SKELETAL MUSCLE SKELETAL MUSCLE PATHOLOGYPATHOLOGY

Part IIPart II

Classification of Muscle Classification of Muscle DiseaseDisease

DystrophiesDystrophies– Duchenne’s Muscular DystrophyDuchenne’s Muscular Dystrophy– Becker’s Muscular DystrophyBecker’s Muscular Dystrophy– Myotonic DystrophyMyotonic Dystrophy

Metabolic MyopathiesMetabolic Myopathies -Glycogen Storage Diseases -Glycogen Storage Diseases

-Mitochondrial Myopathies-Mitochondrial Myopathies

Inflammatory MyopathiesInflammatory Myopathies– Infectious MyositisInfectious Myositis– Non-Infectious Myositis (Auto-immune )Non-Infectious Myositis (Auto-immune )

1-Polymyositis1-Polymyositis

2-Dermatomyositis2-Dermatomyositis

3-Inclusion body myositis3-Inclusion body myositis

Endocrine and Toxic MyopathiesEndocrine and Toxic Myopathies-Thyrotoxic Myopathy-Thyrotoxic Myopathy

-Alcohol Myopathy-Alcohol Myopathy

-Steroids Myopathy-Steroids Myopathy

--HyperparathyroidismHyperparathyroidism

-Adrenal insufficiency-Adrenal insufficiency

-Hypokalemia-Hypokalemia

Diseases of the Neuromuscular JunctionDiseases of the Neuromuscular Junction-Myasthenia Gravis-Myasthenia Gravis

-Lambert-Eaton Syndrome-Lambert-Eaton Syndrome

Myotonic Myotonic DystrophyDystrophy

IntroductionIntroduction::

The word myotonic is the adjective for the word The word myotonic is the adjective for the word myotonia, an inability to relax muscles at will myotonia, an inability to relax muscles at will (delayed relaxation of a muscle after voluntary (delayed relaxation of a muscle after voluntary contraction)contraction)

Prevalence: 1 in 8000Prevalence: 1 in 8000

Cause: Cause: AbnormalityAbnormality in a gene on chr in a gene on chromosomeomosome 19 19

Adult form: Adult form: Autosomal dominant inheritanceAutosomal dominant inheritance

Weakness of the voluntary muscles Weakness of the voluntary muscles usually is the most noticeable usually is the most noticeable symptomsymptom

Myotonia makes it difficult to relax Myotonia makes it difficult to relax the fingers after a firm hand gripthe fingers after a firm hand grip

Muscle pain also can occur in MMDMuscle pain also can occur in MMD

Myotonic dystrophyMyotonic dystrophy

Normal grip

Weak grip of MMD

MMD has two forms the adulthood MMD MMD has two forms the adulthood MMD and the congenital MMDand the congenital MMD

Adulthood MMD usually allows people to walk Adulthood MMD usually allows people to walk before it becomes a problem and patients are before it becomes a problem and patients are fairly independent throughout their lives.fairly independent throughout their lives.

In the congenital form of MMD there is severe In the congenital form of MMD there is severe muscle weakness, including weakening of the muscle weakness, including weakening of the muscles that control breathing and muscles that control breathing and swallowing. These problems can be life-swallowing. These problems can be life-threatening and need intensive care.threatening and need intensive care.

A child born with congenital myotonic dystrophy is likely to have facial muscle weakness. The eye muscles also may be affected

Pathology of MMDPathology of MMD::Limb musclesLimb muscles

Weakness of the voluntary musclesWeakness of the voluntary muscles

The distal muscles usually are the first to be affectedThe distal muscles usually are the first to be affected

People with MMD often notice that their grip is weak People with MMD often notice that their grip is weak and that they have trouble using their wrist or hand and that they have trouble using their wrist or hand musclesmuscles

The foot flops down leading to tripping and falling. This The foot flops down leading to tripping and falling. This is called foot drop.is called foot drop.

Weakness and wasting of voluntary muscles in the face, neck and lower arms and legs

Muscles between the ribs and those of the diaphragm, which moves up and down to allow inhalation and exhalation of air, also can be weakened.

Myotonic Myotonic dystrophydystrophy

Myotonic dystrophyMyotonic dystrophy

Head, neck and face musclesHead, neck and face muscles The muscles of the neck, jaw and parts of The muscles of the neck, jaw and parts of

the head and face weakenthe head and face weaken

Eyelids droop (ptosis)Eyelids droop (ptosis)

The chewing muscles can be affected The chewing muscles can be affected which makes the temples appear hollow which makes the temples appear hollow and the face look thinand the face look thin

Myotonic dystrophyMyotonic dystrophy

Breathing and swallowing muscles:Breathing and swallowing muscles: Respiratory muscles can become weak Respiratory muscles can become weak

Weakness of the diaphragm and other breathing Weakness of the diaphragm and other breathing muscles lead to symptoms of breathing difficultymuscles lead to symptoms of breathing difficulty

Swallowing muscles, if weakened, can lead to Swallowing muscles, if weakened, can lead to choking with food or liquid going down the tracheachoking with food or liquid going down the trachea

Myotonia also can affect the muscles of the tongue Myotonia also can affect the muscles of the tongue and jaw causing difficulty with speech and and jaw causing difficulty with speech and chewing.chewing.

