Electrodiagnosis of Neuromuscular Junction Disorders

Transcription

1 NMT overview Electrodiagnosis of Neuromuscular Junction Disorders Motor NAP arrives at nerve terminal Voltage-gated calcium channels open Ca +2 moves into presynaptic nerve terminal SNARE proteins elicit ACh vesicle exocytosis Vern C. Juel, M.D. OHSU Colloquium on Neuromuscular Disorders February 9, 2019 ACh diffuses across 50 nm cleft, binds with AChR Na + channels open Endplate depolarizes, producing EPP EPP reaching threshold elicit MFAP Merriggioli M, Sanders DB. Lancet Neurol 2009;8: ACh storage ACh is stored in vesicles Vesicles contain ~6-10K ACh molecules ACh storage pools Primary or Immediate Secondary or Mobilization Tertiary or Reserve Influences on ACh release 1. Depletion of primary ACh stores Each NAP depletes by ~20% Firing rates >0.1 Hz produce serial decline of ACh release for initial 4-5 impulses Subsequent mobilization of secondary ACh stores EPP amplitudes stabilize 2. Presynaptic [Ca +2 ] ACh release probability proportional to presynaptic [Ca +2 ] Ca +2 removed from motor nerve terminals over ms If firing rate >10 Hz, presynaptic [Ca +2 ] increases, and ACh release is potentiated Stalberg E, Sanders DB. J Clin Neurophysiol 1993;10: Fukunaga H, Engel AG, Osame M, Lambert EH. Muscle Nerve 1982;5:

2 The EPP The Safety Factor When EPP reaches threshold, a MFAP results Jitter derives from the temporal variability in MFAP latencies due to variable times when EPP reaches threshold Blocking occurs when a NAP fails to generate a MFAP Excess EP depolarization beyond threshold needed to produce a MFAP Ensures that for each motor NAP, a MFAP is produced Determined by: 1. Amount ACh released 2. Responsiveness of EP to ACh (Number and density of functional AChR) Sanders DB. J Clin Neurophysiol 1993;10: Safety factor Depletion of immediate ACh stores is of no consequence when safety factor is normal RNS Testing Most commonly used neurophysiologic test for NMT disorders When NMJ disease reduces safety factor, depletion of immediate ACh stores may elicit blocking with failure to produce a MFAP Technically-demanding Quality control is essential to avoid artifact, misinterpretation, and misdiagnosis 2

3 RNS principles Slow firing rates (<5 Hz) reduce safety factor in all cases High firing rates (>10 Hz) may improve the safety factor if there is a disorder of ACh release Surface CMAPs are a summation of individual MFAPs after motor/mixed nerve stimulation Decremental responses may be seen in all NMT disorders with low frequency RNS In presynaptic disorders, high stimulation rates or brief exercise may increase quantal ACh release with CMAP facilitation RNS testing: General technique Recording/stimulating electrodes as with motor NCS Stimulus duration 0.05 or 0.1 ms Use supramaximal stimulus (max amplitude %) Electrodes must be well secured Movement of stimulating electrodes causes abrupt changes in CMAP Movement of recording electrodes/leads/body causes baseline instability Immobilize joint/limb RNS testing: Stimulation frequency RNS testing: Pseudofacilitation Low frequency (2-3 Hz) optimal for decremental responses in MG and LEMS 5-10 stimuli in each 2-3 Hz train High frequency/tetanic (>10 Hz) should be avoided Painful (more Hz hurts!) Movement artifact Pseudofacilitation 10 s isometric exercise at MVC is equivalent to high frequency RNS Reserved for patients unable to perform exercise (infants, altered consciousness, severely paretic) Sanders DB. J Clin Neurophysiol 1993;10: Seen with high frequency RNS CMAP amplitude increasesup to 50% CMAP duration decreases No change in CMAP negative peak area Reflects synchronization of MFAP propagation velocities or muscle shortening DB Sanders 3

4 RNS testing: Temperature RNS testing: Activation methods Hand and foot muscles should be warmed to C Warming increases AChE activity and reduces presynaptic [Ca +2 ] In MG, no decrement may be seen in cool muscles In LEMS, resting CMAP is much smaller with warming No need to warm proximal or craniobulbar muscles 3 Hz RNS in APB in MG with warming. DB Sanders Resting ADQ CMAP in LEMS with warming DB Sanders Exercise Postactivation exhaustion (PAE) 2-5 min after s MVC Increased sensitivity for MG Postactivation facilitation (PAF) Immediately after brief, 10 s MVC A more specific finding in LEMS Ischemia Curare infusions PAF in LEMS. Resting APB CMAP is 50% normal w/ 500% PAF VC Juel RNS: Muscle selection Test clinically weak muscles In MG, bulbar and proximal muscles are most sensitive In LEMS, hand muscles are most sensitive Data analysis: Decrement % Decrement = [(CMAP n CMAP 1 )/CMAP 1 ] x th or 5 th CMAP will be lowest due to depletion of primary ACh stores CMAP amplitude increases after the 5 th CMAP due to mobilization of secondary ACh stores Hand and foot muscles require warming; proximal and bulbar muscles do not Hand muscles are best tolerated and easiest to immobilize That s where the money is. ADQ, 3 Hz stimulation with 34% decrement 1 4 4

