IN THE NAME OF

ALLAH

NEUROMUSCULAR JUNCTION DISORDERS

G.R.SHAMSAEI, M.DG.R.SHAMSAEI, M.DNeurologist and Neuromuscular fellowshipNeurologist and Neuromuscular fellowship

Jundishapour University of Medical SciencesJundishapour University of Medical Sciences

NEUROMUSCULAR JUNCTION DISORDERS

• Groups of disorders which exhibit several striking features,the essential

one being a fluctuating weakness

or fatigability of muscle.

NEUROMUSCULAR JUNCTION

A Typical Motor Unit

NEUROMUSCULAR JUNCTION

NEUROMUSCULAR JUNCTION

Neuro-muscular junctionNeuro-muscular junctionactionactionpotentialpotential

synapticsynapticcleftcleft

NaNa++

postsynapticpostsynapticterminalterminalachach

receptorreceptormoleculemolecule

presynapticpresynapticterminalterminal

cellcellmembranemembrane

NEUROMUSCULAR JUNCTION• PRESYNAPTIC EVENTS OF N-M JUNCTION:When the action potential reaches the presynaptic nerve

terminal,CA channels open,allowing influx of CA ions.This triggers release of Ach from presynaptic vesicles into the synaptic cleft.

• POSTSYNAPTIC EVENTS OF N-M JUNCTION:The binding of Ach molecule to each Ach receptor activate

NA-K pump.When a sufficient number of receptors are activated simultaneously,the endplates potential becomes large enough to trigger an action potential.

Ach receptor : 1-Muscarinic 2-Nicotinic

Neuromuscular Junction PhysiologyNeuromuscular Junction Physiology

MYASTHENIA GRAVIS• Abnormal production of autoantibodies to nicotinic Ach receptors .• Overall, 80-90% of patients with MG are positive for AchR

antibodies • AChR antibodies are synthesized by B cells in the thymus gland• The thymus gland of MG patients is almost always abnormal.

– Most (>65-70%)have lymphoid hyperplasia.– 15% have thymomas(slightly more common in older patients)

• AchR antibodies directly interfere with Ach binding, and there is a decrease in the number of Ach receptors with simplification of the postsynaptic folds and a widened synaptic cleft.

• The amplitude of the MEPPs are not sufficient to trigger an AP in some fibers. When transmission fails at many junctions, the power of the whole muscle is reduced(weakness)

MYASTHENIA GRAVISMechanisms by which antiAch receptor antibody

cause M.G:

1. Pharmacologic blockade

2. Activation the cascade of complement reactions and damage to receptors

Results:1. Decrease in number of receptors

2. Widening of synaptic cleft

MYASTHENIA GRAVIS• PATHOGENESIS:is not clear but the thymus gland

plays a major role:1. Most patients with M.G have a histologic abnormality in

the thymus,such as hyperplasia or thymoma.2. Removal of the thymus improves M.G.3. Thymic B-lymphocytes produce antiAch receptor

antibodies disproportionally more than other antibodies.4. Myoid cell are present in the thymus,and the thymus is

the site of T-lymphocyte maturation with acquisition of immunologic tolerance.

(myoid cells are muscle like cells found mainly within the medulla of the thymus with nicotic Ach receptor)

MYASTHENIA GRAVIS

• The main feature of M.G is a : 1- Fluctuating weakness of certain voluntary

muscles,particularly those innervated by motor nuclei of the brainstem,i.e,ocular,masticatory,facial, deglutitional,and lingual.

2-Quick restoration of power with rest or anti-

cholinestrase drugs.

MYASTHENIA GRAVIS• Myasthenic symptoms are always due to weakness

and not to rapid tiring.In contrast,patients who complain of fatigue, if they are not anemic or harboring a malignant tumor,almost always have emotional problems,usually depression.

• The fluctuating nature of myasthenic weakness is unlike any other disease.The weakness varies in the course of a single day,sometimes within minutes,and it varies from day to day or over longer periods.

