REPETITIVE NERVE STIMULATION (RNS)
- 2. • Physiology of Neuromuscular junction • Procedure & technical aspects • Interpretation • Application in various conditions
- 3. ANATOMY AND PHYSIOLOGY OF NEUROMUSCULAR JUNCTION The NMJ essentially forms an electrical-chemical- electrical link between the nerve and muscle. The chemical neurotransmitter at the NMJ is Acetylcholine (ACH). ACH molecules are packaged as vesicles in the presynaptic terminal in discrete units known as Quanta (Bags of neurotransmitter (ACH).)
- 4. definitions • Quantum. A quantum is the amount of Ach packaged in a single vesicle. • Each quantum (vesicle) 1 mV change of postsynaptic membrane potential. • The number of quanta released after a nerve action potential depends on the number of quanta in the immediately available (primary) store and calcium stores • Normally 50-300(60) vesicles
- 5. The quanta are located in three separate stores: Primary or immediately available store 1000 quanta- beneath presynaptic nerve terminal membrane. Secondary or mobilization store 10,000 quanta- supplies the primary stores after few seconds. Tertiary or reserve store. More than 10,000 quanta –in the axon and cell body
- 6. Calcium and quanta dynamics • calcium :diffuses slowly out of the presynaptic terminal in 100–200 msec. • Ach stores: immediately available (primary) store and secondary (or mobilization) store • rapid RNS (more than every 100 msec, or stimulation rate >10 Hz), calcium influx is greatly enhanced and the probability of release of Ach quanta increases.
- 7. PHYSIOLOGY • When an nerve action potential invades and depolarizes the presynaptic junction, voltage dependent calcium channels are activated, allowing an influx of calcium. • Results in release of ACH from the presynaptic terminals • The greater the calcium inside the greater the more quanta (ACH) are released. • ACH then diffuses across the synaptic cleft and binds to ACH receptors (ACHRs) on the post synaptic membrane • In the post synaptic membrane – numerous junction are found with ACH dependent gated channels and receptors. • Thus the binding of ACH to ACHRs clustered opens ion channels… resulting in a local depolarization, the End Plate Potential (EPP). • The size of EPP depends on the amount of ACH that binds to the ACHRs.
- 11. definitions • End plate potential -EPP is the potential generated at the postsynaptic membrane following a nerve action potential and neuromuscular transmission. • 60 mV change in the amplitude of the membrane potential. • Safety factor: The safety factor of neuromuscular transmission is simply defined as the difference between the EPP and the threshold potential for initiating an action potential.
- 12. RNS EFFECT During repetitive nerve stimulation in normal subjects, ACH quanta are progressively depleted from the primary store and fewer quanta are released with each stimulation. The corresponding EPP falls in amplitude but b/c of normal safety factor it remains above the threshold to ensure generation of a muscle action potential with each stimulation. After few seconds(1-2sec) the secondary store begins to replace the depleted quanta with a subsequent rise in the EPP.
- 13. PHYSIOLOGY OF RAPID RNS In rapid RNS (10-50 Hz), depletion of quanta from the presynaptic terminals is counterbalanced not only by the mobilization or secondary stores but also by accumulation of calcium. Normally it takes 100 msec for ca2+ to diffuse back out of the presynaptic terminals. If RNS is rapid enough so that new ca2+ influx occurs before previously infused ca2+ had diffused back out, ca2+ continues to accumulate in the presynaptic terminals, causing an increased release of quanta. This combination of factors usually leads to an increased number of quanta released and a corresponding higher EPP. However, the result in normal subject is same i.e the generation of a muscle action potential.
- 14. SLOW AND RAPID RNS • The effect of rapid and slow RNS is the same to generate the Muscle action potential in normal subjects. In Pathological Conditions: • Where the safety factors is reduced i.e. the baseline EPP is reduced but still above the threshold the slow RNS will cause depletion of quanta and may drop the EPP below threshold, resulting on the absence of muscle action potential. • Where the baseline EPP is below the threshold and a muscle action potential is not generated, rapid RNS may increase the number of quanta released, resulting in a larger EPP so that threshold is reached.
