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

Mitoxantrone for Devic's disease

Weinstock-Guttman B et al. Study of mitoxantrone for the treatment of recurrent neuromyelitis optica. Arch Neurol 2006;63:957-963 The authors studied five patients over two years and felt they improved on MRI, edss.

Familial effects of the clinical course of MS

Hensieck AE et al. Neurology 2007; 68:376-383. There is concordance among family members for age at onset, NOT for severity. There are no apparent transmission patterns nor evidence for genetic loading. However, familial factors do affect the probability of an eventual progressive course (either PPMS or after RRMS, SPMS).

Normal appearing white matter (NAWM)& disability

Vrenken H. Altered diffusion tensor in multiple sclerosis normal-appearing brain tissue: cortical diffusion changes seem related to clinical deterioration. Journal of Magnetic Resonance Imaging 2006; 23:628-636.

Prospective controlled study of normal looking white and gray matter. 64 MS patients and 20 healthy controls. The 64 MS patients had 38 RRMS, 14 SPMS, and 12 with PPMS. Whole brain diffusion coefficient (ADC maps) and fractional anisotropy (FA) were obtained. In NAWM, global FA was decreased and global ADC increased in MS patients v. controls. The changes in ADC in NAWM correlated with disability more strongly than T2 lesion load. In gray matter regional analysis, changes in both ADC and FA were significant.
Note the correlation with disability was still "modest at best"

Copaxone and neuroprotection

Kahn O. Axonal metabolic recovery and potential neuroprotective effect of glatiramer acetate in relapsing-remitting multiple sclerosis. Multiple Sclerosis 2005; 11:646-651.

Two year study partly blinded with MR spectroscopy in treatment naive MS patients and controls. GA (Copaxone) reduced NAA, a surrogate of axonal injury. 18 patients who started GA were assessed, and four controls (subjects who elected not to begin therapy). The NAA/Cr increased in both groups. In the VOI (volume of interest) over two years, and the NAWM (normal appearing white matterO it increased by 10.7 and 7.1 in the treated group, and DECREASED by 8.9 and 8.2 % in the respective control groups.

Fred Lublin comments that while the number of patients is small, the study is ongoing (four more years) but warns that the attempts to correlate surrogate MRI markers for clinical disability have been "continually disappointing." Lublin wants to see proof that the marker NAA in MRS correlates with clinical measures, and also with other MRI measures such as balck holes and atrophy.