MYASTHENIA GRAVIS• CLINICAL MANIFESTATIONS:• Onset usually insidious but there are instances of fairly

rapid development,sometimes by an emotional upset or infection(usually respiratory).

• Once the disease has begun,a slow progression follows.• Symptoms may first appear during pregnancy or the

puerperium or in response to drugs used during anesthesia.• Smooth and cardiac muscles are not involved.• Sensory and reflexes are normal even in weak muscle.

MYASTHENIA GRAVISThree groups of muscles are affected:1-Weakness of the levator palpebrae and extraocular

muscles:• Is the initial manifestation in about 50% and these muscles

are involved eventually in more then 90%.• Ptosis and intermittent diplopia are the most

common complaint.• Ocular palsies(diplopia) and ptosis(eyelid opening) are

usually accompanied by weakness of eye closure, a combination observed regularly only in this disease and muscular dystrophy.

MYASTHENIA GRAVIS1-Weakness of the levator palpebrae and extraocular

muscles(cont,)• Unilateral painless ptosis without ophthalmoplegia will

most often prove to be due to myasthenia.• Normal pupillary responses to light and on

accommodation in the face of weakness of extraocular muscles and orbicularis oculi are virtually diagnostic of myasthenia gravis.

• Attempts to overcome the ptosis may impart a staring expression.

• Bright sunlight is said to aggravate the ocular signs and cold,to improve them.

MG: Ptosis

MG: Limitation of adduction

Right ptosis due to myasthenia gravis showing fatiguability of the right lid on sustained upgaze

1

2

MYASTHENIA GRAVIS2-Muscles of the facial expression,mastication,swalloing

and speech are frequently affected(80%),but in only 5-10% are they the first or only muscles to be involved.

• The natural smile becomes transformed into a snarl.• The jaw may hang,so that it must be propped up by the

patient,s hand.• Chewing tough food may be difficult,and the meal may

have to be terminated because of inability to masticate and swallow.

• The voice fades and becomes nasal after sustained conversation.

MYASTHENIA GRAVIS2-Muscles of the facial expression,mastication,swalloing

and speech(cont,)• Women may complain of inability to fix their hair

because of fatigue of the shoulders,or of difficulty in applying lipstick because of inability to purse and roll the lips.

• Weakness of the neck muscles causes fatigue in holding up the head.

• Weakness of the tensor tympani muscles may cause low tones to be muffled,and stapedius weakness may cause hyperacusis.

• Crisis seems most likely to occur in patient with oropharyngeal or respiratory muscle weakness.

MYASTHENIA GRAVIS3-Weakness of the muscles of the limb and trunck:• The clinical rule holds firm that the proximal muscles

are more vulnerable than distal ones,as they are in other forms of myopathy.

• Of the trunck muscles,the erector spinae are the most frequently affected.

• Almost never are limbs affected alone(in conjunction with cranial weakness).

• Muscular wasting of variable degree is found in about 10% of patients,but is not focal and is usually encountered only in patients with malnutrition due to severe dysphagia.

MYASTHENIA GRAVIS• EPIDEMIOLOGY:1. Prevalence:43-84 /million2. Begin at any age,but onset in the first decade is

relatively rare(10%)3. Peak age of onset(women 20-40)(men 50-70)4. Under the age of 40,females are affected 2-3 times

as often as male,whereas in later life,the incidence in males is higher

5. Of patients with thymomas,the majority are older(50-60years)and male predominate.

MYASTHENIA GRAVIS• EPIDEMIOLOGY(cont,): 6- Thymic tomurs occur in 10-15% of patients

7- Hyperplasia of the thymic medulla in 65%

• M.G and other autoimmune disaese:

thyrotoxicosis,SLE,R.A,sjogren,mixed connective tissue disease,anticardiolipin AB, polymyositis(5%)

MYASTHENIA GRAVIS• CLINICAL COURSE:

• The course of the illness is extremely variable.

• The death from M.G is greatest in the first year after the onset of the disease.

• A second period of danger in progressive cases is from 4-7 years after onset.After this time the disease tends to stabilize and the risk of severe relapse diminishes.

