Neuromuscular

MYASTHENIA GRAVIS

Dr. Miguel Alejandro Dávalos Benítez

​PRELECTIO QUIZ

​​GO TO MIS CURSOS WEEK 4 -> PRELECTIO QUIZ

​OPENS 10:00 AM

​CLOSES 10:20 AM

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​5 QUESTIONS - 5 MINUTES

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​GOOD LUCK!

DEFINITION

• ​Myasthenia gravis (MG) is an autoimmune disease that affects the postsynaptic membrane at the neuromuscular junction.

• The predominant manifestation is muscle weakness, which typically worsens with repeated muscle work.

​NEUROMUSCULAR JUNCTION

• ​The neuromuscular junction comprises the presynaptic nerve terminal and the postsynaptic muscle cell.

• Agrin released from the nerve terminal binds to lipoprotein-receptor-related protein 4 (LRP4) and muscle-specific kinase (MuSK), leading to the activation of MuSK, which in turn causes clustering of the acetylcholine (ACh) receptors (AChRs), which is necessary for the maintenance of the postsynaptic structures and muscle contraction.

​CLINICAL CASE

​PATIENT PRESENTATION

Female of 27 years old, teacher.

MAIN COMPLAINT

Complains of double vision and difficult to talk for a prolonged period of time.

​HISTORY

Episodes of double vision began 6 weeks ago. Her husband reported a history of 4 weeks of fluctuating droopy eyelids, in the morning and evening. She also described asthenia and generalized weakness when gardening. Symptoms are worst at the end of the day.

Multiple Choice

Which age has the higher peak of presentation?

• 10-20 years

• 40-50 years

• 50-60 years

• 70-80 years

​AGE

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The age at onset of MG has a bimodal pattern, with a lower peak at 30 years of age and a higher peak at 70–80 years of age.

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​CLINICAL CASE

Past medical history: No chronic diseases, no allergies.

Medication: Denied.

Surgical interventions: Appendix removed 10 years ago.

Family history: Her mother is dyslipidemic, her sister has type 1 diabetes.

Multiple Choice

Which of the following is not a risk factor for myasthenia gravis?

• Thymoma

• Female

• Epstein-Barr infection

• Lung cancer

​RISK FACTORS

• Predisposing genetic factors and environmental factors play crucial roles in the induction of MG.

• Concordance of 35% in monozygotic twins and 5% in heterozygous twins (genetic factors).

• Oestrogens can influence anti-inflammatory and pro-inflammatory responses, depending on their dose, timing and the microenvironment​.

• ​B cells infected with Epstein–Barr virus were reported in the thymus of patients with MG.

• ​The thymus is affected in most patients with AChR MG, with thymoma in 10% of patients or with thymic follicular hyperplasia in >80% of patients with early-onset MG.

PHYSICAL EXAMINATION

HR 78xmin / RR 17xmin / BP 124/82 mmHg / Temperature 36.8^oC

She looks tired, no pallor, no rash, no cough.

Cardiovascular examination reveals normal heart sounds, all pulses present. Chest without deformities, good bilateral air entrance, no crackling sounds.

Abdomen normal.

The neurological examination reveals bilateral ptosis, limitations in eye movements of both eyes when looking to the right and to the left, no paralysis of other cranial nerves, normal pupillary reflexes, normal reflexes of upper and lower limbs, intact sensation, vibration and proprioception.

In the examination of the musculoskeletal system is found a normal axial tone, normal strength of lower and upper limbs, waddling gait after 100 m walking, need to use hands to stand up after 5 squats.

Multiple Choice

This test consist in a brief overshoot twitch of the eyelid when downgaze is followed by the return of gaze to the primary position:

• Cogan’s lid twitch test sign

• Conard’s lid twitch test sign

• Collar’s lid twitch test sign

• Cotran’s lid twitch test sign

​Sensitivity of 50–75% and specificity of >90% for MG

Multiple Choice

If you use an ice pack for orbital cooling in a MG patient with ptosis, which will be the expected result?

• Improvement of >2 mm in ptosis after 5 minutes of orbital cooling

• Improvement of >1 mm in ptosis after 10 minutes of orbital cooling

• Worsening in ptosis >5 mm after 2 minutes of orbital cooling

• Worsening in ptosis >2 mm after 5 minutes of orbital cooling

Multiple Choice

This sign describes the worsening of ptosis in the least-affected eye when the lid of the most-severely affected eye is lifted:

• Curtain sign

• Dropping sign

• MG sign

• Cogan's sign

Multiple Choice

Which of the following is the organ responsible of central tolerance in the immune system?

• Liver

• Thymus

• Spleen

• Lymph nodes

Multiple Choice

The recognition of self-antigens in the thymus is facilitated by multigene transcription factors, such as:

• AIRE

• CD8

• p53

• LRP4

​AIRE

​The recognition of self-antigens in the thymus is facilitated by multigene transcription factors, such as AIRE (autoimmune regulator), which is expressed in thymic medulla.

AIRE leads to the expression of major peripheral proteins on the surface of thymic epithelial cells, after which T cells that recognize these proteins (or ‘self-antigens’) are targeted for negative selection and undergo apoptosis.

