Myasthenia Gravis (Part 1): Introduction, Pathophysiology & Clinical Features | Harrison Simplified — Transcript

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1. 0:01Welcome. Today we are diving deep into
2. 0:04myastthenia gravis and other diseases of
3. 0:06the neuromuscular junction. Mythenia
4. 0:09gravis is a neuromuscular junction
5. 0:12disorder. It is characterized by two
6. 0:14hallmark features. Weakness and fatigue
7. 0:18ability of skeletal muscles.
8. 0:21Now what is the underlying defect? The
9. 0:24fundamental problem is a decrease in the
10. 0:26number of available acetylcholine
11. 0:28receptors at the neuromuscular junctions
12. 0:31and this happens due to an antibbody
13. 0:33mediated autoimmune attack. Available
14. 0:36treatments for MG are highly effective.
15. 0:38However, side effects can limit their
16. 0:41use and a cure has remained elusive.
17. 0:44To truly understand MG, we must first
18. 0:47understand how the normal neuromuscular
19. 0:49junction works. At the neuromuscular
20. 0:52junction, acetylcholine is synthesized
21. 0:55in the motor nerve terminal and stored
22. 0:57in vesicles, also called quanta. When an
23. 1:01action potential travels down a motor
24. 1:03nerve and reaches the nerve terminal, AC
25. 1:06from 150 to 200 vesicles is released.
26. 1:10This AC then combines with ACRs which
27. 1:14are densely packed at the crests of post
28. 1:17synaptic folds on skeletal muscle. This
29. 1:20permits the rapid entry of cations ions
30. 1:22chiefly sodium which produces
31. 1:24depolarization at the end plate region
32. 1:27of the muscle fiber. If this
33. 1:29depolarization is sufficiently large it
34. 1:32initiates an action potential that
35. 1:33propagates along the muscle fiber
36. 1:36triggering muscle contraction. This
37. 1:38process is then rapidly terminated by
38. 1:41two mechanisms. First hydraysis of AC by
39. 1:45acetal colonsterase which is present
40. 1:47right within the synaptic cleft. Second
41. 1:50diffusion of AC away from the receptor.
42. 1:54Now the ACR has a very specific
43. 1:57structure. It consists of five subunits
44. 2:01arranged around a central pore. These
45. 2:03five subunits are two alpha subunits,
46. 2:06one beta subunit, one delta subunit and
47. 2:09one gamma or epsilon subunit.
48. 2:12When AC combines with the binding sites
49. 2:15on the alpha subunits of the ACR, the
50. 2:18channel opens. Influx of the cations
51. 2:21ions, chiefly sodium, into the muscle
52. 2:23cell serves as the electrical engine
53. 2:26driving the depolarization of the end
54. 2:28plate region of the muscle fiber. Now
55. 2:30let us talk about some critical proteins
56. 2:32at the NMJ. Agrin is released from the
57. 2:36presinaptic motor nerve terminal. It
58. 2:39then binds lowdensity lipoprotein
59. 2:41receptor related protein 4 known as
60. 2:44LRP4.
61. 2:45This aggrin LRP4 complex activates Musk.
62. 2:50Musk activation then facilitates the
63. 2:52recruitment of cytoplasmic proteins
64. 2:55including downstream of tyrrosine kynise
65. 2:577 called DOC7 and Rapsin to assist in
66. 3:02clustering the ACRs.
67. 3:04Muscle specific tyrrosine kinase or musk
68. 3:07is a post-saptic transmembrane protein
69. 3:10that helps stabilize posts synaptic
70. 3:12clustering of ACRs.
71. 3:15These proteins musk, LRP4, DOC7 and
72. 3:19Rapsin are important not only in the
73. 3:22pathogenesis of MG but also in some
74. 3:24hereditary congenital mythenic
75. 3:26syndromes.
76. 3:28So what goes wrong in mythenia gravis?
77. 3:31In MG, the fundamental defect is a
78. 3:34decrease in the number of available
79. 3:36ACHRs at the post synaptic muscle
80. 3:39membrane. Additionally, the post
81. 3:41synaptic folds are flattened, reducing
82. 3:43the total surface area. So although AC
83. 3:47is released normally, it produces only
84. 3:49small end plate potentials which may
85. 3:52fail to trigger muscle action potentials
86. 3:54and the failure of transmission results
87. 3:56in muscular weakness.
88. 3:59Now here is an important concept.
