Electrophysiological Tests in the Neuromuscular Junction Disorders Seung Hyun Kim, M.D., Hak Jae Roh, M.D.* Department of Neurology, School of Medicin

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1 Electrophysiological Tests in the Neuromuscular Junction Disorders Seung Hyun Kim, M.D., Hak Jae Roh, M.D.* Department of Neurology, School of Medicine, Hanyang University Department of Neurology, School of Medicine, Soonchunhyang University* Electrodiagnostic studies are valuable in confirming the diagnosis of a disorder of neuromuscular transmission. They are used to distinguish presynaptic and postsynaptic abnormalities. These studies provide an objective measure of the severity of the illness and may be useful in assessing the response to therapy. This article reviews the electrodiagnostic techniques that are commonly used today and highlights their specificity, sensitivity, and pitfalls. Repetitive nerve stimulation test (RNST) and single-fiber electromyography (SFEMG) are the most available electrophysiologic test in the diagnosis of neuromuscular junction disorders. RNS showing 10% decrement in amplitude from the first to fourth or fifth intravolley waveform while stimulating at 2~5 Hz is valid for the diagnosis of MG. The degree of increment needed for the diagnosis of LEMS is at least 25% but most accurate when greater than 100%. Abnormal jitter or impulse blocking are the appropriate criteria for diagnosis of NMJ disorders when using SFEMG. SFEMG is more sensitive than RNS for the diagnosis of disorders of neuromuscular transmission, especially in MG but may be less specific or may not be available. Key Words : Neuromuscular transmission, Myasthenia gravis, Lambert-Eaton myasthenic syndrome, Repetitive nerve stimulation, Single-fiber electromyography Address for correspondence Seung Hyun Kim Department of Neurology, Hanyang University Hospital Hengdang-dong 17, Seongdong-gu, Seoul , Korea Tel : Fax : kimsh1@hanynag.ac.kr Copyright 2002 by the Korean Society for Clinical Neurophysilology 171

Figure 1. Neuromuscular transmission. At normal neuromuscular synapses (right half of A & B), VGCC in the nerve terminal s specialized active zones open in response to a depolarizing impulse.

2 Figure 1. Neuromuscular transmission. At normal neuromuscular synapses (right half of A & B), VGCC in the nerve terminal s specialized active zones open in response to a depolarizing impulse. Ca 2+ entry facilitates fusion of synaptic vesicles with the active zone membrane where Ach is released. The binding of Ach to its post-synaptic receptor opens the receptor s ionic channel, depolarizing the muscle fiber. This triggers an action potential and fiber contraction.(a) In MG, antibodies cause a loss of functional AchRs. If this loss exceed a crucial level, there is insufficient post-synaptic depolarization to trigger an action potential, and the muscle fiber fails to contract.(b) In LEMS, antibodies reduce the number of pre-synaptic Ca 2+ channels. With a critical reduction of Ach release, there is failure to activate a sufficient number of post-synpatic receptors to trigger an action potential, and contraction does not occur. 172 J Korean Society for Clinical Neurophysilology / Volume 4 / November, 2002

3 α β γ δ α α α Figure 2. Generation of EPP and action potential J Korean Society for Clinical Neurophysilology / Volume 4 / November,

4 Figure 3. Generation of single-fiber action potential (SFAP) and compound muscle action potential (CMAP) Figure 4. Low rate stimulation(<5hz) in normal state Table 1. MEPP amplitude and quantal content in normal, MG and LEMS MEPP Amplitude resting quantal (quantal response, q) frequency content(m) Normal 1mV 0.2/sec 60~100 MG Low Normal Normal LEMS Normal Normal Low 174 J Korean Society for Clinical Neurophysilology / Volume 4 / November, 2002

5 Figure 5. Low rate stimulation in normal, MG and LEMS J Korean Society for Clinical Neurophysilology / Volume 4 / November,

6 Figure 6. High rate stimulation (>10Hz) in normal state Figure 7. High rate stimulation in normal, MG and LEMS. 176 J Korean Society for Clinical Neurophysilology / Volume 4 / November, 2002

7 Figure 8. post-tetanic or post-exercise response Figure 9. The relationship between EPPs, CMAPs, single-fiber EMG action potential (SFAPs) & CMAPs recorded in normal & myasthenic muscle. Normally, all EPPs reach the threshold for action potential generation, producing CMAPs of constant size. In MG, EPPs fail to reach threshold in some end-plate, which then do not produce APs or SFAPs. The CMAP, which represent the average number of APs, then falls. J Korean Society for Clinical Neurophysilology / Volume 4 / November,

A Figure 10. Post-activation facilitation in a patient with LEMS.(A) shows CMAP responses obtained with repetitive stimulation of the median nerve recording from abductor pollicis brevis muscle.

