MyopathiesMyopathies

Aldy S. Rambe

General Considerations

Myopathy means a primary disorder of muscle causing wasting and/or weakness in the absence of sensory abnormalities

Can result from a variety of inherited and acquired disorders.

Pattern of weakness remain similar despite the broad spectrum of etiologies.

Detailed family history, broad systemic reviews, and careful drug history are mandatory.

ESSENTIALS of DIAGNOSISESSENTIALS of DIAGNOSIS

Weakness greater proximally than distally (myopathic distribution)

Normal sensation Normal sphincter function Relative preservation of deep tendon reflexes Muscle biopsy is often definitive Genetic testing can confirm diagnosis of hereditary

disorders caused by specific mutations.

Muscular DystrophiesMuscular Dystrophies

Muscular dystrophies are myopathies that tend to be prgressive with ongoing degeneration and regeneration and fatty infiltration of muscle fibers.

DUCHENNE MUSCULAR DUCHENNE MUSCULAR DYSTROPHYDYSTROPHY The most common muscular dystrophy Prevalence : 1 : 3500 male births Almost always in male, while female are carriers X-linked recessive disorders 1st case was reported in Italy in 1836, and in 1852 was

recognized and described as an inherited disorder of boys by the english physician Meryon.

In DMD no dystrophin is found in muscle or other body tissue cell walls.

DMD – Clinical Patterns DMD – Clinical Patterns

Typically infants with DMD are thought to have no physical problems.

Muscle weakness is usually first recognized between ages 3 and 5 years. It progress symmetrically and linearly until age 14, when progression slows and occurs in a predictable pattern, with extensor muscles being weaker than flexor muscles.

Children tend to walk on their toes from outset and may never be able to walk with the feet flat (toe walking)

DMD – Clinical Patterns (cont.c)DMD – Clinical Patterns (cont.c)

They also tend to waddle (waddling gait) and have to climb up their legs, thighs and hips when getting up from the floor or from a chair (Gower’s sign).

The ability to run is not attained. Walking velocity begins to decrease linearly between ages 4 and

6 and is about 29% of normal by age 10. Patients developed an imbalance in muscle strength at every

joint. Flexors remain stronger extensors. This lead to musculotendinous contractures and loss of joint range of motion. The stronger muscles on one side of the joint stretch their weaker antagonists cause the weaker muscles get weaker even faster because they are no longer at their ideal length for contracting.

GOWER’S SIGN

CALF PSEUDOHYPERTROPHY

TOE WALKING

DIAGNOSISDIAGNOSIS

Elevated muscle enzymes level :CK, AST, ALT, LDH, aldolasecreatinuria, myoglobinuria

Abnormal ECG : tachycardia, RBBB, Q wave Abnormal EMG : short-duration, small-amplitude

motor unit potentials with early recruitment (so-called myopathic features)

DNA analysis : mutation Muscle biopsy

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THERAPYTHERAPY

NO specific treatmentPrednisone 0.75 g/kb/day significant

increase in muscle strength and prolong ambulation up to 3 years.

Deflazacort 0.9 mg/kg/day lower side effects

Physical therapy, bracing, orthoses, and orthopaedic surgery are often required

Becker Muscular DystrophyBecker Muscular Dystrophy

X-linked recessive disorder A milder allelic form of DMD, with decreased or

altered dystrophin rather than absence. Onset usually after 12 yearsof age, and delayed

onset after the 4th decade is occasionallly seen Limb-girdle weakness is typical Cardiac involvement may occur Mental retardation is rare

Becker Muscular Dystrophy (cont.d)Becker Muscular Dystrophy (cont.d)

Life expectancy is reduced Most survive into the 4th or 5th decade The clinical approach is similar to DMD

DRUG-INDUCED MYOPATHYDRUG-INDUCED MYOPATHY

Mechanism of drug-induce myopathy Drug MechanismCholesterol lowering agent NecrosisCosticosteroids Fiber atrophyDiuretics Metabolic disturbancesD-Penicillamine, L-Tryptophan InflammationEmetine, amiodarone, colchicine, Vacuolar changesand chloroquineVaccines adjuvants containing MacrophagicAluminium hydroxide myofasciitisValproic acid Carnitine deficiencyZidovudine Mitochondrial dysfunction

CORTICOSTEROID MYOPATHYCORTICOSTEROID MYOPATHY

ESSENTIALS of DIAGNOSIS : Slowly progressive proximal weakness (most common) Rapidly progressive weakness in some patients (rare) Follows long-term treatment with corticosteroid doses

greater than 30 mg/day Cushingoid appearance Serum CK level is usually normal Normal findings on EMG, or myopathic features without

spontaneous activity Muscle biopsy evidence of type 2b fiber myopathy

CHOLESTEROL-LOWERING AGENT CHOLESTEROL-LOWERING AGENT MYOPATHYMYOPATHY

Every agents including statins, niacin, clofibrate, and

gemfibrozil has myotxic effects.

