The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL.

OBJECTIVE: To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab. METHODS: In two randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon beta-1a [INF beta]1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing multiple sclerosis, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab. Antibodies to natalizumab were measured using an ELISA. Patients were categorized as "transiently positive" if they had detectable antibodies (>or=0.5 microg/mL) at a single time point or "persistently positive" if they had antibodies at two or more time points >or=6 weeks apart. RESULTS: In the AFFIRM study, antibodies were detected in 57 of 625 (9%) of natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive. Persistently positive patients showed a loss of clinical efficacy as measured by disability progression (p

Natalizumab reduces visual loss in patients with relapsing multiple sclerosis.

OBJECTIVE: To examine the effects of natalizumab on low-contrast letter acuity as a prespecified tertiary endpoint in two randomized clinical trials and to evaluate the usefulness of low-contrast letter acuity testing as a candidate test of visual function in multiple sclerosis (MS). METHODS: AFFIRM and SENTINEL were randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials of natalizumab in relapsing MS. Natalizumab was evaluated as monotherapy in AFFIRM and as add-on to interferon beta-1a in SENTINEL. Vision testing was performed at 100% contrast (visual acuity) and low-contrast (2.5% and 1.25%). RESULTS: The risk of clinically significant visual loss (predefined as a two-line worsening of acuity sustained over 12 weeks) at the lowest contrast level (1.25%) was reduced in the natalizumab treatment arms by 35% in AFFIRM (hazard ratio = 0.65; 95% CI: 0.47 to 0.90; p = 0.008) and by 28% in SENTINEL (hazard ratio = 0.72; 95% CI: 0.54 to 0.98; p = 0.038, Cox proportional hazards models). Mean changes in vision scores from baseline were also significantly different, reflecting worsening in non-natalizumab groups. CONCLUSIONS: Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Low-contrast acuity testing has the capacity to demonstrate treatment effects and is a strong candidate for assessment of visual outcomes in future multiple sclerosis trials.

The scientific basis of migraine.

Through genetic studies and neuroimaging techniques, our knowledge of the scientific basis of migraine continues to grow. The assumption that migraine is an inherited disorder has gained considerable support from studies of twins and of patients with familial hemiplegic migraine, in whom specific gene defects have been identified. Neuroimaging techniques, such as perfusion-weighted imaging, diffusion-weighted imaging, and blood oxygen level-dependent imaging, have allowed the visualization of changes in the brain that occur during the aura. Such information should help in the effective management and possible prevention of migraine attacks.

Terminal component of complement (C9) in the cerebrospinal fluid of patients with multiple sclerosis and neurologic controls.

We measured the concentration of C9 in the CSF and plasma of 93 consecutive patients referred for CSF examination in an outpatient multispecialty clinic. We noted no differences in CSF C9 or C9 index between patients with multiple sclerosis and neurologic controls.

A reappraisal of the epidemiology of multiple sclerosis in Olmsted County, Minnesota.

A review of multiple sclerosis (MS) case reports, using the unified record system at the Mayo Clinic for the Olmsted County population, revealed age- and sex-adjusted prevalence rates per 100,000 persons of 160 for Olmsted County and 173 for Rochester, Minnesota, on January 1, 1985. The annual age- and sex-adjusted incidence rate per 100,000 person-years from 1975 to 1984 for Olmsted County was 6.2 and for Rochester, 6.3. This incidence rate is significantly higher than what had been reported previously in Rochester (3.6/100,000) or in other communities. The estimated 25-year survival of the MS population was 76.2% +/- 4.5% compared with 87.7% for the general US white population of a similar age and sex. Survival for men was less than for women. There was no increase in survival for patients diagnosed with MS in more recent decades. No significant increase was found in cancer or autoimmune disease rates in the MS patients.

Update on the epidemiology of multiple sclerosis.

Neuroepidemiology has been important in providing clues about the cause and pathogenesis of multiple sclerosis. In this review, we update the incidence and prevalence rates of multiple sclerosis in Olmsted County, Minnesota, and examine the potential role of viruses, exposure to animals, toxins, trauma, and diet in the development of this disease. Diseases of probable autoimmune nature have also been linked to multiple sclerosis. These descriptive data may contribute to the formulation of testable specific hypotheses about the pathogenesis and treatment of multiple sclerosis and other demyelinating diseases.