MYASTHENIA GRAVIS• CLINICAL COURSE(cont,):• The prognosis and response to treatment varies with

the pattern of muscle involvement and severity,though it remains difficult to predict the outcome in an individual case.

• An increasing duration of purely ocular myasthnia is associated with a decreasing risk of late generalization of weakness.

• In general,patients with a younger age of onset ran a more benign course.

MYASTHENIA GRAVIS• Special form of M.G:1. Neonatal myasthenia:about 12% of infants born to

myasthenic mothers (first 48 hr last days or weeks)

• Impaired sucking,weak cry,limp limbs,and

exceptionally respiratory insufficiency.

• AchR antibodies are demonstrable in both mother

and child

MYASTHENIA GRAVIS2-Congenital myasthenia:typically characterized by

the neonatal or infantile onset of extraocular,facial, bulbar,and limb weakness and fatigability that persist into adult life.

• Electrophysiology same as M.G• Unlike neonatal M.G mother shows no evidence of

the disease,AchR antibodies are not detectable in plasma,and the disease is not transient.furthermore patients do not respond to thymectomy or other treatments

MYASTHENIA GRAVIS3-Drug induced myasthenia:In patients treated

with penicillamine(R.A,scleroderma,or wilson)

• The clinical manifestations and AchR antibody titers

are similar to those of typical adult M.G,but both

disappear when drug administration is discontinued.

MYASTHENIA GRAVIS• Diagnosis of M.G:• The symptoms of MG have three general characteristics that

together provide a diagnostic combination. Formal diagnosis depends on demonstration of the

1. Response to cholinergic drugs2. Electrophysiologic evidence of abnormal neuromuscular

transmission3. And demonstration of circulating antibodies to AChR or MuSK

MYASTHENIA GRAVIS• Diagnostic tests for M.G:

1. Tensilon or neostigmine tests

2. Electrophysiologic tests

3. Antibodies to Ach receptor

MYASTHENIA GRAVIS• Diagnostic tests for M.G:1. Edrophonium(tensilon)or neostigmine test:• Edrophonium:1-10mg iv(initial dose up to 2mg followed in 60

sec by an additional 3mg and in 60sec 5mg to a maximum of 10mg).Improvement is observed within 30sec and last a few minutes.

• Neostigmine:1.5-2mg and atropine sulfate,0.4mg, are given I.M.Objective improvement in muscular power is recorded at 20min intervals up to 2hrs.

Because of the immediate and dramatic nature of the response ,tensilon is preferred for evaluation of ocular and other cranial muscle weakness,and neostigmine is generally reserved for evaluation of limb and respiratory weakness,which may require more time.

MYASTHENIA GRAVIS• Diagnostic tests for M.G:2-Electrophysiologic tests:A-Repetitive nerve stimulation(3-5Hz)or jolly testB-SFEMG3-Antibodies to AchR: are found in 85-90% of patients

of all ages. Antibodies may not be detected in patients with strictly

ocular disease,in some patients in remission,or after thymectomy or even in some with severe symptom.

The titer dose not match the severity of symptoms.

MYASTHENIA GRAVIS• DIFFERENTIAL DIAGNOSIS:All diseases that are accompanied by weakness of

oropharyngeal or limb muscles:1-muscular dystrophy 2-ALS 3-progressive bulbar

palsy 4-ophthalmoplegia of other causes 5-asthenia 6-hyperthyroidism

There is usually no difficulty in differentiating these from M.G by the findings on physical and neurologic examination and by the failure of symptoms in these conditions to improve after parenteral injection of neostigmine or tensilon

MYASTHENIA GRAVIS

• TREATMENTS: divided into 2 groups:1. Symptomatic(anticholinestrase drug therapy ,

plasmapheresis and IVIG)2. Treatments that alter the course of the

disease(thymectomy,steroids,immunosuppressive drugs)

MYASTHENIA GRAVIS1. Symptomatic treatments:a) Anticholinestrase drugs:should be given as soon as

the diagnosis is made. three available drugs(neostigmine,pyridostigmine bromi-de, and ambenonium) pyridostigmine: is most popular,the muscarinic side effects of abdominal cramps and diarrhea are the same but are least severe with pyridostigmine. Starting dose is 60mg TID but may increase to max 360mg/d. If the patient have difficulty eating,doses can be taken about 30min before a meal.

