Faculty Bibliography

BACKGROUND: Natalizumab (NTZ), a monoclonal antibody to human alpha4beta1/beta7 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.

Adult-onset, chronic progressive spastic paraparesis may be due to a large number of causes and poses a diagnostic challenge. There are no recent evidence-based guidelines or comprehensive reviews to help guide diagnostic work-up. We survey the literature on chronic progressive spastic paraparesis, with special emphasis on myelopathies, and propose a practical, MRI-based approach to facilitate the diagnostic process. Building on neuro-anatomic and radiographic conventions, we classify spinal MRI findings into six patterns: extradural; intradural/extramedullary; Intramedullary; Intramedullary-Tract specific; Spinal Cord Atrophy; and Normal Appearing Spinal Cord. A comprehensive differential diagnosis of chronic progressive myelopathy for each of the six patterns is generated. We highlight some of the more common and/or treatable causes of progressive spastic paraparesis and provide clinical pointers that may assist clinicians in arriving at the diagnosis. We outline a practical, comprehensive MRI-based algorithm to diagnosing adult-onset chronic progressive myelopathy.

We discuss the case of a patient with Progressive Multifocal Leukoencephalopathy (PML), developed after treatment with Natalizumab for 42 months for relapsing remitting multiple sclerosis (RRMS). Imaging was consistent with wide-spread PML with features that portended a high risk of development of Immune Reconstitution Inflammatory Syndrome (IRIS). After completion of plasmapheresis, she was started on oral maraviroc, chemokine receptor 5 antagonists. Our patient did not develop radiological signs or symptoms of clinical IRIS and tolerated maraviroc without adverse side-effects. We propose that maraviroc merits further examination as an agent that may prevent IRIS in patients with natalizumab-associated PML