Wednesday, October 03, 2007

Susac Syndrome-- Pearls

Triad of BRAO (branch retinal artery occlusion), hearing loss, encephalopathy

Demographic age9-70 predominantly young adults 2:1 female

BRAO vision spots, loss eye exam-- infarctions, BRAO, Gass plaques and silver lines. Gass plaques are like Hollenhorst plaques but not necessarily at branch points. Clinical variable-- spots, visual obscurations, blurring, inversion of vision transient. Diagnostic test of choice-- fluorescein angiogram, signature finding in young adult esp.

Hearing loss-- affects apex of cochlea first, low tone hearing loss. Bang bang is one ear then other, rare in MS. If affects semicircular canal may cause vertigo, tinnitus, vomiting,confusion with Meniere's disease

Encephalopathy-- usually strong association with headache. May persist.

MRI callosal lesions "snowball" and "spokes" often in center of corpus callosum rather than on ventricular edge, holes in middle of lesions virtually pathognomonic per Susac. May also have lesions in brain substance and meninges, may enhance. Cranial nerves are spared. Cases may even mimic cancer.

Pathology-- vasculopathy not vasculitis. Small arteriolar occlusion. Inflammation afterwards may mimic encephalitis pathologically. Question of relation to juvenile dermatomyositis, rash, looks like erythema nodosum.

Course-- two types: two year type and long term type.

Therapy-- Big sledgehammer and little sledgehammer. protocols in J Neurol Sci? 2007. Include initial Solumedrol and IVIG then Cell Cept, or cytoxan or rituxan.

Monday, October 01, 2007

Notes on extension trials GA v. interferons

Again, Noseworthy's comment that they are more useful for safety than efficacy needs to be considered. Or is that true?

Natural history trials suggest that at 11-15 years, in three trials (lyon, London Ontario, and Olmstead County) 48 % reached EDSS of 4 at eleven years (Lyon), half reached EDSS of 6 at 15 years (London), and 28 percent reached an EDSS of 6 at ten years (olmstead County). IN addition, 10 and 7 percent, respectively, reached an EDSS of 8 (london and Olstead Cty).

Compare to the Copaxone extension trial. Patients in the MITT (modified intent to treat, based on getting GA either in double blind or open label part of the trial) had 7 years of disease duration at study start and 6.25 or 7.63 mean years of exposure to GA, depending if they ever received placebo. Thus they were ill with for fourteen years, about. The median EDSS at study end increased by 0.5 to 3.53, and was 3.06, mean, and 2.50 median, for subjects who received GA from the beginning. The ongoing (always copaxone group) had 24 % reach EDSS of 4, 8 % reach EDSS of 6, and 1 % reach an EDSS of 8. This is better than Olmstead County, where disease is benign and patients are not treated. At the minimum, one could say that subjects who were able to stay on copaxone were able to do better.

If one uses the MITT, that counts subjects who withdrew but who were followed, the percentages reaching EDSS of 4,6,8 were, respectively, 24,11, and 3, still outstanding. However, there were 74 subjects who withdrew and did not have LTFU. The reasons for withdrawal ranged from inability to comply with protocol (moved, pregnancy, , lack transportation) as well as breaking through. 55 % OF WITHDRAWN PATIENTS WERE STABLE WHILE ON GA. oF THE 50 PATIENTS WHO WITHDREW WITH LTFU, THE MEDIAN EDSS AT 10 YEARS WAS 6.0, WITH 68, 50, AND 10 % REACHING EDSS OF 4,6,8 RESPECTIVELY. That is worse than natural history. What impresses about this study is that almost half of patients were able to complete the full ten years on GA and that of those, the vast majority did well and there were only a few bad outcomes.

Looking at interferons, the data is much sketchier on long term. For interferon ib sc, the study lasted five years and there was a trend to less relapses. However, patients were then contacted periodically thereafter and examined spot check exam, and MRI. Of the patients who were originally in treatment arm, and who were on drug > 80 of 16 years, 45 % reached EDSS 6 and 29 % EDSS 7 (v. 52 and 44 for < 10 % time users) although no data what they took in meantime. 54 % of patients in LTF had NABs. 30 percent of patients were still on Betaseron ten years later (however, no followup study to help them stay on).

They had 19 years of disease on average. No EDSS data are given for Champions (long term Avonex) since the endpoint was conversion to CDMS . 42 % of patients were still on interferon 1a i-m at the end of Champions (5 years after initiation of treatment).

PRISMS 4 measured patients on Rebif 22 and 44 v. placebo for two years, then four more years on either rebif 22 or rebif 44. After 7.4 years, 68 percent were reevaluated once, after 8 years. 20 percent reached EDSS 6. Mean time to progression of one step on EDSS was 5.4 years. Treatment interruptions, co-medication and switches were not documented. No comparative controls.

Caution is indicated since head to head trials were not done, and the respective groups might have been non analagous.