- 15. Potentiation • voluntary activation or high frequency stimulation • CMAP amp increases • Facilitation:-recruitment • Pseudo facilitation:-synchronisation of muscle activity
- 17. Neuromuscular junction disorders • Post synaptic • Myasthenia gravis • Organophosphorus poisoning • Curare induced paralysis • Congenital Myasthenic syndromes • Presynaptic • Botulism • LEMS • Magnesium induced paralysis • Combined defect • Gallamine, amino glycoside antibiotics, quinine, suxamethonium.
- 18. Repetitive nerve stimulation ( RNS) • Jolly in 1895 first described progressive reduction in visible muscle contraction in MG (Myaesthenic reaction) • Harvey and Masland(1941) reported electrical decremental muscle response on repetitive motor nerve stimulation. • Ekstedt in 1964 described SFEMG
- 19. RNS- technique • RNS is technically demanding procedure. • Poor electrode placement, sub maximal stimulation, movement artifacts, causes false positive results • Minimise artifacts • Immobilisation
- 20. RNS-technique • RNS is performed on selected motor nerves with recording by surface electrodes. • G1-motor point,G2-tendon • Supramaximal stimulus • Initial sharp negative deflection
- 21. Muscle selection • Clinically weak muscles should be selected. • Usually facial and proximal limb muscles shows greater abnormality than distal muscles. • Nerves involved in other diseases should be avoided. • Cholinesterase inhibitors should be stopped 12- 24 hrs before.
- 22. RNS PROTOCOL • Slow Repetitive Nerve Stimulation (RNS) is performed in following sequence • One Distal and one proximal motor nerves(preferable most involved muscles) • One Sensory nerve • RNS protocol – Resting or base line trace 6 trains at-least (10 trains are preferred) – Post 10 second exercise 6 trains – Post 1 minute exercise 6 trains – 1 minute post 1 minute exercise 6 trains – 2 minute post 1 minute exercise 6 trains – 3 minute post 1 minute exercise 6 trains – 4 minute post 1 minute exercise (optional) 6 trains – If decrement is noted, perform Post 10 second exercise stimulation 6 trains, for facilitation • In Myasthenia gravis persistent Decremental Response > 10% is abnormal. The maximum Decremental response is noted 2 or 3 minute post 1 minute exercise. • If patient is unable to perform exercise, fast RNS at 30Hz or 50Hz may be used.
- 23. Protocol For Evaluating Disorder Of NMJ • Warm the extremity (33 degree centigrade) • Immobilize the muscle as best as possible • Perform RNS at rest. After making sure that the stimulus is supramaximal, perform at 3 Hz RNS, normally there is a less than 10% decrement b/w the first and the fourth response.
- 24. Cont. Protocol If more than 10% decrement occurs and is consistently reproducible: Have patient perform maximal voluntary exercise & immediately repeat 3 Hz RNS post exercise. If a less than 10% decrement or no decrement: Have patient perform maximal voluntary exercise for 1 min & perform 3 Hz RNS immediately and at 1,2,3 and 4 mins. If a significant decrement occurs after 1 min exercise (post exercise Exhaustion), have patient perform maximal voluntary exercise again for 10 sec and immediately repeat RNS at 3 Hz to demonstrate repair of the decrement.
- 25. Cont. Protocol Perform RNS on one distal and one proximal muscles especially the weak muscles. If no decrement is found with a proximal limb muscle, a facial muscle can be tested. If the compound muscle action potential is low at baseline, have patient perform 10 sec exercise, then stimulate the nerve supramaximally immediately post exercise, looking for an abnormal increment response ( greater than 140% of the baseline). If the patient cannot exercises, rapid RNS should be used.
