Neuromuscular junction disorders Notes

NOTES NOTES NEUROMUSCULAR JUNCTION DISEASES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders impairing neuromuscular transmission lead to muscle fatigability, weakness CAUSES ▪ Autoantibody production ▫ Targeted against neuromuscular transmission pathway proteins ▪ Myasthenia gravis (MG) ▪ Lambert–Eaton myasthenic syndrome (LEMS) ▪ Transient acquired neonatal myasthenia ▪ Genetic mutation ▫ Affecting pathway components (e.g., congenital myasthenia) COMPLICATIONS ▪ Respiratory muscles involved → potentially fatal respiratory failure SIGNS & SYMPTOMS ▪ Primary clinical manifestation ▫ Painless muscle weakness without significant muscle atrophy ▫ Ocular, extraocular, oropharyngeal, bulbar, neck, limb, respiratory muscles DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Thymoma (MG) ▪ Small-cell lung carcinoma (LEMS) LAB RESULTS ▪ Serologic test for specific antibodies OTHER DIAGNOSTICS Electrophysiologic study ▪ Repetitive nerve stimulation ▫ Decremental response/improvement ▪ Electromyogram ▫ ↓ muscle action potential Pulmonary function test (PFT) ▪ Periodically ▫ Detect respiratory muscle involvement in forced vital capacity (FVC) ↓ TREATMENT ▪ Treat underlying cause (e.g. LEMS malignancy) MEDICATIONS ▪ Acetylcholinesterase inhibitors ▫ Inhibit acetylcholine degradation → ↑ acetylcholine concentration in neuromuscular junction (symptomatic therapy) ▪ Immunomodulating agents ▫ ↓ autoantibody production ▫ Individuals with poor acetylcholinesterase inhibitor response ▫ Corticosteroids/other immunosuppressive agents ▪ If above fails/emergency (e.g., myasthenic crisis) ▫ Plasmapheresis/intravenous immunoglobulin (IVIG) OSMOSIS.ORG 661

LAMBERT–EATON MYASTHENIC SYNDROME (LEMS) osms.it/lambert-eaton-myasthenic PATHOLOGY & CAUSES ▪ Rare autoimmune disorder ▫ Autoantibodies inhibit presynaptic calcium channels on motor neurons → reduced acetylcholine release in neuromuscular junction ▪ Muscle weakness ▫ Improves temporarily after repeated muscle use (no significant muscle atrophy) ▪ Mostly affects somatic nervous system, can also affect autonomic nervous system’s parasympathetic part ▪ Middle-aged adults (most cases) CAUSES Type II hypersensitivity reaction ▪ B cells produce antibodies that target, block voltage-gated calcium channels located presynaptically on motor neurons → only few unbound channels available to open, allow calcium in → ↓ calcium within neuron (insufficient to trigger acetylcholine release) → ↓ acetylcholine release in neuromuscular junction → attached muscle fiber does not contract ▪ Repeated stimulation by brain’s electrical impulses → enough calcium might get through remaining unbound calcium channels → acetylcholine release → muscle contraction RISK FACTORS ▪ Malignancy ▫ Strong small-cell lung cancer association; stimulus for antibody production is same calcium channel expression in neoplastic cells ▫ Other associated malignancies include 662 OSMOSIS.ORG lymphoproliferative disorders (e.g., Hodgkin’s lymphoma) ▪ Autoimmune diseases ▫ Hashimoto’s thyroiditis, diabetes mellitus type 1, vitiligo COMPLICATIONS ▪ Respiratory muscle involvement → respiratory failure ▪ Underlying malignancy → can lead to death SIGNS & SYMPTOMS ▪ Progressive, symmetrical proximal muscle weakness (e.g., shoulders, hips, thighs) → difficulty climbing stairs/standing when seated ▫ Paraneoplastic LEMS: more rapidly progressive course ▪ Warming-up phenomenon ▫ Repeated muscle use → weakness temporarily relieved ▪ Reflex strength ↓ ▫ Muscle activation → reflex recovery/ improvement ▪ Small minority ▫ Ocular, oropharyngeal muscle involvement ▪ Advanced stages ▫ Possible respiratory muscles involvement → respiratory failure (myasthenic crisis) ▪ Autonomic symptoms ▫ Dry mouth (most common), constipation, blurry vision, erectile dysfunction, urinary problems, syncope

