3. Disorders of the NMJ.pdf

Disorders of the Neuromuscular Junction Dr. Tariq Alfahad 19’ 20’ Arwa Alkhannah [email protected] Bold = exam i used batch 18" tafreegh and added what the dr said in blue good luck guys! hesah alsunaideh He concentrated in the first 2 disorders, and just read the last 2 Everything in bol...

Disorders of the Neuromuscular Junction Dr. Tariq Alfahad 19’ 20’ Arwa Alkhannah [email protected] Bold = exam i used batch 18" tafreegh and added what the dr said in blue good luck guys! hesah alsunaideh He concentrated in the first 2 disorders, and just read the last 2 Everything in bold is important and exam material Myasthenia Gravis (MG) Lambert Eaton myasthenic syndrome (LEMS) Botulism Organophosphate exposure (OE) Cause Auto-antibodies @post-synapstic junction Auto-antibodies @pre-synaptic junction Reduced stimulation of nicotinic + muscarinic receptors Clostiridium botulinum neurotoxin (cleaves SNARE) @pre-synaptic junction 1- home canned food 2- open wound (I.V drugs) 3- Botox treatment Pesticides -> irreversible inhibition of AChE Clinical features 1- Fatiguability 2- Ocular weakness (most common) -> ptosis + diplopia but normal pupil size 3- face weakness+snarl smile 4- dysarthria + dysphagia 5- MG crisis= MG + Respiratory Failure Nicotinic 1- proximal leg weakness (in majority) 2- Eye+bulbar problems (sometimes) 3- Post-exercise facilitation Muscarinic 5- Dry mouth + constipation Descending muscle weakness +Muscarinic symptoms 1- dry mouth 2- constipation 3- dilated pupils 1- Peripheral + central muscarinic stimulation 2- peripheral nicotinic stimulation Muscle involvement Descending order / slow Normal deep tendon reflexes Ascending order / slow Absent deep tendon reflexes Descending order / Rapid Associated conditions 1- other AID (hyperthyroidism) 2- Thymoma in 10% of cases 1- small lung cancer (SCLC) 2- paraneoplastic syndrome Diagnostic studies 1- Ice-pack test 2- Tension test 3- AchR-Ab in 85% of MG 4- MuSK-Ab in 50% who are AchR Abs negative VGCC-Abs in 95% Toxin isolation Repetitive nerve stimulation Decremental response Incremental response Incremental response Treatment 1- Pyridostigmine 2- Glucocorticoids 3- MG crisis -> IVIg or PE 4- Thymectomy 3,4-diminopyridine (3,4-DAP) 1- toxin removal 2- penicillin G 3- botulinum antitoxin 1- Atropine 2- Pralidoxime Upper Motor Neuron Lower Motor Neuron You need to know the difference btw UML and LML Upper Motor Neuron Lower Motor Neuron Upper Motor Neuron Lower Motor Neuron Introduction He said go through the physiology by yourself Not included in the exam Action potential Normal physiology of NMJ this is the LMN Ca2+ Voltage-gated calcium channel Ach vesicle Presynaptic Synaptic Acetylcholine Receptor Postsynaptic Acetylcholinesterase Normal physiology of NMJ Steps: 1. 2. 3. 4. 5. 6. 7. 8. 9. Action potential reached axon terminal Open voltgage-gated calcium channels Calcium influx Triggers vesicles exocytosis SNARE protein help attach vesicle to membrane ACh release into synaptic cleft ACh activates nicotinic ACh receptors on postsynaptic membrane Na+ entry and trigger muscle contraction Ach inactivated by: 1. Acetylcholine esterase (AchE) 2. Escapes out of the synaptic cleft ④ ③ ① ② Neuromuscular junction disorders ① Myasthenia gravis exam loot ② Lambert eaton myasthenic syndrome Foy in exam ③ Botulism got ! it can be 100% ④ Organophosphate exposure lot Myasthenia gravis (MG) MG is important the dr said he's bringing 1/2 questions abt it MG (cause) this is an autoimmune disease rare exam metarial • Antibodies destroy nicotinic acetylcholine receptors at the post-synaptic junction on individual muscle fibers à ↓ numbers of receptors • Acetylcholine release is NORMAL its a postsynaptic problem so everything in the LMN is normal @RECEPTOR LEVEL weakness MG (associated conditions) 1. Other autoimmune disease • Especially hyperthyroidism 2. Thymoma in 10% of cases tumor of the thymus gland exam. MG (clinical picture) • General rules: When you see Fatigability think MG - 25 year female present w/ weakness the patient starts with normal strength and as she's using the muscle more it starts to get more and more fatigue • Fatigability of some muscles with repetitive muscle contraction in morning (normal) / later as they use their Descending order of muscle involvement muscle they get Sensation & reflexes are NORMAL Motor only weaker. • Diurnal variation • • so this fatiguability is with use, and at the end of the day Eye Face Bulbar MG (clinical picture) • Eye (most common) • Face weakness • Bulbar • Proximal muscles • Respiratory muscles (MG crisis) Months/ years Descending Proximal muscle Eye Face Bulbar MG (clinical picture) [Eye symptoms] Smallest and most used skeletal muscles • Ocular weakness is the most common finding in MG • 