5 Data analysis: Facilitation % Facilitation = [(CMAP n CMAP 1 )/CMAP 1 ] x 100 n = Initial postexercise CMAP with 10 s isometric MVC or Highest CMAP in a train with high frequency RNS Quality Control Inspect actual CMAP waveforms Verify stable baseline Look for abrupt changes in CMAP morphology and/or amplitude Document pseudofacilitation in high frequency RNS testing Findings should be reproducible after appropriate rest periods 3 Hz: 15% decrement 1 4 at baseline with 100% PAF Sanders DB. J Clin Neurophysiol 1993;10: RNS in MG Use low frequency (2-3 Hz) RNS in MG: PAE Assess an affected muscle and/or one hand and one proximal/bulbar muscle Initial train of 5-10 stimuli If significant decrement (>10%), repeat to verify reproducibility after at least 1 minute rest Isometric exercise with MVC for s Train of 5 stimuli immediately after exercise and every s for 5 minutes to assess for PAE (usually 2-4 min after MVC) PAF is rare and usually less than 50% 22% baseline decrement 1 4 Decrement repair immediately postexercise 34% decrement 1 5 post-exercise Proximal and bulbar muscles are most likely to be abnormal About 75% MG patients have abnormal RNS in a hand or shoulder muscle 2 Hz RNS, recording ADQ 5

6 RNS in LEMS Use low frequency (2-3 Hz) 5 rest RNS in LEMS Baseline 3 Hz RNS 2 mv amplitude, ADM Assess at least one hand muscle and one foot muscle Rest muscle for 5 minutes before testing 10 post-exercise 1800% facilitation After 10 exercise 5mV (>100% facilitation) Obtain initial CMAP, exercise for 10 s, then obtain postexercise CMAP w/i 5 s Rest muscle, then give train of 5-10 stimuli and follow MG protocol Most specific finding is >100% PAF Most sensitive finding is decrement to low frequency RNS ADM, 35 C (2 mv/div) 30 post-exercise 950% facilitation 60 post-exercise 500% facilitation 90 post-exercise 260% facilitation 20 Hz RNS RNS in Botulism Perform in clinically weak muscles RNS in CMS Use low frequency RNS if possible Specific finding is sustained PAF lasting for minutes without PAE PAF is typically more than 40%, but not as striking as in LEMS Mild cases may exhibit normal RNS testing 50 Hz RNS in ADQ in infant botulism with sustained 50% amplitude facilitation. CMAP duration decreased by 15% with only 40% CMAP area facilitation Decremental responses with low frequency stimulation Prolonged low frequency stimulation may be necessary in endplate CHAT deficiency with prolonged PAE lasting minutes Repetitive discharges in slow channel CMS, congenital AChE deficiency, MuSK, cholinesterase intoxication Punga AR, et al. Muscle Nerve 2006;34: VC Juel 6

7 RNS Testing: Summary Widely available, but technically demanding Abnormal findings not specific to primary NMJ disorders Motor neuron disease Severe peripheral neuropathy Myotonic disorders Should be performed in context of history, physical findings, and EDx findings on motor and sensory NCS SFEMG Record individual MFAPs w/i single MU 25 µm dia recording surface Filter settings: LFF 500 Hz, HFF 10K Hz Sweep: 0.5 ms/div Gain: µv/div Muscle fiber is < 300 µm from recording surface if SF potential is > 200 µv and has < 300 µs rise time Recording electrode comparison Recording field Surface area Needle positioning for jitter vs. fiber density analysis Best for FD Reduced FD Single fiber mm 2 Concentric 0.07 mm 2 Monopolar 0.34 mm 2 Increased FD Best for jitter 7

8 Acceptable MFAP parameters Rise time < 300 µsec Amplitude > 200 µv Well defined peaks with constant shape Clear separation between potentials No notches or shoulders on rising phase MCD 28 µsec MCD 118 µsec 20% blocking Jitter measurement parameters Number of fiber pairs assessed Mean MCD Median MCD % normal pairs % pairs with increased jitter, no blocking % pairs with increased jitter and blocking w/ voluntary activation 8

9 Abnormal jitter Voluntary vs. Stimulated SFEMG MSD used to decrease variability related to slow trends or fluctuating firing rate (when MCD:MSD > 1.25) Assess 20 fiber pairs per muscle Abnormal study if: >3 pairs with increased jitter (> 10% of 20 pairs) Any impulse blocking Voluntary activated jitter Pro Easiest to perform Second needle insertion avoided Fewer artifacts Blocking more easily assessed Con Requires cooperation Variable firing rates may influence MCD Injury potential Split fiber w/ low jitter False triggers Stimulated jitter No cooperation required Can assess effect of firing rate Technical artifacts Difficult to assess blocking Cannot test FD Cannot test all muscles Jitter measurements with CN electrodes ASFAPs (apparent single fiber action potentials) Disposable CN electrodes are sterile, single-use, sharp, do not require maintenance Composite potentials in CN jitter studies Look for shoulders, notches, poor superimposition Reduced selectivity for single muscle fibers (recording surface area mm 2 versus SF electrode recording surface area mm 2, about 40 times larger) Cannot distinguish between single MFAP and composite MFAPs More review and editing required to remove composite spikes Increase LFF to 1 khz Use smallest CN electrode available (DCF-25) Mild increases in jitter may be missed with CN electrodes Stalberg E et al. Muscle Nerve 53: ,

10 Normal jitter values (voluntary activation) Note: Lower with concentric needles Muscle EDC Frontalis OOC ULN Mean MCD (µsec) ULN Pair MCD (µsec) Concentric needle measurements in italics SFEMG: Summary Requires special expertise, technically demanding Concentric needle jitter studies are more time consuming SF electrodes must be maintained Abnormal findings not specific to primary NMJ disorders Immature reinnervation, some myopathies Should be performed in context of history, physical findings, and other EDx findings Summary: RNS testing and SFEMG Require attention to technical detail to prevent misdiagnosis Can confirm abnormal NMT in real time to establish dx Seronegative MG and LEM patients CMS Botulism Prolonged effects of NMBAs Can assess the degree of abnormal NMT in patients with known NMT disorders as a marker of disease activity 10