A good way to treat respiratory muscle weakness is to pump air into the lungs during the night with a small, portable ventilator

Heart problemsHeart problems Conduction block i.e. block in the Conduction block i.e. block in the

electricity signal that keeps the heart electricity signal that keeps the heart beating.beating.

Conduction blocks can usually be corrected by a cardiac pacemaker, an electronic device that’s surgically inserted near the heart to regulate the heartbeat.

A cardiac pacemaker can return the heartbeat to a normal rhythm

Internal organs (Affection of Internal organs (Affection of involuntary muscles)involuntary muscles)

Abnormal weakness of the digestive tractAbnormal weakness of the digestive tract

Crampy pain, constipation and diarrhea Crampy pain, constipation and diarrhea can occur.can occur.

The gallbladder: People with MMD The gallbladder: People with MMD probably are likely to develop gallstones.probably are likely to develop gallstones.

Women with MMD experience Women with MMD experience difficulties in childbirth that can be difficulties in childbirth that can be serious for both mother and baby.serious for both mother and baby.

Men with MMD may experience atrophy Men with MMD may experience atrophy (shrinking) of the testicles and reduced (shrinking) of the testicles and reduced fertilityfertility

Fortunately most patients don’t have Fortunately most patients don’t have problems in urinating or holding onto problems in urinating or holding onto urine in MMD.urine in MMD.

The digestive tract and uterus often are affected in myotonic dystrophy.

These organs contain involuntary muscles which can weaken or have trouble relaxing

The brainThe brain MMD patients are slow, dull, MMD patients are slow, dull,

uncaring, unenthusiastic or uncaring, unenthusiastic or depresseddepressed

Children born with the congenital Children born with the congenital form MMD have a lot of learning form MMD have a lot of learning problemsproblems

The eyesThe eyes Cataracts — cloudy areas of the lens of the Cataracts — cloudy areas of the lens of the

eye that eventually can interfere with eye that eventually can interfere with vision — are extremely common in MMDvision — are extremely common in MMD

Surgery can remove the lens that contains Surgery can remove the lens that contains a cataract and the surgeon inserts an a cataract and the surgeon inserts an artificial lensartificial lens

The eye’s lens focuses light on the back part of the eye to allow vision. When cataracts cloud the lens, the visual image is no longer as clear

If patient is planning surgery, the neurologist, anesthesiologist and surgeon should know if the patient has myotonic dystrophy

Anesthesia

A high rate of complications and even deaths are associated with general anesthesia have been reported in people with MMD

Eaton – Lambert Eaton – Lambert SyndromeSyndrome

Definition:Definition: (“Autoimmune" disease) (“Autoimmune" disease). . The attack occurs at the junction The attack occurs at the junction

between nerve and muscle and between nerve and muscle and interferes with the ability of nerve interferes with the ability of nerve cells to send signals to muscle cellscells to send signals to muscle cells

Associated with some type of cancer Associated with some type of cancer in about 60 percent of cases (mostly in about 60 percent of cases (mostly bronchial small cell carcinoma)bronchial small cell carcinoma)

OnsetOnset - childhood to adulthood - childhood to adulthood

Eaton – Lambert SyndromeEaton – Lambert Syndrome

Cause:Cause: If LES appears in association with cancer If LES appears in association with cancer

then the cause may be that the body’s then the cause may be that the body’s attempt to fight the cancer inadvertently attempt to fight the cancer inadvertently causes it to attack nerve fiber endings causes it to attack nerve fiber endings (specifically, the so-called (specifically, the so-called voltage-gated voltage-gated calcium channels calcium channels found there) found there) (presynaptic calcium channels)(presynaptic calcium channels)

The trigger for LES when not associated The trigger for LES when not associated with cancer is unknown with cancer is unknown

Pathogenesis:Pathogenesis: Nerve impulses in the body are electrical and Nerve impulses in the body are electrical and

currents that travel down a nerve fiber. When they currents that travel down a nerve fiber. When they reach the end of that nerve fiber, they trigger the reach the end of that nerve fiber, they trigger the release of a chemical neurotransmitter such as release of a chemical neurotransmitter such as acetylcholine. acetylcholine.

Acetylcholine must cross a tiny gap called the Acetylcholine must cross a tiny gap called the synapse in order to stimulate the muscle to contract. synapse in order to stimulate the muscle to contract.