89. 4:01Preinaptic rundown. The amount of AC
90. 4:05released per impulse normally declines
91. 4:08on repeated activity. This is called
92. 4:10presinaptic rundown. In healthy
93. 4:13individuals, the starting amplitude is
94. 4:15so high that this dip has no clinical
95. 4:18effect. In my aesthetic patients, the
96. 4:20already reduced efficiency of
97. 4:22neuromuscular transmission combined with
98. 4:25this normal presinaptic rundown results
99. 4:27in activation of fewer and fewer muscle
100. 4:30fibers by successive nerve impulses. The
101. 4:33result increasing weakness known as
102. 4:36mythenic fatigue. This same mechanism
103. 4:39also explains the decremental response
104. 4:41to repetitive nerve stimulation seen on
105. 4:43electrodiagnostic testing.
106. 4:47Now mythenia is an autoimmune disorder.
107. 4:50It is most commonly caused by anti-ACCR
108. 4:53antibodies. These anti-ACCR antibodies
109. 4:57reduce the number of available ACRs at
110. 4:59the NMJ by three distinct mechanisms.
111. 5:03Mechanism one accelerated turnover of
112. 5:06ACRs.
113. 5:07This occurs by cross-linking and rapid
114. 5:10endoccytosis of the receptors. Mechanism
115. 5:13two, damage to the post synaptic muscle
116. 5:16membrane through antibbody mediated
117. 5:18complement activation. Mechanism three
118. 5:21blockade of the active site of the ACR
119. 5:24that is the site that normally binds AC.
120. 5:28Now mythenia is not only about anti-ACR
121. 5:32antibodies. Anti-ACCR antibodies are
122. 5:35most common overall with predominant
123. 5:37subclass being IGG1 and IGG3.
124. 5:41They cause high levels of compliment
125. 5:43activation and they mostly exert their
126. 5:45clinical effects via the three
127. 5:46mechanisms as discussed. However, an
128. 5:49immune response to MUSK also results in
129. 5:52MG with experimental evidence showing
130. 5:54reduction of ACRs.
131. 5:57AntiMUSK antibbody occurs in
132. 5:59approximately 10% of patients and
133. 6:01approximately 40% of ACR antibbody
134. 6:04negative patients with generalized MG.
135. 6:08Now an important distinction, MUSK
136. 6:11antibodies exert their pathogenic effect
137. 6:13by directly inhibiting the binding
138. 6:15between MUSK and LRP4 leading to loss of
139. 6:19ACRs and other MUSK functions.
140. 6:22Critically, MUSK antibodies are of the
141. 6:25IGG4 subtype. As IG4, they do not
142. 6:29activate compliment. Therefore, antimusk
143. 6:32positive MG does not respond to
144. 6:34compliment inhibition. Another 1 to 3%
145. 6:38of patients have antibodies against
146. 6:39LRP4, another critical NMJ protein. LRP4
147. 6:44antibodies in contrast are of the IGG1
148. 6:47subclass. They do cause compliment
149. 6:50mediated destruction similar to ACR
150. 6:53antibodies and possibly interrupt a
151. 6:55induced MUSK activation. Now these
152. 6:58pathogenic antibodies are of the IGG
153. 7:01class and are TE-C cell dependent. This
154. 7:03is why immunotherrapeutic strategies
155. 7:05that target antibbody producing B cells
156. 7:08or helper tea cells or directly reduce
157. 7:10the pathogenic antibodies or block
158. 7:13compliment mediated destruction of ACRs
159. 7:16are all effective in anti-acr positive
160. 7:19MG. Although MG is driven by auto
161. 7:22antibodies, a significant contribution
162. 7:24exists from TE-C cells, particularly T-
163. 7:27regulatory cells. T-reg cells are
164. 7:30critical in suppressing activation of
165. 7:31other immune cells that have escaped
166. 7:33negative selection in the thymus. When
167. 7:36these cells escape negative selection
168. 7:37and are not suppressed in the periphery,
169. 7:39they attack self antigens. Deficiency or
170. 7:43dysfunction of T-reg cells contributes
171. 7:45to the pathogenesis of MG and many other
172. 7:47autoimmune diseases as well. The primary
173. 7:50source of T-reg cells is the thymus and
174. 7:53the thymus is abnormal in approximately
175. 7:5575% of patients with anti-ACCR positive
176. 7:58MG. Breaking this down further, in
177. 8:01approximately 65% the thymus is
178. 8:04hyperlastic with active germinal centers
179. 8:06detected on histologology. Note the
180. 8:09hyperlastic thymus may or may not be
181. 8:11enlarged. An additional 10% of patients
182. 8:14have thymic tumors called thyomomas.
