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Primary muscular disorders

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More than 600 separate muscles

40% of the human weight in adulthood

A muscle contains thousands of musclefibers that extend for variable distances

along its longitudinal axis.

A muscular fiber is a multinucleated cellfrom a few mm to several cm and from 0!

00 micrometers diameter

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Muscle fibers innervated by an anterior

horn cell act as a unit called " #motor unit$

" basic physiologic unit in all reflex

postural and voluntar activity.

A particular muscle may have from a few

&'!4 as extraocular muscles( to hundreds

of M) &li*e the cvadriceps muscle(

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+linical syndrome Motor deficit not restricted to a particular

motor unit.

,istribution of motor wea*ness might

involve a certain group of muscles or

could be more widespread. -n this caseproximal muscles are usually more

involved " wadling gait is characteristic for

pelvian muscles deficit. ,istal myopaties are not uite exceptional.

Muscle tone is diminished

Muscular atrophy and loss of bulc* is

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+ommon activities might get impaired

because of wea*ness related to a

muscular disorder/

al*ing running climbing stairs arising from

sitting &special sign " 1owers " #patient

climbing on himself$( *neeling suatting orreclining position wor*ing with hands above

shoulder2s level.

!! 3ocalied muscle wea*ness might be a sign

of a muscular disorder as well/ drooping of the

eyelids diplopia and strabismus change in

facial expression and voice difficulty in

chewing closing the mouth swallowing etc..

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5on muscular abnormalities in muscular

diseases ,islocation of the hips

*in involvement

+ardiac abnormalities 7etinian changes

+erebellum and cranial nerves

8ronto!temporal dementia ,ysmorphic features of cranium

9ndocrine abnormalities

Skin lesions typical rash in dermatomyositis

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,ifferential diagnosis with

polineuropathies :endon reflexes are spared

5o sensory signs

5o sphincterian troubles 5o autonomic signs

;ut we can have/

pain spasms cramps rippling muscularhypertrophy &true or false( fatigue

myotonia stiffness muscle mass or

change in muscle volume

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,iagnosis

;lood tests

9lectrophysiology

-maging studies ;iopsy

1enetic tests

Asses cardiac function for associatedcardiomiopathy

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;lood tests

+hec* up for/ +reatin*inase &elevated in active progressive

disorders to thousands of units(

Aldolase

:ransaminases

9lectrolites/ sodium potasium cloride

:iroidian chec* up

Autoimmune battery

:oxicology

erology for viral or parasitic infections

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9lectrophysiology

5erve conduction studies are normal

5eedle electrode test of muscular activity

at rest and gradual to maximal contraction

At rest we can find/ fibrillation potentials ! markers for spontaneous

contractions of individual muscle fibers as a consequence of

membrane instability" very prominent in inflammatory myopathies during theactive episodes

myotonic discharge ! repetitive high frequency potentialsexpression of delayed muscle relaxation after voluntary contraction"action myotonia or mechanical stimulation"percussion myotonia :ypes +hloride

channel!related disorders"eg myotonia congenita :homsen type< protein *inase!

related disorders"eg myotonic dystrophy< sodium channel!related disorders"eg

hyper*alemic periodic paralysis< idiopathic

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5ormal

recruitment

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9arly recruitment during gradual

contraction in myopathic conditions with

low amplitude and short duration of

individual motor units

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-maging +: scan M7- or ultrasound

>elp to define the pattern of involvementbeing particularly helpful for profound muscles

?ery helpful for detecting inflammation

edema muscular mass &hematoma tumor

ossification etc..(

5ormal appearance of thigh muscles

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Axial :@ weighted spin echo M7 imageshowing edema and inflammation ofmuscle fibers and s*in &solid arrows( in apatient with polimyositis.

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Muscle biopsy 8ragment of muscle is removed surgically and

prepared to be examined by microscope loo*ingfor necrosis inflammation edema cytoplasmic

inclusions regeneration activity increase in

lipocytes fibrosis etc

and tested by immunostaining loo*ing for

specific proteins &distrophin utrophin emerina

sarcoglicans etc(

the selection of the muscle is based onevidence of involvement

Although involved a certain muscle should be

avoided if the loss of muscle fibers is very

prominent and advanced.

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>9 staining showing inflammatory cells

&purple( attac*ing muscle fibers in apatient with polimyositis

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>istopathology of gastrocnemius muscle from

patient who died of pseudohypertrophic muscular

dystrophy ,uchenne type. +ross section of

muscle shows extensive replacement of musclefibers by adipose cells.