MYASTHENIA GRAVIS1. Symptomatic treatments(cont,)b) Plasmapheresis or IVIG therapy: are used for 2

purpose 1-prior to thymectomy 2-treatment of myasthenic crisis• Myasthenic crisis: is defined as the need for assisted ven-

tilation,a condition that arises in about 10% of patients. It is more likely to occur in patients with dysarthria,dysp-hagia,and respiratory muscle weakness. Other causes include:respiratory inf,thymectomy,emotio-nal stress

MYASTHENIA GRAVIS1. Symptomatic treatments(cont,)

although cholinergic drug therapy sometimes give impressive results,there are serious limitation.In ocular myasthenia,ptosis may be helped,but some diplopia almost always persists. In generalized MG,patients may improve remarkably,but some symptoms usually remain.Cholinergic drugs do not return function to normal,and the risk of crisis persists because the disease is not cured. Therefore,usually one the other treatments is used promptly to treat generalized MG.

MYASTHENIA GRAVISc) Thymectomy: recommended for most patients

with generalized and bulbar form. Although it is safe , it is not usually recommended for ocular myasthenia unless there is a thymoma. about 80% of patients without thymoma become asymptomatic or go into complete remission after thymectomy.Decision for children or patients older than 65 must be individualized.

MYASTHENIA GRAVISd) Steroids and immunosuppresive therapy: If a patient is still disabled after thymectomy, most

clinicians use prednisone(60-100mg every other day)to achieve a response within a few days or weeks.An equally satisfactory response can be seen with a lower dosage,but it takes longer; for instance ,if the dose is 25-40mg,benef-it may be seen in 2-3months.Once improvement is achieved,the dosage should be reduced gradually to 20-35mg every other day.

If no response after 6 months azathioprine(imuran) or cyclophosphamide(2.5mg/kg/d for an adult)

LAMBERT-EATON MYASTHENIC SYNDROME(LEMS)LAMBERT-EATON MYASTHENIC SYNDROME(LEMS)

• LEMS is an uncommon condition that is usually associated with an underlying small cell lung carcinoma (paraneoplastic syndrome)

• It is caused by antibodies directed against the presynaptic P/Q-type voltage-gated calcium channel. By reducing presynaptic calcium entry, these antibodies reduce the release of acetylcholine, leading to weakness.

• CLINICAL MANIFESTATIONS• Patients present with fatigable proximal weakness. DTRs are

reduced or absent. In contrast to MG, bulbar and ocular symptoms are rare, but autonomic complaints (dry eyes, dry mouth, and impotence) are common.

LAMBERT-EATON MYASTHENIC SYNDROME (LEMS)LAMBERT-EATON MYASTHENIC SYNDROME (LEMS)

• The characteristic finding is that of muscle facilitationmuscle facilitation: with brief intense exercise, muscle strength increases, and reflexes may appear transiently. Fatigue develops with sustained activity.

• The presence of elevated anti- voltage-gated calcium channel antibody titers together with an incremental response on fast repetitive nerve stimulation (RNS) helps to establish the diagnosis.

RNS in a patient RNS in a patient with M.Gwith M.G

High frequency RNS in a patient High frequency RNS in a patient with LEMSwith LEMS

LAMBERT-EATON MYASTHENIC SYNDROME (LEMS)LAMBERT-EATON MYASTHENIC SYNDROME (LEMS)

• TREATMENT• The diagnosis of LEMS should prompt a thorough search for an

underlying malignancy, even though a tumor is not always found. Initial therapy is directed at the underlying malignancy; in many patients, no further therapy is required.

• Steroids, azathioprine, IVIg, and plasmapheresis have all been used, but with less success than in MG.

• 3,4-diaminopyridine is the most effective medication for improving muscle strength in patients with LEMS and may be more effective if used together with pyridostigmine.