- 28. Slow RNS • supra maximal CMAP • 3–5 stimuli to a mixed or motor nerve at a rate of 2–3 Hz. • slow enough to prevent calcium accumulation, high enough to deplete the quanta • maximal decrease in Ach release occur after the first four stimuli • reproducible decrement • exercises for 10 seconds to demonstrate repair of the decrement (‘‘post-exercise facilitation’’) • If no decrement occurs -1 minute max voluntary exercise –”post exercise exhaustion”
- 29. Slow RNS
- 30. Rapid RNS • optimal frequency is 20–50 Hz,for 2–10 seconds • brief (10-second) period of maximal voluntary isometric exercise has the same effect as rapid RNS • Depletion of quanta vs calcium accumulation • Incremental response in LEMS
- 31. Rapid RNS
- 32. Patterns of response to slow RNS
- 33. RNS in pre and post synaptic disorders ParameterParameter Pre-synapticPre-synaptic Post-synapticPost-synaptic CMAP amplitudeCMAP amplitude SmallSmall NormalNormal Low rate RNSLow rate RNS RestingResting Post exercisePost exercise facilitationfacilitation Post exercisePost exercise exhaustionexhaustion DecrementDecrement PresentPresent AbsentAbsent DecrementDecrement PresentPresent PresentPresent High rate RNSHigh rate RNS IncrementIncrement Decrement orDecrement or normalnormal
- 34. Electrophysiological investigation • Nerve conduction studies-usually normal (low CMAP in LEMS) • Concentric needle EMG-usually normal • Repetitive nerve stimulation • Single fiber EMG
- 35. RNS in MYASTHENIA GRAVIS • Most commonly used test, easy. • RNS is relatively insensitive,10-50% in ocular myastenia,75% in generalised MG • RNS is relatively specific(90%) • SFEMG is Most sensitive.(90% in ocular,95% in MG) • Normal baseline CMAP • Greater than 10% decremental response at rest and post exercise • No role for high frequency stimulation
- 37. Baseline and 10sec exercise
- 39. Congenital Myasthenic Syndromes • Newborns of non-Myasthenic mothers. • No Ach R antibodies. • Respiratory distress, feeding difficulty, Ptosis are common. • Decremental response on 2 Hz RNS, abnormal SF-EMG. • End plate acetyl cholinesterase deficiency and slow channel syndrome , a repetitive CMAP is elicited by a single supramaximal stimulus.
- 40. Repetitive CMAP
- 41. Lambert Eaton Myasthenic Syndrome (LEMS ) • Weakness and fatigability of proximal muscles. • Relative sparing of EOM, bulbar muscles. • Hyporeflexia • Dry mouth • Associated with SCC lung • Antibodies against VGCC (voltage gated calcium channel)
- 42. LEMS
- 43. LEMS • Distal muscles RNS preferred • 3 pattern recognized • Low normal CMAP amplitude, decremental response at low rate RNS, normal at high rate. • Low CMAP amplitude, decremental response at low rate, and incremental response at high rate RNS (>100%)—classical triad. • Low CMAP amplitude, decremental low rate RNS, initial decrement at high rate RNS.
- 44. Incrementing response after brief exercise (10-15 sec) in LEMS. Increment is 10-fold, with CMAP of 3.2 mV. CP CMAP amplitude is 0.35 mV (normal >1 mV).
- 45. Incremental response in LEMS
- 47. Botulism • Defective release of Ach from nerve terminals. • It cleaves synaptic vesicle protein. • Extra ocular and bulbar weakness limb and respiratory weakness. • Blurred vision, dilated pupil, constipation, urinary retention. • Electro physiologically resemble LEMS
- 48. Botulism • Reduced CMAP in at least two muscles • At least 20 percent CMAP amplitude facilitation on tetanic stimulation • Persistance of facilitation atleast 2 minutes after activation • No postactivation exhaustion