2/3 of MG present with ptosis & diplopia • Pupil size is NORMAL 7 Because it’s controled by Autonomic nervous system • 15% of patients have pure ocular MG Proximal muscle Eye Face Bulbar Proximal muscle MG (clinical picture) [Eye symptoms] • Ptosis: drooping eyelid After 2 minutes of looking up After using the eye Eye Face Bulbar Proximal muscle MG (clinical picture) [Eye symptoms] both eyes • Diplopia (double vision) • Seeing 2 images of an object instead of 1 image YEoccurs when the eyes are not properly aligned, and the image of an object that projects onto one retina does not fall spatially to the matching point on the other retina. the muscles of one eye are weakened while the other eye is normal so when the images are sent to the back of the brain they're not gonna be properly aligned and i'll be seeing 2 images Eye Face Bulbar Proximal muscle MG (clinical picture) [face symptoms] Face weakness Snarl smile Eye Face Bulbar Proximal muscle MG (clinical picture) [Bulbar symptoms] • Dysarthria: difficulty with articulation • Especially after speaking for some time • Dysphagia: difficulty with swallowing • Mild cause chocking & nasal regurgitation gum-end of meal When they are chewing gum they are using the muscles So after that if they decided to eat a meal they will have a di culty • Respiratory muscle weakness can occur (MG crisis) (life threating) Eye Face Bulbar Proximal muscle MG (clinical picture) [proximal muscle weakness] • Difficulty walking up stairs the dr gave an example of a student in shdadeyah that has a problem going to lectures upstairs -> proximal weakness and ended up diagnosed by MG proximal muscles =shoulder+hip muscles • Difficulty lifting objects above head-level using the shoulder muscles proximal y use muscle Peripheral neuropathy more distal muscle icepack Tensilon Antibody MG (Diagnostic studies) *Icepack test 1. Tensilon test 2. Autoantibodies 3. Repetitive nerve stimulation 4. Chest CT scan RNS CT icepack Tensilon Antibody RNS CT MG (Diagnostic studies) • Ice-pack test: Now it is used as an observation not a diagnosis • Apply icepack to ptosis for 2 minutes à improvement Improved icepack Tensilon Antibody RNS CT (not used anymore) (test-material) MG (Diagnostic studies – Tensilon test) • Tensilon (edrophonium) is an acetylcholinesterase inhibitor • IV Tensilon à ↓Ach destruction by AchE at synaptic cleft à ↑ Ach à rapid improvement of symptoms minutes o IV Tensilon administered tensilon isnt used for treatment, why? short duration of action ‫راح يروح تاثيره عقب جم دقيقه‬ o Short recovery icepack Tensilon Antibody RNS CT MG (Diagnostic studies – repetitive nerve stimulation) the idea here is that we put a needle in the muscle, connect it to the machine and start giving electrical stimulation that would result in the contraction of the muscle • Stimulate a muscle @3Hz à decremental response in MG Normal resppnse ideally u should get the same strength AP everytime exam Decremental response muscle strength /. decreate. S icepack Tensilon Antibody RNS CT MG (Diagnostic studies – Autoantibodies) • Acetylcholine receptor antibodies (AchR-Ab) are found in 85% of MG patients • Only in 50% in patients who have only ocular symptoms • Muscle specific receptor tyrosine kinase (MuSK) antibodies • Found in 50% of whose who are AchR-Ab negative there are other Abs, but we test only for these 2 Used if AchR-Ab test is negative icepack Tensilon Antibody RNS MG (Diagnostic studies – CT scan) • All patients with MG should have a chest CT scan to rule out thymoma CT MG (Treatment) • Symptomatic treatment Benign • Pyridostigmine: longer acting AchE inhibitor is the initial therapy in MG • Adverse effect: muscarinic effects like stomach cramps & diarrhea give medication to block muscarinic effects MG (Treatment) If Pyridostigmine doesn’t work we use • Immune therapies exam • Glucocorticoids are effective, but have side effects with longterm use • Steroid-sparing medications: • To avoid longterm side effects of glucocorticoids Don’t memorize • Like zathioprine, cyclosporin, rituximab Used for almost all immune mediated disease MG (Treatment) → diffucty breathing • MG Crisis management crisis meaning that he has a respiratory failure and MG • IVIg (IV immunoglobulin) or PE (plasma exchange) ↳ give patient Ig which bind to the Anti-ACH recptor Ab and clear it out of the system faster recovery draw blood from the patient in one arm ,goes to machine, remove all the protiens and send the blood back to the patient • Thymectomy: removal of the thymus gland • In case of thymoma patient with MG even if there is no thymoma • Recommended if: patient <60, Ach-R Ab positive, & generalized MG Lambert Eaton myasthenic syndrome (LEMS) LEMS (cause) 1- the problem here is presynapstic 2- it affects voltage gated calcium