ESSENTIALS of DIAGNOSIS :

Exposure to cholesterol-lowering agentsMyalgiasProximal muscle weakness

CHANNELOPATHIESCHANNELOPATHIES

Channelopathies are rare diseases caused by functional

disturbances of ion channel proteins as a result of specific

mutations. These disorders include the familial periodic

paralyses and disorders with myotonia

ESSENTIALS of DIAGNOSIS : Inherited disorder Weakness (episodic), myotonia, or both Precipitating factors are usually identifiable

CHANNELOPATHIESCHANNELOPATHIES

1. Hypokalemic periodic paralysis *2. Hyperkalemic periodic paralysis *3. Paramyotonia congenita *4. Myotonia congenita (Thomsen) *5. Generalized myotonia (Becker) **6. Malignant Hyperthermia * * autosomal dominant inheritance** autosomal recessive inheritance

HYPOKALEMIC PERIODIC PARALYSISHYPOKALEMIC PERIODIC PARALYSIS

Type 1 Ca channel defect, type 2 Na channel defect Onset : puberty to third decade Clinical findings :

* episodic attacks of weakness (presence, typical duration, severity)

* normal or mildly elevated serum CK level during attack

* myotonia confined to eyelids

* no muscle hypertrophy

HYPOKALEMIC PERIODIC PARALYSISHYPOKALEMIC PERIODIC PARALYSIS

Precipitating factors : carbohydrate load, postexercise period, pregnancy, emotional stress, cold.

Treatment :* Potassium chloride 0,25 mEq/kg PO (may repeat

every 30 minutes until weakness subsides)* Avoid IV potassium because of risk of uncontrollable hyperkalemia

Prophylaxis :* Acetazolamide ; titrate up to 3 x 250 mg/day* Dichlorphenamide ; 3 x 25 mg/day

DISORDERS OF THE DISORDERS OF THE NEUROMUSCULAR JUNCTIONNEUROMUSCULAR JUNCTIONMyasthenia GravisLambert-Eaton Myasthenic Syndrome Congenital Myasthenic SyndromesBotulismTick Paralysis

MYASTHENIA GRAVISMYASTHENIA GRAVIS

The most common NMJ disorders Acquired, predominantly antibody-mediated autoimmune

disease Ab are targeted against the nicotinic AChR at NMJ

overall reduction in the number of AChR and damage to the postsynaptic membrane

Prevalence 1 : 10.000 - 20.000 people. Male : fifth and sixth decade Female : second and third decade

PATHOGENESISPATHOGENESIS

In generalized MG, Ab (+) in up o 90%, in purely ocular MG, only about 50% Ab (+)

Ab cross-link the AChRs and facilitate unusually rapid endocytosis receptor loss on postsynaptic membrane

Complement-mediated damage to the membrane results in fewer membrane folds and widened synaptic cleft.

The Ab production is a T-cell-mediated process thoght to be associated with thymic dysfunction.

Thymic hyperplasia - 70% MG ; Thymoma – 10% MG

ACETHYLCHOLINE SYNTHESIS

CLASSIFICATIONCLASSIFICATION

Group 1 : ocular myasthenia

Group 2 : mild generalized myasthenia

Group 3 : severe generalized myasthenia

Group 4 : crisis myasthenia

CLINICAL FINDINGSCLINICAL FINDINGS

Clinical characteristics : fluctuating, fatigable weakness of commonly used muscles.

Hallmark features : ptosis, diplopia, dysarthria, dysphagia, respiratory and limb muscles weakness.

50% presents with ocular findings. Ocular muscles weakness usually bilateral and asymmetric

and result in ptosis, diplopia or both. The pupil is spared. Almost all MG develop ocular symptoms, in some limited

to the extraocular muscles

PtosisPtosis

DIAGNOSTIC STUDIESDIAGNOSTIC STUDIES

1. Tensilon (edrophonium) test2. Prostigmin test3. Laboratory studies :

serologic testing : AChR-binding Ab (most sensitive) AChR-modulating Ab AChR-blocking Ab

4. Electrodiagnostic studies : slow repetitive nerve stimulation

5. Imaging and other studies : CT or MRI scan of the chest

TREATMENTTREATMENT

A. Symptomatic Treatment :

cholinesterase inhibitors which increase the

concentration of Ach at the AChR.

Eg. : Pyridostigmine bromide, up to 600 mg/day PO

Ambenomium, 5 – 25 mg PO 3-4 x/day,

max 200 mg/day

Neostigmine, up to 150 mg/day PO

TREATMENTTREATMENT

B. Immunosupressive Treatment :

1. Thymectomy :

* most effective during the first 2 years of disease

* should be considered at any age of MG

* necessary in neoplastic thymoma

* in patients without thymoma, thymectomy increase the likelihood of remission

* best surgical procedure debatable

TREATMENTTREATMENT

2. Medical Therapy.a. Corticosteroid : first line agent.b. Nonsteroidal immunosuppression :

* Azathioprine* Mycophenolate mofetil* Cyclosporine

c. Short-term treatment :Plasmapharesis or IVIGinduce rapid clinical improvement but have only short-term effects