High rates of JCV seroconversion in a large international cohort of natalizumab-treated patients.

AIMS: To retrospectively assess factors associated with John Cunningham virus (JCV) seroconversion in natalizumab-treated patients. BACKGROUND: Natalizumab is highly effective for the treatment of relapsing-remitting multiple sclerosis (RRMS), but its use is complicated by opportunistic JCV infection. This virus can result in progressive multifocal leukoencephalopathy (PML). Serial assessment of JCV serostatus is mandated during natalizumab treatment. METHODS: Patients treated with natalizumab for RRMS at six tertiary hospitals in Melbourne, Australia (n = 865) and 11 MS treatment centres in Brazil (n = 136) were assessed for change in JCV serostatus, duration of exposure to natalizumab and prior immunosuppression. Sensitivity analyses examined whether sex, age, tertiary centre, prior immunosuppression or number of JCV tests affected time to seroconversion. RESULTS: From a cohort of 1001 natalizumab-treated patients, durable positive seroconversion was observed in 83 of 345 initially JCV negative patients (24.1%; 7.3% per year). Conversely, 16 of 165 initially JCV positive patients experienced durable negative seroconversion (9.7%; 3.8% per year). Forty patients (3.9%) had fluctuating serostatus. Time-to-event analysis did not identify a relationship between JCV seroconversion and duration of natalizumab exposure. Prior exposure to immunosuppression was not associated with an increased hazard of positive JCV seroconversion. Male sex was associated with increased JCV seroconversion risk [adjusted hazard ratio 2.09 (95% confidence interval 1.17-3.71) p = 0.012]. CONCLUSION: In this large international cohort of natalizumab-treated patients we observed an annual durable positive seroconversion rate of 7.3%. This rate exceeds that noted in registration and post-marketing studies for natalizumab. This rate also greatly exceeds that predicted by epidemiological studies of JCV seroconversion in healthy populations. Taken together, our findings support emerging evidence that natalizumab causes off-target immune changes that may be trophic for JCV seroconversion. In addition, male sex may be associated with increased positive JCV seroconversion.

Multiple Sclerosis as a Syndrome-Implications for Future Management.

We propose that multiple sclerosis (MS) is best characterized as a syndrome rather than a single disease because different pathogenetic mechanisms can result in the constellation of symptoms and signs by which MS is clinically characterized. We describe several cellular mechanisms that could generate inflammatory demyelination through disruption of homeostatic interactions between immune and neural cells. We illustrate that genomics is important in identifying phenocopies, in particular for primary progressive MS. We posit that molecular profiling, rather than traditional clinical phenotyping, will facilitate meaningful patient stratification, as illustrated by interactions between HLA and a regulator of homeostatic phagocytosis, MERTK. We envisage a personalized approach to MS management where genetic, molecular, and cellular information guides management.

The role of venous sinus outflow obstruction in pediatric idiopathic intracranial hypertension.

OBJECT: The authors examined the role of venous sinus obstruction in the etiology of idiopathic intracranial hypertension (IIH) by reviewing more than 200 MR venograms performed in suspected cases of IIH. METHODS: Individual MR venograms performed in cases of suspected IIH at the Children's Hospital at Westmead in Sydney, Australia, were reviewed. The authors excluded cases in which an intervention was performed before the scan or a structural cause for venous obstruction was identified. Cases with confirmed hydrocephalus were also excluded. For each of the 145 remaining scans, the authors completed a detailed review on a slice-by-slice basis of the 2D source images used to compile the rendered 3D MR venogram. The anatomical configuration of the dural venous sinuses and any areas of decreased flow in circulation were then noted. Where possible, they correlated their radiological findings with evidence of raised intracranial pressure based on LP opening pressures. They also reviewed a control group of 50 MR venograms. RESULTS: Seventy-six (52%) of 145 scans showed evidence of venous obstruction in the dominant-side circulation. Substantial nonphysiological collateral circulation was seen in 68% of cases with dominant-sided obstruction, suggesting a process of recanalization. In contrast, in the absence of dominant-sided obstruction, collateral circulation was uncommon. In 27 cases, CSF opening pressure measurements were available. In 20 cases the opening pressures were in excess of 20 cm H(2)O. Of those, 17 demonstrated evidence of dominant-sided venous outflow obstruction. Among those cases, the median opening pressure was 34 cm H(2)O. Dominant-sided venous outflow obstruction was seen in only 2 of 50 MR venograms in the control group. Furthermore, evidence of collateral circulation was also uncommon in the control group. There was a highly statistically significant difference between rates of dominant-sided venous obstruction in the suspected IIH and control groups (p ≤ 0.001). CONCLUSIONS: A majority of patients presenting for investigation of suspected IIH demonstrated evidence of dominant-sided venous obstruction on MR venogram. In addition there was a high correlation between elevated CSF opening pressures and dominant-sided venous sinus obstruction. This correlation was further supported by evidence of collateral recanalization in patients with elevated CSF pressures and dominant-sided venous obstruction. A control group of 50 MR venograms indicated that dominant-sided venous outflow obstruction is an unlikely incidental finding, and a highly statistically significant difference was found between rates of obstruction in the suspected IIH and control groups.