Myopathic Myopathic DisordersDisordersG.R.ShamsaeiG.R.Shamsaei

Jundishapour University of Jundishapour University of Medical SciencesMedical Sciences

Myopathic DisordersMyopathic Disorders• Myopathy simply refers to an abnormality of the muscle• H/X-Proximal symmetric weakness without sensory loss.• P/E-Show proximal weakness without sensory loss. The muscles are usually

normal in size, without atrophy and or fasciculations, and muscle tone is usually normal or mildly decreased. Reflexes are also normal or mildly decreased.

• Classification: these disorders as either inherited or acquired. The inherited disorders encompass :I. Muscular dystrophiesII.The congenital myopathiesIII. ChannelopathiesIV. Metabolic ((refer mainly to abnormalities of muscle biochemistry that impair the re- synthesis refer mainly to abnormalities of muscle biochemistry that impair the re- synthesis

of adenosine triphosphate (ATP) or cause an abnormal storage of material in the cell)of adenosine triphosphate (ATP) or cause an abnormal storage of material in the cell)

V. Mitochondrial myopathies

Myopathic DisordersMyopathic Disorders• The acquired disorders include: 1.The inflammatory myopathies2.Endocrine(refers to myopathies associated with disorders

of the thyroid and parathyroid glands and to myopathies associated with corticosteroids)

3.Drug or toxin-induced myopathies4.Myopathies associated with systemic illnesses

Myopathic DisordersMyopathic DisordersDx in myopathic disorders:•A detailed history and examination with particular attention to the A detailed history and examination with particular attention to the age of onset, the presence of a family history, the nature of the age of onset, the presence of a family history, the nature of the symptoms and pattern of weakness as well as the tempo of the symptoms and pattern of weakness as well as the tempo of the disease disease should allow a reasonable preliminary diagnosis to be made. should allow a reasonable preliminary diagnosis to be made. •Investigations like Investigations like serum creatine kinase (CK), EMG, muscle serum creatine kinase (CK), EMG, muscle biopsybiopsy• and judicious use of genetic testingand judicious use of genetic testing should then lead to a definitive should then lead to a definitive diagnosis in most cases.diagnosis in most cases.

Myopathic DisordersMyopathic DisordersDx in myopathic disorders:The tempo of the symptoms is of major diagnostic importance. For example, acute or subacute onset of progressive weakness is a feature of some of the inflammatory myopathies, whereas chronic, slowly progressive (over years) weakness is most often encountered in the muscular dystrophies. Episodic weakness suggests one of the channelopathies or metabolic myopathies.The age of onset may also help point to a particular disease process. For example, among the dystrophies, the onset of Duchenne muscular dystrophy (DMD) is usually around the age of 3 years, while many of the limb-girdle dystrophies begin only during adolescence. Of the inflammatory myopathies, dermatomyositis (DM) may occur at any age, but polymyositis (PM) is rare in children, and inclusion body myositis (IBM) usually affects the elderly.The family history may be very helpful, and the specific pattern of inheritance should be determined.

Myopathic DisordersMyopathic Disorders Weakness is the most common and important symptom. A detailed history of

the sorts of activities with which the patient has difficulty provides a good indication of the pattern of weakness.

The symptoms of muscle disease may be negative (weakness and fatigue) or positive (muscle pain, cramps, or stiffness).

Generalized fatigue or tiredness does not indicate a muscle disease, particularly when this is an isolated symptom

Muscle pain (myalgia) is a common symptom and also does not usually imply primary disease of muscle, particularly when it is an isolated symptom. Myalgias may be a feature of the inflammatory and metabolic myopathies.

Myotonia is a state of increased, sustained muscle contraction or impaired relaxation. Patients with myotonia may complain of difficulty releasing a handgrip or of opening their eyes after squeezing them shut tightly.