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>-? infection

-nflammatory

-nfectious

7elated to treatment

Primary endomysial inflammation,

red-rimmed vacuoles, amyloid

deposits,eosinophilic inclusions, and

small round fibres in groups,

all diagnostic of IBM

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1enetic testing

-s a blood test

8or ex/ the muscle!specific isoform of the

dystrophin gene &for ,uchenne dystrophy(

is composed of B exons and ,5A testingand analysis can usually identify the

specific type of mutation of the exon or

exons that are affected. ,5A testingconfirms the diagnosis in most cases and

detect the carrier status

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Prenatal tests

-f one or both parents are CcarriersC of a particular condition there is a

ris* that their unborn child will be affected by that condition.

CPrenatal testsC are carried out during pregnancy to try to find out if

the fetus &unborn child( is affected.

:he tests are only available for some neuromuscular disorders.,ifferent types of prenatal tests can be carried out after about

wee*s of pregnancy.

+horion villus sampling &+?( can be done at "4 wee*s and

amniocentesis after D wee*s while fetal blood sampling can be

done at about E wee*s. 9arlier testing would allow early termination but it carries a slightly

higher ris* of miscarriage than later testing &about @% as opposed

to 0.D%(.

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9tiology of muscular disorders -. -nflammatory myopathies

A. -nfective or presumably infective forms of polymyositis

:richinosis

:oxoplasmosis

+ysticercosis

>-? >:3?!

;. -diopathic polymyositis and dermatomyositis " usuallyassociated to connective tissue disorders affect primarily striated

muscle and s*in

ometimes paraneoplastic syndromes

Fnly ,M affects children

,iagnosis based upon specific changes in muscle and s*inbiopsy

+. -nclusion body myositis &-;M( Predominates in males

Fnset in middle or late adult life more freuent than PM

,iagnosis based on intracytoplasmatic vacuoles and congophilic inclusionsin both cytoplasma and nuclei of degenerated muscular fibers

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>eritable muscular dystrophies &M,(

include the following/

ex lin*ed

! ,uchenne

! ;ec*er

! 9mery ,reifussAutosomal dominant

! 8acioscapulohumeral

! ,istal

! Fcular

! Fculopharingeal

Autosomal recessive

! 3imb girdle

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Pathophysiology

Multiple proteins are involved in the

complex interactions of the muscle

membrane and extracellular

environment. For sarcolemmal stability,dystrophin and the dystrophin-

associated glycoproteins (!"s# are

important elements

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Fther muscular dystrophies

Myotonic dystrophy &teinert disease( "

B

Proximal myotonic myopathy &P7FMM( "

'

,istal myopathies " brea*ing the rule of proximaldistribution of wea*ness according to myopathic pattern " affects distal

muscles and might resemble a polineuropathy

elander type " autosomal dominant

Miyoshi " dysferlin gene on cr @p "

autosomal recessive

7ecently described a distal myopathy

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Metabolic and toxic myopathies

>ereditary metabolic abnormality " glycogen storage

myopathies lipid metabolism disorders

econdary to a disorder of endocrine function &thyroid "

thyrotoxic and hypothyroid myopathy pituitary adrenal

gland(

Myotoxic drugs and other chemical agents "

rhabdomyolysis to alcohol abuse statins cocaine

organophosphates high doses of corticosteroids &critical

ilness myopathy( Fther mecanisms/ hypo*alemic &diuretics laxatives alcohol(

lysosomal storage &amiodarone chlorouine( inflammatory

&procainamide ,!penicilamine( etc

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+F5195-:A3

59)7FM)+)3A7 ,-F7,97 ,evelop in utero 7elatively nonprogressive

+ould have the clinical onset at a later age even in middle adult life

,iagnosis based on specific morphologic changes on muscle biopsy

revealed by systematic application of hystochemical stains to froen

sections and by phase and electron microscopy

+entral core presence in the central portion of a condensation of myofibrillar material

high ris* for malignant hyperthermia &B " lin*ed to the ryanodine receptor

gene(

5emaline Miriads of rods seen beneath the plasma membrane of the muscle fiber

+entronuclear or myotubular +entral nucleation and smalnees of fibers

G!lin*ed and A7 in children and A, in adult onset form

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+hannelopathies ,iseases caused by mutations in genes that code

proteins that function as channels in muscle fibersmembrane " ion channel disease

-. +hloride channel diseases

Myotonia congenita &:homsen disease " A, early life onset

myotonia muscular hypertrophy and nonprogressive course(

1eneralied myotonia &;ec*er disease " A7 manifestation of

myotonia after 0!4 y of age(

--. odium channel diseases

Myotonia fluctuans and permanens

Acetaolamide "responsive myotonia

---. +alcium channel diseases

>ypo*alemic periodic paralysis " A, attac*s evolving over

minutes to hours of diffuse wea*ness &legs before arms before

trun* muscles( usually sparing of faciobulbar muscles

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econdary *alemic periodic paralyses " transitory

episodes of wea*ness *nown to be associated to

acuired derangements of potassium metabolism :hyrotoxicosis Aldosteronism

alfa hydroxilase deficiency

;arium poisoning

Malignant hyperthermia ,uring general anesthesia " rising body temperaturemuscular rigidity and ris* of death &inherited defect of the

ryanodine receptor protein component of the calcium

channel in the sarcoplasm(

Malignant neuroleptic syndrome >yperthermia occurs as an idiosyncratic reaction to

neuroleptic drugs with widespread myonecrosis.

