulatory drugs used for typical multiple sclerosis seem ineffective for relapse prevention. We recommend systemic immunosuppression, usually with azathioprine and oral corticosteroids, for most patients. Fulminant disease and breakthrough disease may respond to other forms of humoral immunotherapy such as rituximab.

Journal Article↗
PubMed2004

The natural history of recurrent optic neuritis.

BACKGROUND: Optic neuritis (ON) may occur in isolation or may herald multiple sclerosis (MS) or neuromyelitis optica (NMO). Occasionally, ON may recur many times without intervening evidence of dissemination in space. OBJECTIVE: To define the clinical course and prognosis of patients with recurrent ON. DESIGN: Retrospective medical record review and telephone follow-up survey. SETTING: Clinic-based practice in a large tertiary referral institution. MAIN OUTCOME MEASURES: Survival analysis of conversion to MS and NMO and final visual impairment. We studied the association of clinical and demographic factors, the presence of brain lesions on magnetic resonance images, and the use of corticosteroid treatment at the time of the first ON occurrence with conversion to MS and NMO. RESULTS: We identified 1274 patients with ON between 1994 and 2000 and selected 72 (5.7%) with recurrent ON without intervening symptoms of a disseminated demyelinating condition for further analysis. The 5-year conversion rate to NMO was 12.5% and to MS, 14.4%. Among 5 patients with 2 or more lesions consistent with MS on brain magnetic resonance images, 2 (40.0%) converted to MS and none to NMO, while among 11 patients without such lesions, none converted to MS and 2 (18.2%) converted to NMO (P =.16). Conversion to MS occurred in 7 (19.4%) of 36 individuals treated for their first ON episode with corticosteroids vs 4 (44.4%) of 9 untreated individuals (P =.19). There was no difference in the conversion rate to MS between those treated with intravenous steroids (4 [16.7%] of 24) vs oral steroids (3 [25.0%] of 12) (P =.33). Conversion to NMO occurred earlier than conversion to MS (2.3 +/- 1.6 vs 5.3 +/- 4.3 years, respectively; P =.01). Women tended to convert to NMO more frequently than men (female-male ratio for NMO converters, 7:1; MS converters, 2:1; nonconverters, 2:1; P =.56), as did those with a higher annual frequency of ON episodes (NMO converters, 2.0 +/- 1.3; MS converters, 1.0 +/- 1.0; nonconverters, 0.6 +/- 0.5; P =.04). The number of ON events in the first 2 years following the first ON episode was higher in the NMO group (NMO converters, 2.4 +/- 0.9; MS converters, 1.9 +/- 1.1; nonconverters, 1.7 +/- 0.7; P =.04). The final visual impairment was greatest in the NMO group (P =.02). CONCLUSIONS: Patients with rapid succession of severe ON events are more likely to develop a generalized demyelinating disease. Patients with NMO had a worse visual outcome.

Administration, Oral↗
PubMed2004

Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study.

In 2001, we followed up all patients from the 1991 Olmsted County Multiple Sclerosis (MS) prevalence cohort. We found that the longer the duration of MS and the lower the disability, the more likely a patient is to remain stable and not progress. This is particularly powerful for patients with benign MS with Expanded Disability Status Scale score of 2 or lower for 10 years or longer who have a greater than 90% chance of remaining stable. This is important because these patients represent 17% of the entire prevalence cohort. These data should assist in the shared therapeutic decision-making process of whether to start immunomodulatory medications.

Cohort Studies↗
PubMed2004

CD95 polymorphisms are associated with susceptibility to MS in women. A population-based study of CD95 and CD95L in MS.

CD95/CD95L interaction results in activation-induced apoptosis thereby regulating clonal expansion of T cells outside the thymus. Genetic defects in this system result in autoimmune lymphoproliferation in mice and men. CD95-induced cell death may be defective in MS. We studied the association of CD95 and CD95L polymorphisms with MS in 221 unique patients representing 79% ascertainment in Olmsted County, MN, and 442 gender-, age- and ethnicity-matched controls. Being a homozygote for the G allele of CD95 5'(-670)*A-->G SNP (p=0.034; OR: 1.59, 95% CI: 1.06-2.38) and for the C allele of CD95 E7(74)*C-->T SNP (p=0.007; OR: 1.73, 95% CI: 1.17-2.56) increased susceptibility to MS exclusively in women. There was strong but incomplete linkage disequilibrium between the two markers (p<0.001; D'=0.546). Homozygosity for 5'(-670)*A or E7(74)*C explained 28% of risk of MS in women but 0% of the risk in men in Olmsted County, MN. Our results agree with the previously published studies and highlight that the association of the polymorphisms is restricted to women with MS. We did not find an association between CD95L and susceptibility to MS nor CD95 or CD95L and age of onset, disease course and disease severity.

Cohort Studies↗
PubMed2004

Demyelination during anti-tumor necrosis factor alpha therapy with infliximab for Crohn's disease.

BACKGROUND: Inflammatory demyelinating disease of the central nervous system may be linked to anti-tumor necrosis factor alpha therapy. CASE HISTORY: A 19-year-old female with Crohn's ileocolitis developed right arm and leg numbness and right hand weakness 4 weeks after the initiation of infliximab. Neurologic examination confirmed upper and lower right extremity sensory and motor deficits. MRI examination of the head and thoracic cord showed multiple gadolinium-enhancing lesions with distribution and configuration most suggestive of multiple sclerosis or other demyelinating process. The infliximab therapy was immediately stopped and follow-up at 8 weeks revealed symptomatic improvement. CONCLUSION: This case report describes the onset of a demyelinating process after the institution of infliximab therapy in a patient with Crohn's disease.

Adult↗