Myotonia

Myopathic DisordersMyopathic Disorders• (Muscular dystrophies):(Muscular dystrophies):1.1. DYSTROPHINOPATHIES : DYSTROPHINOPATHIES : DMD(Duchenne) and BMD(Becker) DMD(Duchenne) and BMD(Becker) • DMD and Becker muscular dystrophy (BMD) result from different mutations of the same DMD and Becker muscular dystrophy (BMD) result from different mutations of the same

gene, dystrophin, should be thought of as a single disorder representing a spectrum of gene, dystrophin, should be thought of as a single disorder representing a spectrum of severity, with DMD more severe than BMD. severity, with DMD more severe than BMD.

• Inheritance is X-linked, and onset is usually in childhood. The child may use an arm to Inheritance is X-linked, and onset is usually in childhood. The child may use an arm to push down on his thighs when arising from the floor (Gowers' sign), and there may be push down on his thighs when arising from the floor (Gowers' sign), and there may be pseudohypertrophy of the calf muscles. Proximal muscle weakness, including in neck pseudohypertrophy of the calf muscles. Proximal muscle weakness, including in neck flexors, predominates; there is usually sparing of ocular and bulbar muscles.flexors, predominates; there is usually sparing of ocular and bulbar muscles.

• DMD is relentlessly progressive, with the child becoming wheelchair-bound by the age of DMD is relentlessly progressive, with the child becoming wheelchair-bound by the age of 10 or 12. 10 or 12.

• Although primarily a disorder of skeletal muscle, cardiac and gastrointestinal smooth Although primarily a disorder of skeletal muscle, cardiac and gastrointestinal smooth muscle involvement, as well as CNS involvement, are common. muscle involvement, as well as CNS involvement, are common.

• In DMD, death usually occurs around age 20 because of respiratory insufficiency and In DMD, death usually occurs around age 20 because of respiratory insufficiency and aspiration. Life expectancy is also reduced in BMD, but usually not so severely.aspiration. Life expectancy is also reduced in BMD, but usually not so severely.

Myopathic DisordersMyopathic Disorders• (Dystrophinopathies): (Dystrophinopathies): • DIAGNOSTIC EVALUATION: • The CK level is typically markedly elevated in DMD and

moderately so in BMD. A normal CK level provides strong presumptive evidence against the diagnosis.

• Muscle biopsy shows dystrophic features, with absent or reduced staining for dystrophin.

• TREATMENT : • Glucocorticoids are the only medication currently available that

slows the decline in muscle strength and function in DMD and are recommended for all patients with DMD

Myopathic DisordersMyopathic Disorders2. LIMB-GIRDLE MUSCULAR DYSTROPHIES:• The limb-girdle muscular dystrophies are a group of hereditary conditions in which the

proximal muscles of the arms and legs are affected predominantly.• Limb-girdle muscular dystrophies are characterized clinically by shoulder and hip girdle

weakness with relative sparing of extraocular, pharyngeal, and facial muscles. Cardiomyopathy is less frequent than in the dystrophinopathies

• CLASSIFICATION :There are both autosomal dominant and recessive varieties. Recessive inheritance is more common. The most frequent causes are mutations in calpain-3, dysferlin, one of the sarcoglycans, or fukutin related protein. Some are due to mutations in proteins known as the sarcoglycans, which form part of the multimolecular dystrophin-associated glycoprotein complex.

• DIAGNOSTIC EVALUATION: CK level is usually elevated. The EMG is myopathic, and biopsy demonstrates nonspecific dystrophic changes. Immunohistochemistry and Western blot analysis on muscle biopsy, as well as DNA analysis on whole blood, may help to distinguish the different limb-girdle muscular dystrophies.

They affect both boys and girls and may resemble the dystrophinopathies, requiring muscle biopsy for differentiation.

Myopathic DisordersMyopathic Disorders3. MYOTONIC DYSTROPHY: • Myotonic dystrophy is the most common adult onset muscular dystrophy.• Inheritance is autosomal dominant and the genetic defect is either an unstable CTG

expansion in the DMPK (dystrophia myotonica protein kinase) gene or a CCTG expansion in the ZNF9 gene.

