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MYASTENIA GRAVIS DENGAN THYMOMA PADA PENDERITA ANAK USIA 5

THN

Kemala Hayati

Moderator : Dr. Maimun, ZA, M.Kes.

SpPK

Patologi Klinik Laboratorium Sentral

RSSA MALANG

DISKUSI KASUS

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DATA DASAR

• An. MM, 4 thn, perempuan• Anamnesa : • Keluhan utama : mata seperti

mengantuk• Mata seperti mengantuk sjk 3 minggu

SMRS. Saat bangun tidur mata dpt membuka lebar,tp siang hari / setelah aktifitas mata kembali tampak spt mengantuk.

• Riwayat keluarga dengan penyakit serupa disangkal

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PEMERIKSAAN FISIK• Pemeriksaan umum : Tampak sakit• KU : Cukup• Vital sign : Nadi : 88x/mnt, R : 28X/mnt,

t : 36.5°C• Kepala : • Mata kiri : kelopak mata menutupi

separuh mata Konjungtiva anemi : -/-, Sklera ikterik : -/-

• Thorax : taa• Abdomen : taa• Antropometrik : PB : 105 cm,TB : 14,5

kg

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Darah Lengkap 3-1-2010 15-1-2010

Hemoglobin (11.0-16.5 mg/dl)Lekosit (3500-10.000 /µL)LED Trombosit (150.000 - 200.000/µL)Hmt

Hit.JenisMCV (80-99 µm3)MCH (26.5-33.5 pq)MCHC (31.5-35.0 g/dl)RDW (10-15 µm3)

11.56.900

283.00035.3

8126.632.614.2

12.49.600

34351.000

7/-/-/49/38/5/68627.732.413.6

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LABORATORIUMImunologi 5-1-2010

Total T3 (0.79-1.49 ng/dl)Free T4 (0.71-1.85 ng/dl)TSH (0.49-4.67 µIU/ml)

ElektrolitNatrium (136-145 mmol/l) Kalium (3.5-5.0 mm0l/l)Chlorida (98-106 mmol/l)Kalsium (7.6-11.0 mmol/l)Fosfor (2.5-7-0 mmol/l)

Kimia DarahGDS (60-110 mg/dl)Ureum (10-50 mg/dl)Kreatinin (0.7-1.5 mg/dl)

1.090.912.517

1404.541118.54.84

9628.40.37

LAB0RATORIUM

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Kimia Darah 3/1 5/1 14/1 21/1

GDS (60-110 mg/dl)

Ureum (10-50 mg/dl)

Kreatinin (0.7-1.5 mg/dl)

28.4

0.37

96 EMGKesimpulan : Menyokongsuatu myastemia gravis

CT ScanKesimpulan :Massa soft tissue pd mediastinum ant. Suspek Thymoma dg DD retrosternal goiter dan limfoma

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JAWABAN INTERPRETATIF• Pada pemeriksaan laboratorium klinik

didapatkan hasil normal, dengan klinis & Electromyography (EMG) serta CT Scan Thorax mengesankan suatu Myasthenia Gravis dan suspek Thymoma, DD: 1. retrosternal goiter, 2. limfoma

• Saran : pemeriksaan Acetylcholine Receptor Antibodi ( AChR Ab) & Muscle Specipic kinase (Anti MuSk Ab)

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DISKUSI1. Penegakan diagnosa

2. Laboratorium Myasthenia Gravis dan Thymoma

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1. PENEGAKAN DIAGNOSA• Myasthenia Gravis (MG) • an acquired autoimmune disorder in which

the postsynaptic AChRs are reduced in number or function, leading to muscle fatigue and weakness.

• characterized by a fluctuating pathological weakness with remissions & exacerbations involving one or several skeletal muscle groups, mainly caused by antibodies to the acetylcholine receptor (AChR) at the post-synaptic site of the neuromuscular junction

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• Prevalence MG : 85–125 permillion, • The disease has 2 peaks: 1. 20 - 40 years

(♀), 2. 60 - 80 years (♀, ♂)• the fetus acquire immune proteins (Ab) from

a mother affected with MG. • Generally, cases of neonatal MG temporary

& child's symptoms disappear 2-3 months after birth.