183. 8:17Muscle-like cells within the thymus
184. 8:19called myoid cells express ACRs on their
185. 8:22surface. These myoid cells may serve as
186. 8:25a source of auto antigen and may trigger
187. 8:27the autoimmune reaction right within the
188. 8:29thymus gland.
189. 8:33Let us now move to the clinical features
190. 8:35of MG. In terms of epidemiology, MG has
191. 8:39an incidence ranging from 6.3 to 29 per
192. 8:43million. Its prevalence ranges from 100
193. 8:47to 361 per million. Overall, women are
194. 8:51affected more frequently than men in a
195. 8:54ratio of approximately 3:2.
196. 8:57It affects individuals in all age
197. 8:59groups, but peak incidence occurs in
198. 9:01women in their 20s and 30s and in men in
199. 9:04their 50s and 60s. The cardinal features
200. 9:08of MG are two weakness and fatigue of
201. 9:12muscles. Mythenic weakness often worsens
202. 9:15during repeated use that is with fatigue
203. 9:18and or late in the day. It may improve
204. 9:21following rest or sleep. The clinical
205. 9:24course of MG is variable. Exacerbations
206. 9:28and remissions may occur particularly
207. 9:30during the first 1 to 3 years after
208. 9:33disease onset. In approximately 85% of
209. 9:37patients, mythenic weakness becomes
210. 9:39generalized affecting facial, bullbar,
211. 9:43axial and limb muscles in addition to
212. 9:45ocular muscles. If weakness remains
213. 9:48restricted to ocular muscles for 3
214. 9:51years, future generalization is unlikely
215. 9:54and these patients are said to have
216. 9:56ocular MG. However, rare patients have
217. 10:00been seen to generalize more than 5
218. 10:02years after onset of ocular MG.
219. 10:05Unrelated infections, systemic disorders
220. 10:08or tapering of MG therapies can lead to
221. 10:11increased mythenic weakness and may
222. 10:14precipitate mythenthenic exacerbation or
223. 10:17crisis. Some exacerbations, however,
224. 10:20occur without any identifiable
225. 10:22precipitating factors. The distribution
226. 10:25of muscle weakness in MG has a
227. 10:27characteristic pattern. Let us go
228. 10:29through each region systematically.
229. 10:32Cranial muscles, particularly
230. 10:34extraocular and eyelid muscles, are
231. 10:37frequently involved early in the course
232. 10:39of MG. Dipopia and tossis are common
233. 10:42initial symptoms. Facial weakness
234. 10:45produces a snarling expression when the
235. 10:47patient attempts to smile. Weakness in
236. 10:50chewing is most noticeable after
237. 10:52prolonged effort or when chewing hard or
238. 10:55tough foods like meat. Speech may have a
239. 10:58nasal tamber caused by weakness of the
240. 11:01pallet or a disartharthric mushy quality
241. 11:04due to tongue weakness. Horarsseness can
242. 11:07occur from luringial weakness.
243. 11:09Difficulty in swallowing, dysphasia may
244. 11:12occur as a result of weakness of the
245. 11:14pallet, tongue or ferinx giving rise to
246. 11:18nasal regurgitation or aspiration of
247. 11:20liquids or food. Important note here,
248. 11:24bullbar, neck and ventilatory weakness
249. 11:26can be especially prominent in musk
250. 11:29antibbody positive MG. Weakness in neck
251. 11:32extensor muscles can lead to head drop.
252. 11:36Limb weakness in MG is often proximal
253. 11:38and may be asymmetric. However, some
254. 11:42patients manifest with mainly distal
255. 11:44weakness such as finger and wrist drop
256. 11:47or foot drop. There are few important
257. 11:50negatives to remember. Deep tendon
258. 11:52reflexes are typically preserved.
259. 11:55Sensory symptoms, sensory loss, and pain
260. 11:58are absent. Now, two important clinical
261. 12:02definitions. If ventilatory weakness
262. 12:05necessitates intubation or non-invasive
263. 12:08ventilation to avoid intubation, the
264. 12:10patient is said to be in MG crisis. All
265. 12:14other worsening short of that threshold
266. 12:16is termed an exacerbation.
267. 12:19And that brings us to the end of
268. 12:21introduction pathophysiology and
269. 12:23clinical features of mythenia gravis. If
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272. 12:30next part, we will discuss the diagnosis
273. 12:33and management of myastthenia gravis.
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