In LEMS, antibodies stop the nerve releasing enough In LEMS, antibodies stop the nerve releasing enough acetylcholine to get a strong nerve impulse from the acetylcholine to get a strong nerve impulse from the nerve to the muscle – there is not enough nerve to the muscle – there is not enough acetylcholine released.acetylcholine released.

Symptoms:Symptoms: Initially, leg weakness and difficulty walking; weakness of Initially, leg weakness and difficulty walking; weakness of

the eye muscles and those involved in talking, chewing the eye muscles and those involved in talking, chewing and swallowing may occur laterand swallowing may occur later

Dry mouth, constipation and bladder urgency sometimes Dry mouth, constipation and bladder urgency sometimes

occur occur

Males are more commonly affectedMales are more commonly affected

Repeated stimulation to the muscle lead to improved Repeated stimulation to the muscle lead to improved neurotransmission.neurotransmission.

Distribution of affected muscles

Eaton – Lambert Eaton – Lambert SyndromeSyndrome

Eaton – Lambert SyndromeEaton – Lambert Syndrome

Progression Progression - depends on whether - depends on whether it occurs with cancer or not it occurs with cancer or not

Treatable in all formsTreatable in all forms

Inheritance Inheritance - There appears to be a - There appears to be a genetic predisposition to genetic predisposition to autoimmune diseases.autoimmune diseases.

How Is LEMS Diagnosed?

The autonomic The autonomic symptomssymptoms and predominant and predominant leg weakness leg weakness of LEMS help to distinguish it of LEMS help to distinguish it from MG. from MG.

ElectrodiagnosticElectrodiagnostic testing that shows an testing that shows an increased muscle response to repeated increased muscle response to repeated stimulation also favors LEMS rather than MG stimulation also favors LEMS rather than MG (in which the response decreases). (in which the response decreases).

In most cases, LEMS can be confirmed by In most cases, LEMS can be confirmed by detection of detection of anti-VGCC antibodies anti-VGCC antibodies ((voltage-voltage-gated calcium channel )gated calcium channel ) in the blood. in the blood.

Metabolic Diseases Metabolic Diseases of Musclesof Muscles

Metabolic Diseases of Metabolic Diseases of MusclesMuscles

The metabolic diseases of muscle The metabolic diseases of muscle interfere with chemical reactions interfere with chemical reactions involved in drawing energy from involved in drawing energy from food. food.

Metabolic diseases of muscle can affect all the body's voluntary muscles, such as those in the arms, legs and trunk.

Also involve heart or liver diseases, and the kidneys (parenchymatous organs)

Metabolic Diseases of Metabolic Diseases of MusclesMuscles

What Causes What Causes Metabolic DiseasesMetabolic Diseases??

In normal metabolism, food provides fuel that's processed inside the cells, In normal metabolism, food provides fuel that's processed inside the cells, producing energy for muscle contraction and other cellular functions. producing energy for muscle contraction and other cellular functions.

In metabolic myopathies, missing enzymes prevent mitochondria from In metabolic myopathies, missing enzymes prevent mitochondria from properly processing fuel and so no energy is produced for muscle functionproperly processing fuel and so no energy is produced for muscle function

There are 10 metabolic diseases of muscle. Each one There are 10 metabolic diseases of muscle. Each one gets its name from the substance that's lacking:gets its name from the substance that's lacking:1.1. Acid maltase deficiency (pompe's disease) Acid maltase deficiency (pompe's disease)

2.2. Carnitine deficiency Carnitine deficiency

3.3. Carnitine palmityl transferase deficiency Carnitine palmityl transferase deficiency

4.4. Debrancher enzyme deficiency (cori's or forbes' disease) Debrancher enzyme deficiency (cori's or forbes' disease)

5.5. Lactate dehydrogenase deficiency Lactate dehydrogenase deficiency

6.6. Myoadenylate deaminase deficiency Myoadenylate deaminase deficiency

7.7. Phosphofructokinase deficiency (tarui's disease) Phosphofructokinase deficiency (tarui's disease)

8.8. Phosphoglycerate kinase deficiency Phosphoglycerate kinase deficiency

9.9. Phosphoglycerate mutase deficiency Phosphoglycerate mutase deficiency

10.10.Phosphorylase deficiency (McArdle's disease)Phosphorylase deficiency (McArdle's disease)

Acid Maltase Deficiency Acid Maltase Deficiency (Pompe Disease)(Pompe Disease)

Definition:Definition: - - One of a group of muscle diseases that interfere with One of a group of muscle diseases that interfere with

the processing of carbohydratesthe processing of carbohydrates Cause:Cause:

– A defect in the gene for the acid maltase enzyme A defect in the gene for the acid maltase enzyme that prevents the breakdown of glycogen (stored that prevents the breakdown of glycogen (stored sugar) to glucose sugar) to glucose