• MG in juveniles is uncommon. • MG frequently associated with thymic

abnormalities, called thymitis, ± 60% & thymoma ± 10% of patients.

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THYMOMA• Thymoma is an uncommon neoplasm from

the epithelial cells of the thymus. • Well known for association with MG,

histologic variability, & heterogeneity of malignant behavior.

• Thymoma occurs in ± 10% patients MG• MG occurs in ± 33% of patients thymoma

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PATHOPHYSIOLOGY• Acetylcholine (ACh) synthesized in the

motor nerve terminal & stored in vesicles• ACh from 150–200 vesicles released &

combines with AChRs that densely packed at the peaks of postsynaptic folds.

• Structure of the AChR fully elucidated; consists 5 subunits (2α, 1β, 1δ, & 1γ or ε ) arranged around a central pore.

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….pathophysiology Normal

• ACh combines with the binding sites on the subunits of the AChR

• channel in the AChR opens, entry cations, chiefly sodium, produces depolarization at the end-plate region muscle fiber.

• Depolarization triggering muscle contraction.

• Process terminated by hydrolysis of ACh by acetylcholinesterase (AChE), present within the synaptic folds, & by diffusion of ACh away from the receptor.

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….pathophysiology Myasthenia Gravis

• the fundamental defect is a decrease in the number of available AChRs at the postsynaptic muscle membrane.

• postsynaptic folds flattened, or simplified. • These changes result in decreased

efficiency of neuromuscular transmission• although Ach released normally, it produces

small end-plate potentials that may fail to trigger muscle action potentials

• results in weakness of muscle contraction

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…pathophysiology Anti-AChR Ab reduce the number of AChRs by

3 mechanisms:

(1) accelerated turnover of AChRs by a mechanism involving cross-linking & rapid endocytosis of the receptors;

(2) blockade of the active site of the AChR, i.e., the site that normally binds ACh;

(3) damage to the postsynaptic muscle membrane by the antibody in collaboration with complement.

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CLINICAL FEATURE

• Presents between 15-50 years.• ♀ affected > ♂ in younger ages & reverse

at older ages.• It has relapsing / remitting course, esp

during the early years. • The cardinal symptom is abnormal

fatigable weakness of the muscles; movement is initially strong but rapidly weakens.

• Worsening towards the end of the day or following exercise is characteristic.

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..clinical feature• No sensory signs or signs of CNS

involvement, although weakness of the oculomotor muscles may mimic a central eye movement disorder.

• The 1st symptoms usually intermittent ptosis or diplopia, weakness of chewing, swallowing, speaking or limb movement

• Any limb muscle may be affected, most commonly those of the shoulder girdle; unable to undertake tasks above shoulder level, as combing the hair, without frequent rests.

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….clinical feature

• Respiratory muscles may be involved & respiratory failure is a not uncommon cause of death & may be 1st presentation, in which case the dx is difficult if not thought of.

• Aspiration may occur if the cough is ineffectual.

• Sudden weakness from a cholinergic or myasthenic crisis may require ventilatory support.

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DIAGNOSIS & EVALUATIONHistory• Diplopia, ptosis, weakness• Weakness in characteristic distribution• Fluctuation & fatigue: worse with repeated

activity, improved by rest• Effects of previous treatments

Physical examination• Ptosis, diplopia• quantitative testing of muscle strength• Forward arm abduction time (5 min)• Vital capacity • Absence of other neurologic signs

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…diagnosis & evaluation

Laboratory testing• Anti-AChR radioimmunoassay: ~85%

positive in generalized MG; 50% in ocular MG; negative result does not exclude MG. ~40% of AChR Ab negative patients with generalized MG have anti-MuSK Ab.