• Myotonic dystrophy is a multisystem disease .• Weakness and stiffness of distal muscles are usually the presenting symptoms in

young adults. • Action and percussion myotonia are often present. Proximal weakness develops

later in the course of the disease• Systemic findings include cataracts, arrhythmias, dysphagia (from esophageal

myotonia), insulin resistance, testicular atrophy, and frontal balding.• Neurobehaviora1 features (changes in affect, personality, and motivation) as well as

cognitive dysfunction are also observed commonly• DX: DX: DNA testing for the CTG expansion is now available.

Myopathic DisordersMyopathic Disorders3. MYOTONIC DYSTROPHY: • Management is supportive. Cardiac evaluation is important to screen for and prevent

arrhythmias. Judicious use of pacing for patients with underlying cardiac rhythm disturbances may reduce the risk of sudden cardiac death. There is no specific treatment for the muscle weakness, but drugs such as mexilitine, phenytoin and carbamazepine may reduce the myotonia.

• FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHYFACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY• Facioscapulohumera1 muscular dystrophy (FSHD) is the third most common form of

muscular dystrophy, after DMD and myotonic dystrophy• Inheritance is autosomal dominant and the genetic defect is a loss of several pieces of DNA

(known as D4Z4 repeats) on the tip of chromosome 4.• The disorder is named for the typical distribution of weakness-facio (face), scapula (shoulder

blades) and humeral (upper arm). The weakness is typically asymmetric. Over time the muscle weakness "descends“ to also involve the legs.

• Symptoms usually begin in the teenage years and the progression is usually slow.• The heart is usually spared

Myopathic DisordersMyopathic Disorders4.4. FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHYFACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY• DX: DX: typical finding + definitive genetic testing• CHANNELOPATHIESCHANNELOPATHIES• The channelopathies are a group of disorders characterized by ion

channel dysfunction. The clinical manifestations are determined by the specific ion channel involved.

• The periodic paralyses (PP) are autosomal dominant conditions that derive their designation from their cardinal manifestation, episodic muscle weakness.

• Attacks of weakness are usually associated with a change in serum potassium concentration; they are therefore classified accordingly into hypokalemic and hyperkalemic varieties

Myopathic DisordersMyopathic Disorders• MITOCHONDRIAL MYOPATHIES• The mitochondrial myopathies are a heterogeneous group of disorders with

systemic manifestations.• Maternally inherited is the usual mode of inheritance• The myopathy is frequently accompanied by other systemic manifestations

(e.g., seizure, stroke, migraine, diabetes).• DX: There are no characteristic clinical or electrophysiologic findings in

the mitochondrial myopathies, but a common finding is the co-occurrence of a myopathy and a peripheral neuropathy.

• Serum or CSF lactate and pyruvate are often increased. • The histopathologic changes are also nonspecific and include the presence

of ragged red fibers

Myopathic DisordersMyopathic Disorders• MITOCHONDRIAL MYOPATHIES• A number of characteristic syndromes have been identified1. myoclonic epilepsy with ragged red fibers (MERRF)2. mitochondrial myopathy, encephalopathy, lactoacidosis, and

stroke (MELAS)3. progressive external ophthalmoplegia (PEO)4. Kearns-Sayre syndrome.

Myopathic DisordersMyopathic Disorders• INFLAMMATORY MYOPATHIES• The noninfectious immune-mediated inflammatory myopathies include

polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM).

• CLINICAL MANIFESTATIONS• PM and DM are characterized by proximal (usually symmetric) muscle weakness• Weakness in IBM is often asymmetric and may affect both proximal and distal muscles.

Early selective involvement of forearm and finger flexors, as well as of knee extensors (quadriceps) and ankle extensors, should arouse suspicion of this diagnosis.

• Pharyngeal and neck flexor muscles may be affected, but facial and respiratory muscles are usually spared.

• IBM is often diagnosed only when patients thought to have PM fail to respond to steroids.• DM is distinguishable by the associated purplish discoloration of the eyelids (heliotrope)

and popular erythematous scaly lesions over the knuckles (Gottron patches).