Chapter 85 Neuromuscular Junction Disorders DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Chest ▫ Detect underlying small-cell lung cancer ▪ Abdomen, pelvis also recommended ▪ Negative initial malignancy evaluation ▫ Periodical screening recommended LAB RESULTS ▪ Serological tests ▫ Detect antibodies against the voltagegated calcium channels OTHER DIAGNOSTICS ▪ Electrophysiologic studies ▫ Repetitive nerve stimulation: ↑ muscle action potential amplitude ▫ Electromyogram: ↑ muscle action potential amplitude after exercise ▪ PFT ▫ ↓ FVC → respiratory muscle involvement TREATMENT MEDICATIONS ▪ Symptomatic therapy ▫ Acetylcholinesterase inhibitors: minimal effect ▫ Aminopyridines: block potassium channels → prolonged nerve membrane depolarization → ↑ calcium entry → ↑ acetylcholine release in neuromuscular junction ▪ If above methods fail ▫ Immunomodulating agents can be used (corticosteroids, other immunosuppressive agents) OTHER INTERVENTIONS ▪ Occasionally treated with IVIG/ plasmapheresis ▫ More severe cases MYASTHENIA GRAVIS osms.it/myasthenia-gravis PATHOLOGY & CAUSES ▪ Autoimmune disorder; significant skeletal muscle weakness ▫ Decreased acetylcholine receptor function → worsens with muscle use ▫ Most common neuromuscular junction disorder ▪ Type II hypersensitivity reaction ▫ B cells produce antibodies against postsynaptic nicotinic acetylcholine receptors of neuromuscular junction/ receptor-associated proteins ▫ Autoantibodies targeted against muscle-specific receptor tyrosine kinase ▪ ▪ ▪ ▪ (MuSK) → ↓ in acetylcholine receptor function Acetylcholine cannot bind → normal action potentials cannot be generated (adjacent muscle Complement activated → inflammatory response initiation → postsynaptic membrane damage → acetylcholine receptor destruction Bimodal onset age ▫ 20–30 years old (biologically-female predominance) ▫ 60–70 years old (biologically-male predominance) Associated with thymic abnormality; thymus considered antigen source OSMOSIS.ORG 663

promoting autoantibody production (most cases) ▪ Neonatal myasthenia gravis ▫ Transient myasthenia form (newborn from individual with myasthenia gravis) ▫ Maternal antibodies → transplacental passage → neuromuscular junction function interference ▪ Rare non-immune mediated forms ▫ E.g. congenital myasthenia gravis ▫ Mutations affecting neuromuscular transmission COMPLICATIONS ▪ Myasthenic crisis ▫ Decreased respiratory muscle function → life-threatening respiratory failure (requires mechanical ventilation) ▫ Occurs spontaneously/precipitated (e.g. surgery, infection, medication, immunosuppressive-agent withdrawal) SIGNS & SYMPTOMS ▪ Fluctuating muscle weakness ▫ Exacerbated by repetitive muscle use throughout day/after exertion/repetitive movement ▪ Improves with rest ▪ Progression ▫ Symptoms continuously present, fluctuate from mild–severe ▪ Sensation, reflexes preserved Clinical MG forms ▪ Ocular myasthenia ▫ Limited (eyelid, extraocular muscle); individuals (50%) with ocular myasthenia will → generalized myasthenia (< two years) ▪ Generalized myasthenia ▫ Ocular, bulbar, facial, limb, respiratory muscle ▪ Ocular muscles ▫ Eyelid (ptosis), extraocular (binocular diplopia) ▪ Bulbar muscle ▫ Jaw closure (prolonged chewing → weakness), oropharyngeal (dysarthria, 664 OSMOSIS.ORG ▪ ▪ ▪ ▪ dysphagia), palatal (nasal tone, prolonged speech → hypophonia) Facial muscle ▫ Facial weakness, facial expression loss Neck muscle ▫ Cannot keep head up (“drooped head syndrome”) Limb muscle ▫ Proximal, asymmetric muscle weakness Respiratory muscle ▫ Respiratory failure (myasthenic crisis) DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Chest scan to detect associated thymic abnormalities ▫ Abnormal thymus (most cases) ▫ Thymoma LAB RESULTS ▪ Serologic test ▫ Acetylcholine receptor antibodies (AChR-Abs)/muscle-specific receptor tyrosine kinase antibodies (MuSK-Abs) ▫ Most specific tests ▫ Seronegative for AChR-Abs, MuSK-Abs OTHER DIAGNOSTICS ▪ Electrophysiologic studies ▫ Repetitive nerve stimulation studies: progressive decline in muscle action potential amplitude (decremental response) ▫ Single-fiber electromyography: increased jitter ▪ Tensilon test ▫ Edrophonium: acetylcholinesterase inhibitor with rapid onset, short acting duration ▫ Prolongs acetylcholine presence in neuromuscular junction → marked improvement ▫ Easy to perform/limited utility; high false-positive rate, possible complications from muscarinic effects

Chapter 85 Neuromuscular Junction Disorders (especially older adults, e.g. bradycardia, bronchospasm) ▪ PFTs ▫ Periodical FVC monitoring; FVC ↓ reveals respiratory muscle involvement ▪ Ice pack test ▫ Ice pack application (2–5 minutes) → MG-affected muscles ▫ Neuromuscular transmission improvement in low temperature SURGERY ▪ Thymectomy, especially for thymoma; myasthenia often improves/disappears ▪ Rapidly worsening myasthenia/myasthenic crisis ▫ Intubation ▫ Plasmapheresis/intravenous immunoglobulin (IVIG) ▫ Long-acting immunotherapy (e.g., corticosteroids, azathioprine) MNEMONIC Edrophonium vs. pyridostigmine eDrophonium for Diagnosis pyRIDostigmine is to get RID of symptoms Figure 85.1 A biologically-female individual with myasthenia gravis demonstrating ptosis of the right eye before treatment (above) and after treatment (below) with edrophonium. TREATMENT ▪ No curative method MEDICATIONS ▪ Avoid MG-exacerbating drugs (e.g. aminoglycosides, tetracyclines, betablockers, quinidine) ▪ Acetylcholinesterase inhibitors ▫ Symptomatic therapy ▪ Immunomodulating agents ↓ autoantibody production ▫ Individuals with poor acetylcholinesterase inhibitor response ▪ Corticosteroids, other immunosuppressive agents OSMOSIS.ORG 665