​TOLERANCE

• ​Self-reactive T cells that escape central tolerance enter the periphery, where they can undergo apoptosis, enter into a state of anergy or undergo suppression (peripheral tolerance). The central and peripheral tolerance of T and B cells to self-antigens is crucial for health and development.

• In myasthenia gravis, there is a failure of central tolerance, occurring within the thymus in most patients, leading to the development of self-reactive cells.

​EXAMINATION

​EKG: Normal.

Chest-X-ray: Enlargement of upper mediastinum.

Chest computed tomography: Presence of mildly, smooth margin, enhanced mass in the anterior mediastinum, without invasion of adjacent organs.

LABORATORY TEST

Open Ended

Which other laboratory will you like to order in this patient?

Multiple Choice

Which of the following is the most common autoantigen you can find in this patient?

• MuSK

• LRP4

• AChR

• Agrin

​AChR AUTOANTIGEN

• ​Nicotinic AChR of the muscle is the most common autoantigen in MG and is concentrated at the tips of the folds of the postsynaptic membrane.

• ​Allow cation (Na⁺, Ca²⁺ and K⁺) translocation across the membrane.

• ​Anti-AChR antibodies are detected in 80% of patients with MG.

Multiple Choice

Anti-MuSK antibodies are detected in which percent of MG patients?

• 1-10%

• 11-20%

• 21-30%

• 30-40%

​MuSK

• ​Is a transmembrane single-subunit protein that is responsible for the clustering of AChR at the neuromuscular junction and the maintenance of the postsynaptic membrane.

• ​MuSK is activated through phosphorylation induced by the LRP4–agrin complex, after which AChR clustering is induced.

• ​Anti-MuSK antibodies are detected in 1–10% of patients with MG.

Multiple Choice

Is a single-subunit transmembrane protein with a large extracellular domain that contains multiple low-density lipoprotein repeats, binds to agrin normally secreted from the nerves:

• AChR

• LRP4

• MuSK

• Titin

​LPR4

• ​Is a single-subunit transmembrane protein with a large extracellular domain that contains multiple low-density lipoprotein repeats.

• ​The LRP4–agrin complex triggers MuSK activation.

• ​In the largest study, 19% of patients with MG who are double seronegative (that is, those with neither anti-AChR nor anti-MuSK antibodies) had anti-LRP4 antibodies.

Multiple Choice

Which of the following represents a intracellular antigen in MG:

• Kv 1.4

• ColQ

• Tintin

• Agrin

​MG AUTOANTIBODIES

• ​MG-associated autoantibodies can be classified into two major groups: those to transmembrane or extracellular autoantigens and those to intracellular autoantigens.

  1. ​Transmembrane/extracellular: AChR, MuSK, LPR4, agrin, ColQ, Kv1.

  2. ​Intracellular: Titin, ryanodine receptor, cortactin.

​PATHOPHYSIOLOGY

Multiple Choice

The patient presented positivity to anti-AChR and anti-MuSK antibodies, with the clinical presentation and this results you:

• Confirm MG diagnosis

• Order a EMG repetitive stimulation to confirm MG diagnosis

• Order a single-fibre EMG to confirm MG diagnosis

• Order anti-LRP4 antibodies to confirm MG diagnosis

Multiple Choice

Which of the following is usually the first-line medication in patients with MG?

• Ambenonium chloride

• Pyridostigmine bromide

• Prednisolone

• Azathioprine

PYRIDOSTIGMINE BROMIDE

• ​Is a type of anticholinesterase (also known as cholinesterase inhibitor), avoiding the destruction of ACh enhance its bioavailability at the synaptic cleft.

• ​Pyridostigmine bromide is the preferred anticholinesterase for oral treatment and is usually the first-line medication in patients with MG.

Multiple Choice

Despite treatment with pyridostigmine bromide and thymectomy, the patient persisted with symptoms of weakness, you decide to start:

• Prednisolone and azathioprine

• Prednisolone and rituximab

• Intravenous inmunoglobulin

• Plasma exchange

Multiple Choice

With prednisolone and azathioprine the patient presented very good symptom control, you decide:

• Continue with acetylcholinesterase inhibitor

• Continue with lowest possible dose

• Continue with highest possible dose

• Stop the treatment

Multiple Select

After 8 months without symptoms, the patient comes back to the ER presenting severe weakness, you decide to start (select all that apply):

• Plasma exchange

• Intensive care

• Rituximab

• Cyclosporine

​POSTLECTIO ACTIVITY

​GO TO MIS CURSOS WEEK 4 -> READ THE POSTLECTIO PAPER "Randomized Trial of Thymectomy in Myasthenia Gravis"

​ANSWER THE POSTLECTIO QUIZ

​OPENS TODAY AT 12:00 PM

​CLOSES TOMORROW 11:59 PM

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​GOOD LUCK!

​BIBLIOGRAPHY

​Gilhus NE, Tzartos S, Evoli A, Palace J, Burns TM, Verschuuren JJGM. Myasthenia gravis. Nat Rev Dis Primers. 2019 May 2;5(1):30. doi: 10.1038/s41572-019-0079-y. PMID: 31048702.