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Wang FC

What Can We Expect of MUNE in ALS ?. Wang FC. CHU de Liège. Nice, 2004. Motor Unit. M otor U nit N umber E stimate : MUNE. Nice, 2004. Fundamental Principe. 1. Estimation of the mean motor unit size Sample of 10-20 distinct motor unit responses average S-MUP size

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Wang FC

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  1. What Can We Expect of MUNE in ALS ? Wang FC CHU de Liège Nice, 2004

  2. Motor Unit MotorUnitNumberEstimate : MUNE Nice, 2004

  3. Fundamental Principe 1.Estimation of the mean motor unit size Sample of 10-20 distinct motor unit responses average S-MUP size 2. Measure of the maximum CMAP size MUNE = 2 : 1 Nice, 2004

  4. MUNE Techniques • Stimulation MUNE Techniques • Incremental stimulation (McComas et al., 1971) • Original technique (McComas et al., 1971) • Multiple Point Stimulation (Brown and Milner-Brown, 1976) • Adapted Multiple Point Stimulation (Kadrie et al., 1976 ; Wang and Delwaide, 1995) • F-response MUNE techinque (Feasby and Brown, 1974) • Intraneural microstimulation (Arasaki and Tamaki, 1998) • Statistical MUNE (Daube, 1988) • MUESA (Slawnych et al., 1996) • Voluntary MUNE Techniques • Spike triggered averaging (Nandedkar and Barkhaus, 1987 ; Brown et al., 1988 ; Bromberg, 1993) • Rectified integrated EMG (Petajan, 2003) • Motor unit number index (MUNIX)(Nandedkar et al., 2003) Nice, 2004

  5. MUNE Techniques • Stimulation MUNE Techniques • Incremental stimulation(McComas et al., 1971) • Original technique (McComas et al., 1971) • Multiple Point Stimulation (Brown and Milner-Brown, 1976) • Adapted Multiple Point Stimulation (Kadrie et al., 1976 ; Wang and Delwaide, 1995) • F-response MUNE techinque (Feasby and Brown, 1974) • Intraneural microstimulation (Arasaki and Tamaki, 1998) • Statistical MUNE(Daube, 1988) • MUESA (Slawnych et al., 1996) • Voluntary MUNE Techniques • Spike triggered averaging(Nandedkar and Barkhaus, 1987 ; Brown et al., 1988 ; Bromberg, 1993) • Rectified integrated EMG (Petajan, 2003) • Motor unit number index (MUNIX)(Nandedkar et al., 2003) Nice, 2004

  6. Incremental Stimulation • Stimulation MUNE Techniques • Incremental stimulation (McComas et al., 1971) • Original technique (McComas et al., 1971) • one stimulation point • ten increments • Percutaneous nerve stimulation • Short stimulation duration = 0.05 ms • Weak intensity gradually increased byincrements of 0.1 mA Individual and sequential activation of motor axons Nice, 2004

  7. Incremental Stimulation Alternation Phenomenon Five motor units successively recruited by incremental stimulation. But, six distinct motor responses Underestimation of average S-MUP size Overestimation of MUNE Nice, 2004

  8. Incremental Stimulation Alternation Phenomenon 3 mA MU1 Nice, 2004

  9. Incremental Stimulation Alternation Phenomenon 5 mA MU1+MU2 Nice, 2004

  10. Incremental Stimulation Alternation Phenomenon 6 mA MU1+MU2+MU3 Nice, 2004

  11. Incremental Stimulation Alternation Phenomenon 6 mA MU1+MU2+MU4 Nice, 2004

  12. Incremental Stimulation Alternation Phenomenon 6 mA MU1+MU2+MU3+MU4 Nice, 2004

  13. Incremental Stimulation Alternation Phenomenon 9 mA MU1+MU2+MU3+MU4+MU5 Nice, 2004

  14. 1 2 3 4 Incremental Stimulation AMPS • Stimulation MUNE Techniques • Incremental stimulation (McComas et al., 1971) • Original technique (McComas et al., 1971) • one stimulation point • ten increments • Multiple Point Stimulation(Brown and Milner-Brown, 1976) • ten stimulation points • one increment/site • Adapted Multiple Point Stimulation(Kadrie et al., 1976 ; Wang and Delwaide, 1995) • 3-5 stimulation points • 2-3 increments/site Nice, 2004

  15. Spike Triggered Averaging Paris, 2003 Nice, 2004

  16. Statistical method Maximal CMAP Relies on alternation of axon excitability Submaximal CMAP • 120-300 stimuli at fixed, submaximal intensity • If : - Poisson distribution of motor evoked responses - All MU are assumed to have the same size • Variance = Mean Size distribution of submaximal CMAP CMAP variance Single S-MUP size = mean CMAP-minimum CMAP Nice, 2004

  17. Validity of MUNE • Reproducibility of MUNE studies • Comparison of MUNE with anatomic motor unit counts Nice, 2004

  18. MUNE reproducibility Nice, 2004

  19. Electrophysiological vs anatomical counts Nice, 2004

  20. Choice of MUNE Techniques • Incremental stimulation technique :alternation is a major problem • Spike triggered averaging :alternation is not a probleminvasive time comsuming reproducibility of results is not satisfactory Nice, 2004

