Carlo Tornatore

Intrathecal baclofen in multiple sclerosis: Too little, too late?

The majority of patients with multiple sclerosis (MS) have symptoms of spasticity that increasingly impair function as the disease progresses. With appropriate treatment, however, quality of life can be improved. Oral antispasticity medications are useful in managing mild spasticity but are frequently ineffective in controlling moderate to severe spasticity, because patients often cannot tolerate the adverse effects of increasing doses. Intrathecal baclofen (ITB) therapy can be an effective alternative to oral medications in patients who have a suboptimal response to oral medications or who cannot tolerate dose escalation or multidrug oral regimens. ITB therapy may be underutilized in the MS population because clinicians (a) are more focused on disease-modifying therapies rather than symptom control, (b) underestimate the impact of spasticity on quality of life, and (c) have concerns about the cost and safety of ITB therapy. Delivery of ITB therapy requires expertly trained staff and proper facilities for pump management. This article summarizes the findings and recommendations of an expert panel on the use of ITB therapy in the MS population and the role of the physician and comprehensive care team in patient selection, screening, and management.

Extended interval dosing of natalizumab in multiple sclerosis.

Background Natalizumab (NTZ), a monoclonal antibody to human α4β1/β7 integrin, is an effective therapy for multiple sclerosis (MS), albeit associated with progressive multifocal leukoencephalopathy (PML). Clinicians have been extending the dose of infusions with a hypothesis of reducing PML risk. The aim of the study is to evaluate the clinical consequences of reducing NTZ frequency of infusion up to 8 weeks 5 days. Methods A retrospective chart review in 9 MS centres was performed in order to identify patients treated with extended interval dosing (EID) regimens of NTZ. Patients were stratified into 3 groups based on EID NTZ treatment schedule in individual centres: early extended dosing (EED; n=249) every 4 weeks 3 days to 6 weeks 6 days; late extended dosing (LED; n=274) every 7 weeks to 8 weeks 5 days; variable extended dosing (n=382) alternating between EED and LED. These groups were compared with patients on standard interval dosing (SID; n=1093) every 4 weeks. Results 17% of patients on SID had new T2 lesions compared with 14% in EID (p=0.02); 7% of patients had enhancing T1 lesions in SID compared with 9% in EID (p=0.08); annualised relapse rate was 0.14 in the SID group, and 0.09 in the EID group. No evidence of clinical or radiographic disease activity was observed in 62% of SID and 61% of EID patients (p=0.83). No cases of PML were observed in EID group compared with 4 cases in SID cohort. Conclusions Dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy. Further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID.

Best practice recommendations for the selection and management of patients with multiple sclerosis receiving natalizumab therapy

Natalizumab, a humanized monoclonal antibody directed against α4-integrin is a first-in-class disease-modifying therapy for the treatment of relapsing multiple sclerosis. Natalizumab is highly effective but has been associated with a risk of progressive multifocal leukoencephalopathy. Since the efficacy of natalizumab in relapsing forms of multiple sclerosis is viewed as superior to first-line agents, a growing number of neurologists are using natalizumab as the treatment of choice for patients with worsening MS. Owing to the recently reported cases of progressive multifocal leukoencephalopathy, a panel of neurologists met in February 2009 to discuss best practices for the use of natalizumab, with the goal of developing consensus-based recommendations on patient management to minimize the risk of progressive multifocal leukoencephalopathy. The panel consisted of a cross section of academic and community neurologists from the United States who treat multiple sclerosis in large centers and have extensive experience with natalizumab (approximating 2000 patient-years combined experience). This paper summarizes the panels recommendations on the following: (1) appropriate patient selection for natalizumab; (2) routine monitoring and management of adverse events during natalizumab therapy; and (3) clinical vigilance monitoring and risk reduction for progressive multifocal leukoencephalopathy.

Efficacy of Natalizumab Therapy in Patients of African Descent With Relapsing Multiple Sclerosis Analysis of AFFIRM and SENTINEL Data

BACKGROUND Patients with multiple sclerosis (MS) who are of African descent experience a more aggressive disease course than patients who are of white race/ethnicity. In phase 3 clinical trials (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis [SENTINEL]), natalizumab use significantly improved clinical and magnetic resonance imaging outcomes over 2 years in patients with relapsing MS. Because patients of African descent may be less responsive to interferon beta treatment than patients of white race/ethnicity, the efficacy of natalizumab therapy in this population is clinically important. OBJECTIVE To evaluate the efficacy of natalizumab use in patients of African descent with relapsing MS. DESIGN Post hoc analysis. SETTING Academic research. PATIENTS Patients of African descent with relapsing MS who received natalizumab or placebo in the phase 3 AFFIRM study and those who received natalizumab plus intramuscular interferon beta-1a or placebo plus intramuscular interferon beta-1a in the phase 3 SENTINEL study. MAIN OUTCOME MEASURE Efficacy of natalizumab use in patients of African descent with relapsing MS who participated in the AFFIRM or SENTINEL trial. RESULTS Forty-nine patients of African descent participated in AFFIRM (n = 10) or SENTINEL (n = 39). Demographic and baseline disease characteristics were similar between patients treated with natalizumab (n = 21) or placebo (n = 28). Natalizumab therapy significantly reduced the annualized MS relapse rate by 60% (0.21 vs 0.53 in the placebo group, P = .02). Compared with placebo use, natalizumab therapy also significantly reduced the accumulation of lesions observed on magnetic resonance imaging over 2 years: the mean number of gadolinium-enhancing lesions was reduced by 79% (0.19 vs 0.91, P = .03), and the mean number of new or enlarged T2-weighted lesions was reduced by 90% (0.88 vs 8.52, P = .008). CONCLUSION Natalizumab therapy significantly improved the relapse rate and accumulation of brain lesions in patients of African descent with relapsing MS.