channel receptors • Antibody against the presynaptic VGCC à ↓influx of calcium à ↓Ach release à • ↓ stimulation of nicotinic receptors in muscles • ↓ stimulation of muscarinic receptors in parasympathetic nervous system All neurons that use ach will be a ected 1- somatic (nicotinic receptors ) 2- parasympathetic (muscarinic receptors ) (If it’s postsynaptic junction only the muscles is a ected ) Cholinergic neurons Somatic UMN CNS LMN Ganglion (N2) Target organs (M) ➡ weakness Muscle (N1) LEMS (cause) exam • Associated with small cell lung cancer in 50-70% of cases exam Q • Paraneoplastic syndrome: Disorders in which the effects of cancer occur at a site remote from the primary tumor LEMS (clinical picture) just know that it is mostly in the leg and then it’s ascends and a ect the eyes majority of patients have proximal leg weakness, some of them might have eye problems • ↓ stimulation of nicotinic receptors: • Slowly progressive legs weakness & fatigue • Falling, difficulty getting out of chair, gait instabilty Ascending weak proximal muscle G • Eyes & bulbar symptoms can appear later in the disease course, but only in <30% of patients • On examination: absent deep tendon reflexes MG have normal reflexes LEMS (clinical picture) exam • “post-exercise facilitation” We can tell the patient to exercise and then try the re ex or we can repeat the re ex • brief muscle action for 5-10 seconds à transient increase in strength in these patients if u stimulate the muscle more, it gets stronger for some time • Even reflexes may return briefly after muscle activation when u do knee reflex in these patients for the first time tehre is no reflex, when u do it after some time you'll start having a reflex • Unique finding in LEMS • HOWEVER, further muscle contraction will lead to fatiging weakness Short duration of contraction à back-to-back depolarization at nerve terminal à calcium enter faster than leave à Ca2+ accumulation à surge in Ach release à stronger contraction LEMS (clinical picture) • ↓ stimulation of muscarinic receptors: • Autonomic symptoms are common, most often dry mouth & constipation LEMS (Diagnostic studies) • Antibodies against VGCC in up to 95% of patients • Repetitive nerve stimulation: • Incremental response with high frequency repetitive stimulation • CT chest to look for small cell lung cancer imaging every 6 month for 5 years. compare it to MG LEMS (Treatment) Just know this • 3,4-Diaminopyridine (3,4-DAP) • Potassium channel blocker à prolong depolarization à ↑Ach release ✅Stonger contraction. Exam question : Q) MG or LEMS A)Decremental response b) ⬆deep tendon reflex w/exercise C) no response to Pyridostigmine D) CT scan negative E) antibodies for voltage gated CC Botulism no details needed about this disease Botulism (cause) • Clostridium botulinum neurotoxin • Sources: • home canned foods, open Wounds, Botox treatments L ↳ in Kuwait. e. g Iv drugs Botulism (cause) perment damage • Botulinum toxin à cleaves SNARE proteins à prevent fusion of Ach vesicles with presynaptic membrane à no Ach release • It takes weeks to months to recover when new NMJ are formed Botulism (clinical picture) • Symptoms occurs rapidly after exposure decending • “descending weakness”: eye à bulbar à arms & legs à feet . • Muscarinic symptoms: dry mouth, constipation, & dilated pupils Botulism (diagnostic studies) • Toxin isolation in: • Blood, remaining food, vomitus, stool, in open wound • Repetitive nerve stimulation: incremental response presynaptic disorders -> incremental response -> increases gradually postsynaptic disorders -> decremental response -> decreases gradually Botulism (treatment) • Toxin removal • Gastric lavage • Wound cleaning • Penicillin G • Botulinum antitoxin monitor for resp failure. Organophosphate exposure (OE) no details needed here OE (cause) • Accidental exposure to agricultural spraying(pesticides) sudden increase • OE à irreversible inhibition of AChE à ↑↑↑ Ach stimulation of both nicotinic & muscarinic receptors all vesicles are released at once In the synapse Don't remember symptoms remember concept OE (clinical picture) • Peripheral muscarinic stimulation: • Diarrhea, vomiting, sweating, etc… • Central muscarinic stimulation: • Confusion, anxiety, coma… • Peripheral nicotinic stimulation: • Proximal muscle weakness • Respiratory failure OE (treatment) • Supportive • Atropine: • Competes for Ach at muscarinic receptors • Effective for muscarinic hyperstimulation • Pralidoxime: • Is a cholinesterase reactivating agent • Help in nicotinic & muscarinic symptoms MG Slow LEMs Slow Descending B fast Descending Descending É o Thank you & best luck tasty MO 8 [email protected] O most important not in the exam, this is just an intro for the disorders Thank you & best luck [email protected]