5euromuscular Hunction

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5euromuscular Hunction

disorders

Myasthenia gravis Myasthenic " myopathic syndrome of 3ambert

9aton " paraneoplastic sy associated to the oat

cell carcinoma of the lung " presynaptic defect

of Ach release from the nerve terminals +ongenital myasthenic syndromes " genetic

disorders with pre or postsynaptic defects

Myasthenic wea*ness due to antibiotics&neomicin *anamicin polymixin colistin etc( or

toxins &clostridium botulinum(

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Myasthenia gravis

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mechanism

Autoimmune attac* against aceticholine

receptor on the postsynaptic membrane of

the neuromuscular Hunction.

:he antibodies affect only the nicotinic

receptor in the s*eletal &striated( muscles.

?isceral muscles and myocardium are

spared.

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symptoms

8luctuating wea*ness of muscles induced

or aggravated by repetitive or persistent

activity and recovered during rest.

Fnset usually insidious but some factors

li*e emotional upset or infections might be

precipitating.

:he special vulnerability of

certain muscles is also a

characteristic feature.

+raniofacial muscles are in D0% of cases involved at the

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+raniofacial muscles are in D0% of cases involved at theonset &levator palpebrae and extraocular muscles mostof all( and eventually become symptomatic in IB0% ofpatients.

o drooping eyelids and intermittent diplopia arecommon complaints.

Muscles of facial expression mastication swallowingand speech are in E0% of cases affected.

-n patients with wea*ness of the trun* and limbs "proximal muscles are far more vulnerable than the distalones.

-nvolvement of respiratory muscles is associated withrespiratory insuficiency

7apid deterioration with respiratory failure anduadriparesis might occur in a range of hours and istermedmyasthenic crisisbeing considered lifethreatening and a treatment emergency

Precipitating factors/ phisical exercise cold hunger

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5o other clinical signs or symptoms apartfrom the motor ones are present in theclinical picture

Muscle atrophy is not present. +ourse of the illness is extremely variable

but mortality is under D% and treated

correctly most of the patients leadproductive lives.

:hymic gland is involved as primary site of

antibody production

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:hymic involvement

:rue neoplasm are found in 0!D% of

patients

6D% of the remaining patients shows an

important degree of hyperplasia of

lymphoid follicles with active germinal

centers confined to the medullary part of

the thymus gland. Mediastinal +: scann is commonly used

to document thymus morphologic

changes.

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,iagnosis

Measurement of receptor antibodies in

blood " sensitive and highly specific test

7-A is the method of choice

E0!B0% of patients with generalied

myasthenia and 60% of those who are

restricted to ocular muscles

eronegativity does not imply clinical orelectrophysiological differences.

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9lectrophysiology

5erve conduction studies and 9M1 are

both normal in myasthenic patients

7epetitive nerve "muscle stimulation

7apid reduction in amplitude of compound

muscle action potentials after '=sec

stimulation of a peripheral nerve "

decremental response and reversal of thisresponse by anticholinesterase drugs is a

reliable confirmation of diagnosis.

: t t

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:reatment -. !nticholinesterase drugs " neostigmin &miostin( and

pyridostigmine &mestinon(

-ncrese the availability of Ach in the synaptic cleft and improve

the myasthenic deficit

ide effects " cholinergic muscarinic &nausea vomiting

salivation diarrhea miosis bradycardia(

+holinergic crisis " rapid escaladation of muscular wea*ness

due bell shape effect of drugs on neuromuscular Hunction $hymectomy % recommended in the first ' years and in tumoral

patients ! is followed by significant improvement and chance of

better control with corticosteroids afterward

&orticosteroids are the most consistently effective form of

treatment in moderate to severe generali'ed eakness.Managing side effects is chalenging

)mmunosupressants - as an adHunct to steroids or the one that fail

to respond to corticotherapy

P* or )v immune globulin % for myasthenic crisis,

reechilibration for surgery, refractory patients.

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Myasthenic crisis

+areful intubation followed by mechanical

ventilation

Anticholinesterae drugs withdrawn

P9 or -v -g " hasten improvement