Practice patterns of US neurologists in patients with CIS, RRMS, or RIS: A consensus study

SummaryWe assess current practice patterns of US neurologists in patients with clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and radiologically isolated syndrome (RIS) using case-based surveys. For CIS, 87% recommended initiation of disease-modifying therapy (DMT) with MRI brain lesions. An injectable DMT was recommended by 90%–98% for treatment-naive, mild RRMS patients. There was 97% consensus to treat highly active RRMS, but no consensus on therapy choice. With RIS, there was consensus not to initiate treatment with brain but no spinal MRI lesions. Current US treatment patterns emphasize MRI in MS diagnosis and subsequent treatment decisions, treatment of early disease, aggressive initial treatment of highly active MS, and close patient monitoring.

TrkA induces differentiation but not apoptosis in C6‐2B glioma cells

Nerve growth factor (NGF) binds to the TrkA tyrosine kinase and the p75 neurotrophin receptors. Depending upon which receptor is activated, NGF can induce differentiation or apoptosis. C6‐2B glioma cells express the p75 receptor, but NGF decreases their growth only when TrkA is introduced (C6trk). It is unclear, however, whether TrkA reduces C6‐2B cell growth by apoptosis or differentiation. To examine which mechanisms account for the anti‐proliferative effect of NGF in these cells, we first analyzed whether NGF causes apoptosis by flow cytometry, two‐site immunoassay and in situ TUNEL. None of these methods indicated that C6trk undergo apoptosis. Additional apoptotic markers, such as Bcl‐2, Bax, Bad, p53, caspase 3, and NF‐κB were also used. C6trk cells exhibited lower levels of Bcl‐2 compared with the parental C6 mock cells, but no changes in the levels of other apoptotic proteins. Moreover, NGF increased AP‐1 binding activity in C6trk cells, suggesting that NGF may induce differentiation. We then examined whether TrkA changes the glioma phenotype. In C6trk cells, but not in C6mock cells, NGF enhanced the levels of neuron‐specific enolase as well as the levels of A2B5 and 2′, 3′‐cyclic nucleotide 3′‐phosphodiesterase, markers for oligodendrocytes, without affecting the expression of other neuronal markers. Our data suggest that the antiproliferative properties of TrkA may rely on its ability to induce differentiation of C6 cells from undifferentiated glioma to oligodendrocytes. J. Neurosci. Res. 64:636–645, 2001.

Consensus opinion of US neurologists on practice patterns in RIS, CIS, and RRMS Evolution of treatment practices

Purpose of review:To assess current practice patterns of US neurologists in patients with radiologically isolated syndrome (RIS), clinically isolated syndrome (CIS), and relapsing-remitting multiple sclerosis (RRMS) using case-based Web surveys. Recent findings:We identified a total of 47 points of consensus (≥75% agreement) with regard to diagnosis, treatment, and monitoring of RIS, CIS, and RRMS. Current US treatment consensus patterns emphasize (1) MRI in multiple sclerosis (MS) diagnosis and subsequent treatment decisions, (2) treatment of early disease, (3) aggressive initial treatment of highly active MS, and (4) close patient monitoring for clinical response and adverse effects of disease-modifying drugs. Summary:These findings may offer insights into harmonizing MS care and represent the first steps in potentially establishing a more uniform approach to the treatment of patients with MS in the United States without compromising the need for individual treatment for each patient.

TrkA receptors delay C6-2B glioma cell growth in rat striatum.

Nerve growth factor (NGF) acts as an anti-mitogenic factor in C6-2B glioma cells stably expressing TrkA (C6trk+). To study the effect of TrkA on cell growth in vivo, we grafted mock and C6trk+ cells into the striatum of ACI nude rats. Thy 1.1 and p75NTR immunohistochemistry revealed that wild type C6-2B cells formed a tumor mass in the striatum by 14 days. In contrast, C6trk+ transplanted rats did not show the presence of a significant tumor mass until 71 days. Analysis of this tumor showed that expression of TrkA was retained, but the synthesis of NGF was abolished. Our data encourage the speculation that expression of TrkA in glioblastoma in vivo will attenuate tumor progression.

Clinical vigilance for progressive multifocal leukoencephalopathy in the context of natalizumab use

Natalizumab therapy for patients with multiple sclerosis (MS) has been associated with both improved clinical outcomes and an increased incidence of progressive multifocal leukoencephalopathy (PML). We provide details of the etiology and recent history of PML as associated with immunosuppressive disease states, including MS. Furthermore, it offers clinical guidance on differentiating PML from a MS relapse and a review of the current treatment options for patients suspected of having developed the complication.