8 A Figure 10. Post-activation facilitation in a patient with LEMS.(A) shows CMAP responses obtained with repetitive stimulation of the median nerve recording from abductor pollicis brevis muscle.(b) shows results of repetitive stimulation after 10 seconds of maximum voluntary contraction B Figure 11. CMAPs evoked by RNS in patients with MG & LEMS. Top figure shows decremental response to low rate stimulations, early dip phenomenon & partial repair immediately after brief exercise. Increased decrements appears 2~4 minutes after 10 seconds of volitional exercise (post-activation exhaustion). Bottom figure shows low amplitude of CMAPs & decremental responses to low rate stimulation. Abnormal facilitation appears immediately after brief voluntary exercise (post-activation facilitation). 178 J Korean Society for Clinical Neurophysilology / Volume 4 / November, 2002

9 Figure 12. Decremental response in a patient with myasthenia gravis. Responses were obtained with repetitive stimulation of ulnar nerve at 3Hz, recording from abductor digiti minimi muscle. J Korean Society for Clinical Neurophysilology / Volume 4 / November,

10 µ Figure 13. Effect of temperature on the decrement at low rate stimulation in MG Figure 14. The effect of muscle temperature on the response of RNS in abductor digiti minimi muscle in a patients with MG.. The intramuscular temperature & the change in amplitude of 5 th response of each train are shown. 180 J Korean Society for Clinical Neurophysilology / Volume 4 / November, 2002

11 Figure 15. RNS studies at 3 Hz stimulation in the abductor pollicis brevis muscle of a patient with diabetic neuropathy & carpal tunnel syndrome. There is a 15% decrement in the 4 th response, and thereafter the CMAPs return toward the initial size. J Korean Society for Clinical Neurophysilology / Volume 4 / November,

12 Figure 16. An activation cycle characteristic for MG., demonstrating changes in the decrement induced by RNS before and at indicated intervals after activation by maximum voluntary contraction or tetanic nerve stimulation. The percentage change in CMAP amplitude of 4 th response of each train is noted. 182 J Korean Society for Clinical Neurophysilology / Volume 4 / November, 2002

13 Figure 17. Early dip phenomenon. The initial large decrement (stimuli 1 to 3) represent the depletion effect of a previous stimulus. The stabilization of the evoked response amplitude (stimuli 4 to 8) represent mobilization-related facilitation. J Korean Society for Clinical Neurophysilology / Volume 4 / November,

14 184 J Korean Society for Clinical Neurophysilology / Volume 4 / November, 2002

15 µ µ µ Figure 18. SFEMG recordings. A. Recording position of SFEMG electrode. B. Consecutive paired discharges at a slow sweep speed. C. Same pair of potentials at a faster sweep speed. D. Ten superimposed consecutive discharges demonstrating the neuromuscular jitter µ µ µ J Korean Society for Clinical Neurophysilology / Volume 4 / November,

16 Figure 19. SFEMG recordings. During voluntary activation of extensor digitorum communis muscle, normal jitters are shown in normal subject (left) and markedly abnormal jitter in patient with MG (right). 186 J Korean Society for Clinical Neurophysilology / Volume 4 / November, 2002