• Repetitive nerve stimulation; decrement of >15% at 3 Hz: highly probable diagnosis if unequivocally positive

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…diagnosis & evaluation

• Single-fiber electromyography: blocking & jitter, with normal fiber density; confirmatory, but not specific

• Edrophonium chloride (Tensilon) 2 mg + 8 mg IV; highly probable diagnosis if unequivocally positive

• For ocular or cranial MG: exclude intracranial lesions by CT or MRI

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1 . PENEGAKAN DIAGNOSA PASIEN

• Ptosis (+) • Gejala bertambah dgn

aktifitas• CT Scan thorax : suspek

thymoma• EMG : menyokong suatu

Myastenia Gravis

TEORI• Ptosis,diplopia,dysphagia• Dysharthria• Myasthenic crisis (paralysis

of respiratory) • 75% have an abnormality of

the thymus• 10% have a thymoma • single fiber

electromyography (SFEMG)• AChR Ab • Edrophonium test

Myasthenia Gravis dgn thymoma

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2. Laboratorium MG & Thymoma• Tensilon test: IV short-acting

anticholinesterase, edrophonium bromide, is a valuable diagnostic aid; 2 mg initially, with a further 8 mg, half a minute later if no undesirable side-effects. Improvement in muscle power occurs within 30 sec & usually persists for 2-3 min.

• Ice pack test: simple & less risky than tensilon test with improvement in ptosis in 2 mins.

• EMG with repetitive stimulation show the characteristic decremental response.

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… laboratorium MG & Thymoma

• Anti-acetylcholine receptor Ab (AChRA) is found in > 80%, < in purely ocular myasthenia (50%).

• Anti-MuSK Ab found especially in AChRA-negative patients with prominent bulbar involvement.

• Positive anti-skeletal muscle Ab suggest the presence of thymoma, but all patients should have a thoracic CT to exclude this condition, which may not be visible on plain X-ray.

• Screening for other autoimmune disorders, particularly thyroid disease, is important.

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Anti-AChR Ab

• Anti-AChR Ab detectable in serum of ~85% MG• ± 50% patients with weakness confined to the

ocular muscles. • presence of anti-AChR Ab virtually diagnostic of

MG, but a negative test does not exclude the disease.

• The measured level of anti-AChR Ab does not correspond well with the severity of MG in different patients.

• in an individual patient, a treatment-induced fall in the Ab level often correlates with clinical improvement.

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Anti-AChR antibodi

• Acetylcholine receptor (ACHR) Ab not detected in healthy individuals or in patients with neurological disorders or AID other than MG

• the specificity of these assays approaches 100 %

• The most sensitive of the ACHR Ab assays is the ACHR binding Ab assay.

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AChR Ab Measurement• AChR Ab first measured by

immunoprecipitation of 125I a-BuTx-labeled AChR in detergent extracts of human muscle,

• most current assay employ AChRs extracted from muscle-like cell lines that express a mixture of fetal & adult AChRs

• Enzyme-linked immunosorbent assay (ELISA) & other alternative assays not proved successful.

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AChR Ab Measurement• AChR Ab titers highly variable among

MG patients, (0 to >1000 nm/L),• between individuals titers do not

correlate well with clinical severity, • level of Ab within an individual

correlates well with clinical scores after plasma exchange ,thymectomy,or immunosuppressive treatment.

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Interpretasi AChR Ab• Presence of ACHR Ab confirms a dx MG.• ACHR-binding Ab titer of ≥ 0.5 Nm

considered positive.• ACHR-blocking Ab demonstrating ≥ 25%

inhibition/blocking considered positive.• ACHR-modulating Ab demonstrating ≥ 26%

modulation considered positive.• Absence of ACHR Ab does not rule out a dx

of MG, as 10–15 % of MG patients lack detectible ACHR

• Normally, there is no AChr Ab (< 0.05 nmol/L) in the bloodstream.

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MuSK Antibody

• MuSK Ab found ~40% of AChR Ab negative patients with generalized MG

• MuSK Ab rarely present in AChR Ab positive patients or in patients with MG limited to ocular muscles.

• These Ab interfere with clustering of AChRs at neuromuscular junctions, as MuSK is known to do during early development.

• There is also evidence MG patients without demonstrable Ab to either AChR or MuSK have other—as yet undefined—Ab that impair neuromuscular transmission.

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MuSK Antibody• About 10–15% of all MG patients with

generalized symptoms do not have detectable anti-AChRs with AChR Ab“seropositive” generalized MG

• never found, & no HLA association has been identified.

• on clinical and pathologic grounds, the disease appears to have several unusual features.

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THANKS A LOT

THANKS FOR YOUR

ATTENTION

kemala