Myopathic DisordersMyopathic Disorders• DDx DM from PM• Extramuscular manifestations are frequent in DM. Cardiac manifestations include

conduction defects, tachyarrhythmias, myocarditis, and congestive cardiac failure and Interstitial lung disease

• DM may occur in the context of systemic sclerosis or other mixed connective tissue disease, and there is an increased incidence of malignancy in patients with DM.

• PM is more often associated with other autoimmune diseases, including Crohn's disease, vasculitis, sarcoidosis, MG, and others.

• DX: DX: elevated CK(90% of cases), myopathic EMG, and a characteristic muscle biopsy.elevated CK(90% of cases), myopathic EMG, and a characteristic muscle biopsy.

• Treatment Treatment • Corticosteroids are the mainstay of treatment in PM and DM, but they are of no benefit

in IBM. IVIg has been shown to be beneficial in DM, but its role in PM is less clear. Plasmapheresis is probably not beneficial. Steroid-sparing agents such as azathioprine and methotrexate should be reserved for patients with refractory disease.

Myopathic DisordersMyopathic Disorders• ENDOCRINE MYOPATHIESI. THYROTOXIC MYOPATHY• Although weakness is rarely the presenting complaint of patients with

thyrotoxicosis, it is found on examination in many.• Proximal muscle weakness and atrophy with normal or brisk reflexes are

the most common clinical features, but rarely distal weakness may be the earliest manifestation.

• Bulbar and respiratory muscle involvement is uncommon. • If Graves disease is the cause of thyrotoxicosis, then the differential

diagnosis of muscle weakness should include myasthenia gravis.• The pathogenesis of thyrotoxic myopathy is unknown but may reflect

enhanced muscle catabolism. CK level is typically normal, and EMG demonstrates myopathic units.

Myopathic DisordersMyopathic Disorders• ENDOCRINE MYOPATHIESII.HYPOTHYROID MYOPATHY• Myopathic symptoms develop in about one-third of patients

with hypothyroidism.• The typical presentation is that of proximal muscle weakness,

fatigue, myalgias, and cramps.• Reflexes may demonstrate delayed relaxation. • There may be an associated distal polyneuropathy. • CK level is typically elevated (and can be as high as 10 times the

normal value). EMG shows nonspecific myopathic changes. • Weakness usually improves following thyroid replacement, but

recovery may lag behind a return to the euthyroid state.

Myopathic DisordersMyopathic Disorders• ENDOCRINE MYOPATHIESENDOCRINE MYOPATHIESIII.III.STEROID MYOPATHYSTEROID MYOPATHY• Myopathy may result from increased glucocorticoids from Myopathy may result from increased glucocorticoids from either endogenous either endogenous

production or exogenous administrationproduction or exogenous administration. The latter is more common, and although . The latter is more common, and although any synthetic glucocorticoid can cause myopathy, it is more common any synthetic glucocorticoid can cause myopathy, it is more common with fluorinated with fluorinated compounds (e.g., triamcinolone and dexamethasone).compounds (e.g., triamcinolone and dexamethasone).

• Doses in excess of the equivalent of 30 mg of prednisone per day Doses in excess of the equivalent of 30 mg of prednisone per day are associated with are associated with an increased risk of myopathy. The risk is reduced with alternate-day regimens.an increased risk of myopathy. The risk is reduced with alternate-day regimens.

• Typically, weakness begins after Typically, weakness begins after chronic administration of steroidschronic administration of steroids, but it may occur , but it may occur within a few weekswithin a few weeks. Weakness is . Weakness is predominantly proximal, with sparing of the ocular, predominantly proximal, with sparing of the ocular, bulbar, and facial muscles.bulbar, and facial muscles.

• CK level is usually normal. EMG is usually normalCK level is usually normal. EMG is usually normal. Muscle biopsy typically . Muscle biopsy typically demonstrates type II fiber atrophy, but this finding is nonspecific. demonstrates type II fiber atrophy, but this finding is nonspecific.

• Treatment requires a Treatment requires a reduction in the steroid dose, switching to an alternate-day reduction in the steroid dose, switching to an alternate-day regimen, or using a nonfluorinated compound.regimen, or using a nonfluorinated compound.