17 WL, Osserman KE. Immunofluorescence demonstration of a muscle binding, complement fixing serum globulin fraction in myasthenia gravis. Proc Soc Exp Biol Med 1960;105: Desmedt JE. The neuromuscular disorder in myasthenia gravis. In: Desmedt JE. New Developments in Electromyography and Clinical Neurophysiology. Basel: Karger. 1973; Botelho SY, Deaterly CF, Austin S, Comroe JH. Evaluation of the electromyogram of patients with myasthenia gravis. Arch Neurol Psychiatry 1952;67: Desmedt JE, Monaco P. Analyse electromyographique de l electivite possible de l atteinte myasthenique dans certains groupes musculaires. Revue Neurol (paris) 1960;103: µ Ozdemir C, Young RR. The results to be expected from electrical testing in the diagnosis of myasthenia gravis. Ann NY Acad Sci 1976;274: Horowitz SH, Krarup C. A new regional curare test of the elbow flexors in myasthenia gravis. Muscle Nerve 1979 ; 2: Sanders DB, Howard JF. Single-fiber electromyography in REFERENCES 01. Kendel ER, Schwartz JH, Jessell TM. Synaptic transmission. In: Principles of Neural Science. 3 rd ed. New York: Elsevier, 1991; Maselli RA. Pathophysiology of Myasthenia and Lambert- Eaton Syndrome. In: Neurologic Clinic. 1994; Oh SJ. Anatomical and Physiological Basis for Electromyography Studies In: Clinical Electromyography. 2nd ed. Baltimore: Williams and Wilkins. 1993; Jolly F. Ueber Myasthenia gravis pseudoparalytica. B e r l Klin Wochenschrr 1895;32: Kimura J. Principles of nerve conduction study. In: Kimura J. Electrodiagnosis in Diseases of Nerve and mus - cles. 2 nd ed. Philadelphia: Oxford. 1989; Strauss AJ, Seegal BC, Hsu KC, Burkholder RM, Nastuk myasthenia gravis. Muscle Nerve 1986;9: MacDermitt N, Schady W. Differential involvement of proximal muscles in myasthenia. J Neurol Neurosurg Psychiatry 1990;53: Borenstein S, Dwsmedt JE. Local cooling in myasthenia. Improvement in neuromuscular failure. Arch Neurol 1975;32: Borenstein S, Desmedt JE. Temperature and weather correlates of myasthenic fatigue. Lancet 1974;2: Howard JF, Sanders DB, Massey JM. The electrodiagnosis of myasthenia gravis and the Lambert-Eaton Myasthenic syndrome. Neurologic Clinics 1994;12: Desmedt JE. Methodes d etude de la function neuromus- culaire chez l homme. Acta Neurol Belg ; 5 8 : Singer PA, Lin JTY. Decremental response in carpal tunnel syndrome. Muscle Nerve 1982;5: Gilchrist JM, Sanders DB. Myasthenic U-shaped decrement in multifocal cervical radiculopathy. Muscle Nerve 1989;12: Slomic A, Rosenfalck A, Buchthal F. Electrical and mechanical responses of normal and myasthenic muscle. Brain Res 1968;10: Scoppetta C, Casali C, D Agostini S, La Cesa I, Parisi L. Repetitive stimulation in myasthenia gravis: decrementing response revealed by anticholinesterase drugs. EEG Clin Neurophysiol 1990;75: Tim RW, Sanders DB. Repetitive nerve stimulation studies in the Lambert-Eaton myasthenic syndrome. M u s c l e Nerve 1994;17: Desmedt JE, Borenstein S. Double-step nerve stimulation test for myasthenic block: sensitization of postactivation J Korean Society for Clinical Neurophysilology / Volume 4 / November,

18 exhaustion by ischemia. Ann Neurol 1977;1: Harvey AM, Masland RL. A method for the study of neuromuscular transmission in human subjects. Bull Johns Hopkins Hosp 1941;68: Gilchrist JM, Sanders DB. Double-step repetitive nerve stimulation in myasthenia gravis. Muscle Nerve ; 1 0 : Horowitz SH, Genkins G, Kornfield P. Electrophysiologic diagnosis of myasthenia gravis and the regional curare test. Neurology 1976;26: Ricker KW, Hertel G, Reuther P. Repetitive proximal nerve stimulation and systemic curare test in myasthenia gravis. Ann NY Acad Sci 1981;377: Foldes FF, Klonymus DH, Maisel W, Osserman KE. A new curare test for the diagnosis of myasthenia gravis. JAMA 1968;203: Ekstedt J. Human single muscle fiber action potentials. Acta Physiol Scand1964;suppl 226; Sanders DB, Howard JF, Jr. Johns TR. Single-fiber electromyography in myasthenia gravis. Neurology ; 2 9 : Stalberg E, Trontelj JV. Single fiber electromyography. 2 nd ed. New York: Raven Press, 1994; Sunwoo IN. Diagnostic Value of Single Fiber Electromyography in Myasthenia Gravis in Korea. J Korean Neurol Assoc 1986;6: Trontelj JV, Mihelin M, Fernandez JM, Stalberg E. Axonal stimulation for end-plate jitter studies. J Neurol Neurosurg Psychiatry 1986;49: Stalberg E, Schiller HH, Schwartz MS. Safety factor in single human motor end-plate studies in vivo with singlefiber electromyography. J Neurol Neurosurg Psychiatry 1975;38: Murga L, Sanchez F, Menendez C, Castilla JM. Diagnostic yield of stimulation and voluntary single-fiber electromyography in myasthenia gravis. Muscle Nerve 1998;21: Kim DS, Park KH. Clinical Significance of Axonal Stimulation Single Fiber Electromyography in Patients with Myasthenia Gravis. J Korean Neurol Assoc 2000 ; 18(4): J Korean Society for Clinical Neurophysilology / Volume 4 / November, 2002

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975_983 특집-한규철, 정원호 Focused Issue of This Month Gyu Cheol an, MD Department of Otolaryngology ead & Neck Surgery, Gachon University of College Medicine E - mail : han@gilhospital.com Won-o Jung, MD Department of Otolaryngology