  21. Choice of MUNE Techniques Nice, 2004

  22. Choice of MUNE Techniques Nice, 2004

  23. Choice of MUNE Techniques Nice, 2004

  24. Choice of MUNE Techniques Nice, 2004

  25. Choice of MUNE Techniques Nice, 2004

  26. Choice of MUNE Techniques Nice, 2004

  27. Choice of MUNE Techniques Nice, 2004

  28. Choice of MUNE Techniques Nice, 2004

  29. Normative data • Extensor digitorum brevis muscle = 154 MU(mean of 11 studies with 6 distinct methods) • Median nerve innervated thenar muscles = 229 UM(mean of 22 studies with 7 distinct methods) Nice, 2004

  30. MUNE in ALS : sensitivity 177 thenar muscles Above 60 years Below 60 years Lower normal limit Number of muscles MUNE Turnbull et al., 2003 Nice, 2004

  31. MUNE Months Wang et al, 2003 MUNE in ALS : sensitivity -72%/1 year Dantes & McComas, 1991 Nice, 2004

  32. MUNE in ALS : sensitivity As measure of progression in ALS, MUNE seems to be a more sensitive technique than are strength, CMAP amplitude, forced vital capacity and the apple scale. Felice, 1997 Probably because collateral sprouting is able to compensate for the effects of motor unit loss Nice, 2004

  33. 300 MUNE 100 10 3 70 100 1000 2000 Average SMUP size (µV.ms) MUNE in ALS : reinnervation r = - 0.60 r = - 0.60 P < 0.001 p < 0.001 Wang & Delwaide, 1998 Nice, 2004

  34. EHB twitches (g) 400 XC 300 200 100 0 20 120 40 60 80 100 200 MUNE (EDB) XC MUNE in ALS : reinnervation McComas et al., 1971 Nice, 2004

  35. MUNE in ALS : pathophysiology • SPINAL MOTONEURON LOSS • is not immediately widespread • regions more than others • motoneuron groups more than others - thenar > hypothenar - extensor digitorum brevis > plantar • cells more than others - some cells are in the degenerescence process - other cells are healthy and capable of doing an intense collateral reinnervation - apparent resilience, to the degenerative process, of about 10% of cells Nice, 2004

  36. MUNE in ALS : pathophysiology • COLLATERAL REINNERVATION • intense at start • more efficacious when the MU loss is slow • is able to maintain the CMAP size and the global muscular twitch tension in the normal range as long as : Reinnervation capacity > denervation rate Nice, 2004

  37. MUNE in ALS : pathophysiology • TERMINAL PHASE • reinnervation capacity reduction : the MU loss is responsible for the decreased number of MU with overlaping territories • terminal collapsus of MU Nice, 2004

  38. MUNE in ALS : motoneuron dysfunction Reversiblemotoneuronaldysfunction ? Dantes & McComas, 1991 Nice, 2004

  39. 1,8 Placebo 1,6 Riluzole Sanofi 1 1,4 Sanofi 1 + Ril 1,2 Sanofi 2 1 MUNE/MUNE (T0) Sanofi 2 + Ril 0,8 0,6 0,4 0,2 0 0 2-3 5-6 Months MUNE in ALS : motoneuron dysfunction Double blind controlled therapeutic trial in ALS Gooch, 2002 Nice, 2004

  40. MUNE in ALS : diagnosis value • Decreased MUNE and increased average SMUP size • non-specific data, related to peripheral motor denervation • in a suggestive clinical context, a decreased MUNE, particularly in an asymtomatic territory, is in favour of the diagnostic hypothesis • MUNE within the normal range, at several occasions over time, should induce a doubt about the diagnostic certainty Nice, 2004

  41. Thenar MUNE 400 Survival r = - 0.42p < 0.05 > 3 years 100 < 3 years 10 r = - 0.69p < 0.05 2 0 5 10 15 20 25 30 35 40 45 50 55 60 Desease duration (months) MUNE in ALS : rate of progression Transversal study in ALS Wang et al., 2003 Nice, 2004

  42. 0 -10 Thenar MUNE r = 0.71 p < 0.001 -20 -30 -40 -50 -60 -70 -80 -90 -100 -50 -40 -30 -20 -10 -0 -60 MUNE decline at T4/T0 (%) MUNE in ALS : predictive value MUNE decline at T12/T0 (%) Wang et al., 2002 Nice, 2004

  43. 100 80 60 40 20 0 8 16 24 32 40 MUNE in ALS : predictive value Longitudinal study in 15 ALS patients MU loss the first 4 months > 30% MU loss the first 4 months < 30% Survival (%) Time (months) Wang (unpublished data) Nice, 2004

  44. 100 80 60 40 20 0 8 16 24 32 40 MUNE in ALS : predictive value Longitudinal study in 11 ALS patients MU loss the first 8 months > 40% MU loss the first 8 months < 40% Survival (%) Time (months) Wang (unpublished data) Nice, 2004

  45. 100 80 60 40 20 0 8 16 24 32 40 MUNE in ALS : predictive value Longitudinal study in 10 ALS patients MU loss the first 12 months > 65% MU loss the first 12 months < 65% Survival (%) Time (months) Wang (unpublished data) Nice, 2004

  46. MUNE in ALS : therapeutic trials • Sensitive tool • Reproducible results • Physiological signification • Well tolerated, non expansive • Predictive value • Able to detect diffrences in the rate of MU loss MUNE might be valuable in determining the effectiveness of drugs in slowing the rate of motor unit loss. Nice, 2004

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