Myasthenia gravis: an animated, cited guide

This page needs JavaScript for its animations. The outline and key answers are below, and every claim in the full version carries a numbered citation.

Not medical advice. Myasthenia Gravis Companion is an educational synthesis of published literature. It does not replace a clinician.

What is in it

What myasthenia gravis is Who gets it, the numbers, the muscles it reaches.
The neuromuscular junction One nerve impulse in slow motion, and the safety factor.
Antibodies at the junction AChR, complement, MuSK and LRP4, animated.
Weakness over a day Why muscles tire with use and recover with rest.
Diagnosis Antibodies, nerve tests, single-fibre EMG, a calculator.
MGFA class & scores MGFA classes I to V, MG-ADL and QMG, scored live.
The differential Lambert-Eaton, botulism, ALS, eye and muscle disease.
Pyridostigmine, animated Buying time at the receptor, dose by dose.
The treatment ladder From symptom relief to immunotherapy and biologics.
Thymectomy over the years The thymus, thymoma and the MGTX trial.
Complement & FcRn inhibitors The newer biologics, trial week by trial week.
Myasthenic crisis Triggers, the breathing numbers, ICU care.
Drugs that can worsen MG A cited checker: antibiotics, magnesium and more.
Nursing care Assessment, timing the doses, teaching, documentation.
Living with MG Pregnancy, surgery, exercise, vaccines, work.
Toward a cure CAR-T, B-cell targets and the evidence for each route.
History & people From Willis in 1672 to the biologics.
Flashcards, quiz and glossary Revision for students.
Sources Every reference behind the guide.

Part 1 · The disease

Antibodies at the junction

How MG antibodies take receptors away from the junction: AChR antibodies cross-link receptors and call in complement; MuSK antibodies break the signal that keeps receptors clustered. Pick an antibody type and press play.

Antibody

Timeline

Schematic, not to scale; the cleft is drawn wide to make room for the antibodies.

Where treatments act

Four antibody types side by side

	AChR	MuSK	LRP4	Clustered-AChR only
Main IgG subclass	IgG1 and IgG3: IgG1 in 100%, IgG3 in 64% of patients tested ⁴⁵⁴	IgG4, which cannot activate complement ²⁵⁹	Mainly IgG1 ²³⁷	Mainly IgG1 ³¹⁵
Complement	Yes: MAC at every endplate in 30 patients ³⁸⁰	No (IgG4)	C5b-9 in all 7 biopsies studied ²⁴¹	Activate complement in vitro ³¹⁵
Main action	Cross-linking and internalization; complement lysis of folds; blockade in a minority ^106,243,472	Blocks the MuSK–LRP4 link, so agrin cannot drive clustering ²⁵⁸	Blocks LRP4 binding to its ligand ²³⁷	Bind receptors held in rapsyn clusters ³¹⁵
Thymus	Germinal centres in early-onset MG; thymoma ^87,339	Largely unremarkable ³¹⁴	Not covered here	Not covered here
How common	Radioimmunoassay positive in 83% of validated MG sera with the standard antigen, about 88% with a mixed antigen ⁵³⁵	70% of AChR-negative patients in the first report ²³⁸	2% to about 50% of double-seronegative patients, by cohort ⁵⁶⁹	38% of RIA-negative patients in routine testing ⁴⁵⁶

Where the antibodies come from

Schematic. Click a step.

The evidence, and where it disagrees

Antibody alone can cause MG

In 1973, rabbits immunized with AChR purified from electric eel made anti-AChR antibodies and developed flaccid paralysis with neuromuscular blockade, relieved by edrophonium or neostigmine. ⁴¹⁸

In 1975, an immunoglobulin fraction of MG patients' serum, injected into mice daily, lowered mEPP amplitude and junctional AChR numbers; some mice showed the decrement on repetitive stimulation, reversed by neostigmine. ⁵¹⁹

In passive transfer, IgG and C3 coat fold tips by 6 hours, coated fold segments are shed by 24 hours, and endplates are still smaller at day 54. ¹²⁵

Established

Titre does not equal severity

Across patients, AChR antibody titre correlates poorly with how weak a person is: some with severe weakness have low titres and some in remission have high ones. Specificity, affinity and subclass differ between people. ^243,322

Within a person over time: titres fell in 92% of those who improved but also in 63% of those who did not. A fall predicted improvement with 83% positive and 59% negative predictive value. ⁴⁷⁵

Receptor counts track severity better: junctional AChR loss correlated with clinical severity. ⁴²¹

Disagreement: must the antibody cross-link?

YesIntact IgG or divalent F(ab')₂ sped receptor loss about threefold; monovalent Fab did nothing unless a second antibody cross-linked it. ^106,432

Not alwaysIn passive transfer, F(ab')₂ hybrids with only one AChR-binding arm, and even Fab, reduced endplate channel number. ⁵⁰⁵

The two sets of results point different ways: the 1986 passive-transfer data suggest cross-linking is not an absolute requirement.

Disagreement: is IgG4 the whole story in MuSK MG?

IgG4 is enoughPurified IgG4, not IgG1–3, from MuSK patients paralysed mice; monovalent IgG4 was the most potent form. ^294,531

Not the only factorIgG1–3 MuSK antibodies still inhibited agrin-induced clustering and dispersed preformed clusters; coexisting IgG1–3 question IgG4 as the sole cause. ^297,537

The main immunogenic region

Half or more of MG antibodies target one conformational patch at the top of the α1 subunit, the MIR. It was found with monoclonal antibodies, one of which transferred experimental MG to rats. ^328,520 Human MIR sequences grafted into a sea-slug (Aplysia) ACh-binding protein induced experimental MG much more potently than the unmodified protein. ³²³

Why the eyes?

One candidate reason: extraocular muscle makes less of the complement brakes DAF (CD55) and CD59. Their staining was intense at diaphragm junctions but weak or absent at extraocular ones. ²⁷⁹ Mice lacking DAF and CD59 go into crisis in experimental MG. ⁶

Hypothesis

Complement: why target C5

C5 is the last common step before the lytic complex. Blocking its cleavage prevents MAC formation and leaves upstream C3 coating intact. ²⁴⁵ Rats lacking C6 develop neither weakness nor terminal complex after AChR antibodies; adding C6 back restores both. ⁶ The eculizumab trial REGAIN enrolled AChR-antibody-positive patients. ²⁴⁴

Complement and FcRn inhibitors follows the trials.

Susceptibility genes

The classic link is the HLA A1-B8-DR3 haplotype in early-onset MG with thymic hyperplasia. ²⁰² Genome-wide studies add CTLA4, HLA-DQA1 and TNFRSF11A, and a signal inside CHRNA1, the AChR α gene itself. ^80,450

Exam hookAChR antibodies are mostly IgG1 and IgG3, fix complement and damage the folds; MuSK antibodies are mostly IgG4, do not fix complement, and act by blocking the agrin–LRP4–MuSK clustering signal. ^{258,259,380,454} The C5 inhibitor trial REGAIN enrolled AChR-positive patients. ²⁴⁴ Across patients, titre correlates poorly with severity. ²⁴³

In plain wordsThe immune system makes antibodies that stick to the muscle's catchers. Some pull the catchers inside to be broken down, some call in a protein cascade that punches holes in the membrane, and a few simply plug them. In MuSK MG the antibodies cut a signal that keeps the catchers bunched together, so they drift apart.