Tysabri risk and possible interventions

Stuve O et al. Potential risk of PML with natalizumab therapy. Arch Neurol 2007; 64:169-176. Neurological Review. The authors point out that neurologists must be aware of possible therapies because the n of patients studied is likely to be low. Possible treatments include antivirals, immunomodulatory treatments, hematopoietic growth factors, plasma exchange, IVIG, leukopheresis and autotransfusion of leukocytes. Points of note: 1) the risk of developing PML among 3116 patients treated in studies was 0.1 % and the risk of PML among patients treated longer is not known. 2) JC virus is ubiquitous in all people in kidney, peripheral blood cells and normal brain at autopsy. The prevalence of antibodies is around 90 %. 3) The biological half life of natalizumab is around six months , far exceeding its pharmacological half life. Goals of a possible therapy: 1)eliminate JCV; 2) generate new competent WBC's with unbound VLA-4; 3)neutralize free natalizumab, and 4)eliminate free natalizumab. 1)Antivirals help PML in HIV patients. Reconstitution of CD4 and CD* lymphocytes maybe required to ensure a positive outcome in the patients. 2) Natlizumab is present in blood for 3-8 weeks after dosing. Elimination depends upon the interaction with VLA 4 which is reversible bond and follows normal thermodynamic rules. The idea is to change the binding strength and the in vivo binding equilibrium between natalizumab and VLA4. Existing interventions: cytarabine iv and it did not help HIV patients with PML. Cidofovir showed no benefit in one study. Drugs can cause renal failure and myelosuppression. Interferon alpha and beta and IL2 have case reports of improvement. No data exist of their efficacy. Serotonin 2 alpha blockers may prevent JC viral infection of oligodendrocytes. These drugs include olanzepine, ziprasidone, and risperidone. Hematopoeitic growth factors: pros: Theoretically IL7, G CSF, GM-CSF is well tolerated and might produce unbound lymphocytes. In theory it could be used with IVIG or plasma exchange. Cons: see article