Neuromuscular junction disorders

NEUROMUSCULAR JUNCTION
DISORDERS
G.R.SHAMSAEI, M.DG.R.SHAMSAEI, M.D
Neurologist and Neuromuscular fellowshipNeurologist and Neuromuscular fellowship
Jundishapour University of Medical SciencesJundishapour University of Medical Sciences

DISORDERS
• Groups of disorders which exhibit
several striking features,the essential
one being a fluctuating weakness
or fatigability of muscle.

A Typical MotorUnit

Neuro-muscular junctionNeuro-muscular junction
actionaction
potentialpotential
synapticsynaptic
cleftcleft
NaNa++
postsynapticpostsynaptic
terminalterminalachach
receptorreceptor
moleculemolecule
presynapticpresynaptic
terminalterminal
cellcell
membranemembrane

• 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 GRAVIS
Mechanisms 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 GRAVIS
Three 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 GRAVIS
1-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.

Right ptosis due to myasthenia gravis showing fatiguability
of the right lid on sustained upgaze
1
2

MYASTHENIA GRAVIS
2-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 GRAVIS
2-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 GRAVIS
3-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 /million
2. 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 GRAVIS
2-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 GRAVIS
3-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 drugs
2. Electrophysiologic evidence of abnormal neuromuscular
transmission
3. 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
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
2-Electrophysiologic tests:
A-Repetitive nerve stimulation(3-5Hz)or jolly test
B-SFEMG
3-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,immunosuppres
sive drugs)

MYASTHENIA GRAVIS
1. 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

MYASTHENIA GRAVIS
1. 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 GRAVIS
1. 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 GRAVIS
c) 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

MYASTHENIA GRAVIS
d) 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 with M.GRNS in a patient with M.G
High frequency RNS in a patient with LEMSHigh frequency RNS in a patient with 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 DisordersMyopathic Disorders
G.R.ShamsaeiG.R.Shamsaei
Jundishapour University of MedicalJundishapour University of Medical
SciencesSciences

• 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 dystrophies
II.The congenital myopathies
III. Channelopathies
IV. Metabolic ((refer mainly to abnormalities of muscle biochemistry that impair the re- synthesisrefer 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

• The acquired disorders include:
1.The inflammatory myopathies
2.Endocrine(refers to myopathies associated with disorders
of the thyroid and parathyroid glands and to myopathies
associated with corticosteroids)
1.Drug or toxin-induced myopathies
2.Myopathies associated with systemic illnesses

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

Dx 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.

 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.

• (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 sameDMD 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 ofgene, 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 toInheritance 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 bepush 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 neckpseudohypertrophy 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 ofDMD 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 smoothAlthough 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 andIn 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.

• (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

2. 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.

3. 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.

3. 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

4.4. 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

• 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

• MITOCHONDRIAL MYOPATHIES
• A number of characteristic syndromes have been identified
1. myoclonic epilepsy with ragged red fibers (MERRF)
2. mitochondrial myopathy, encephalopathy, lactoacidosis, and
stroke (MELAS)
3. progressive external ophthalmoplegia (PEO)
4. Kearns-Sayre syndrome.

• 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).

• 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.
• TreatmentTreatment
• 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.

• ENDOCRINE MYOPATHIES
I. 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.

• ENDOCRINE MYOPATHIES
II.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.

• ENDOCRINE MYOPATHIESENDOCRINE MYOPATHIES
III.III.STEROID MYOPATHYSTEROID MYOPATHY
• Myopathy may result from increased glucocorticoids fromMyopathy may result from increased glucocorticoids from either endogenouseither 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 commonany synthetic glucocorticoid can cause myopathy, it is more common with fluorinatedwith 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 dayDoses in excess of the equivalent of 30 mg of prednisone per day are associated withare 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 afterTypically, 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 aTreatment requires a reduction in the steroid dose, switching to an alternate-dayreduction in the steroid dose, switching to an alternate-day
regimen, or using a nonfluorinated compound.regimen, or using a nonfluorinated compound.

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