Onset:Onset: infancy to adulthoodinfancy to adulthood

Onset:Onset: infancy to adulthoodinfancy to adulthood

Symptoms:Symptoms:– Slowly Slowly progressive weaknessprogressive weakness of respiratory of respiratory

muscles and muscles of the hips, upper legs, muscles and muscles of the hips, upper legs, shoulders and upper armsshoulders and upper arms

– Cardiac involvementCardiac involvement in infantile-onset form in infantile-onset form

Inheritance:Inheritance: – Autosomal recessive, meaning caused by Autosomal recessive, meaning caused by

the contribution of a defective gene from the contribution of a defective gene from each parenteach parent

Progression:Progression:– Slowly progressive in adult-onset formsSlowly progressive in adult-onset forms– Infantile form usually leads to death within Infantile form usually leads to death within

first year of life unless treated earlyfirst year of life unless treated early

Phosphorylase DeficiencyPhosphorylase Deficiency(McArdle Disease)(McArdle Disease)

Definition:Definition:– One of a group of muscle diseases that One of a group of muscle diseases that

interfere with the processing of carbohydrates interfere with the processing of carbohydrates for energy productionfor energy production

Inheritance:Inheritance:– Autosomal recessive, meaning caused by the Autosomal recessive, meaning caused by the

contribution of a defective gene from each contribution of a defective gene from each parentparent

Cause:Cause:– A genetic defect in the phosphorylase A genetic defect in the phosphorylase

enzyme, which affects the breakdown of enzyme, which affects the breakdown of glycogen, the stored form of glucose glycogen, the stored form of glucose (sugar)(sugar)

OnsetOnset

- - Usually before age 15 Usually before age 15

Symptoms:Symptoms: – Exercise intolerance; cramps, muscle Exercise intolerance; cramps, muscle

pain and weakness shortly after pain and weakness shortly after beginning exercisebeginning exercise

Progression:Progression: – Generally not progressiveGenerally not progressive

How Are the Metabloic Diseases of How Are the Metabloic Diseases of Muscle Diagnosed?Muscle Diagnosed?

Blood testsBlood tests can be used to detect the presence of can be used to detect the presence of certain chemicals in the blood that may indicate certain chemicals in the blood that may indicate some metabolic diseases.some metabolic diseases.

An exercise testAn exercise test is used to monitor a person's is used to monitor a person's response to intense or moderate exercise. response to intense or moderate exercise.

Electromyography (EMG)Electromyography (EMG) uses small needle uses small needle electrodes to measure the electrical currents in a electrodes to measure the electrical currents in a muscle as it contracts.muscle as it contracts.

A muscle biopsyA muscle biopsy requires the removal of a small requires the removal of a small piece of muscle tissue for microscopic analysis..piece of muscle tissue for microscopic analysis..

Genetic testsGenetic tests using a blood sample can analyze using a blood sample can analyze the person's genes for particular defects that cause the person's genes for particular defects that cause metabolic disease.metabolic disease.

Other testsOther tests that may be needed include an that may be needed include an electrocardiogramelectrocardiogram to test heart function and to test heart function and brain brain imaging studiesimaging studies such as CT or MRI scans. such as CT or MRI scans.

Mitochondrial Mitochondrial MyopathiesMyopathies

Mitochondrial MyopathiesMitochondrial MyopathiesDefinition:Definition: Diseases that affect the mitochondria (tiny Diseases that affect the mitochondria (tiny

energy factories found inside all cells) and energy factories found inside all cells) and interfere with the function of musclesinterfere with the function of muscles

Onset:Onset: – Varies according to diseaseVaries according to disease

Cause:Cause:– A defect in a mitochondrial gene that A defect in a mitochondrial gene that

affects the function of the mitochondriaaffects the function of the mitochondria

Pathological Findings: Pathological Findings: 1-Increased numbers of mitochondria with 1-Increased numbers of mitochondria with

abnormalities in their sizes and shapes abnormalities in their sizes and shapes causing irregular muscle fiber contourcausing irregular muscle fiber contour

2-May contain inclusion bodies (parking lot) or 2-May contain inclusion bodies (parking lot) or alterations in the structure of the cristaealterations in the structure of the cristae

Normal Muscle Irregular Muscle Normal Muscle Irregular Muscle ContourContour

Normal Muscle Normal Muscle Parking lotParking lot

Symptoms:Symptoms: Nervous system impairment Nervous system impairment Eye problemsEye problems Cardiac abnormalitiesCardiac abnormalities Skeletal muscle abnormalitiesSkeletal muscle abnormalities Disorders of the gastrointestinal tractDisorders of the gastrointestinal tract

Some people with mitichondrial myopathies lose strength in their legs and need a wheelchair

How are mitochondrial How are mitochondrial diseases diagnoseddiseases diagnosed??

The symptoms of mitochondrial disease: The symptoms of mitochondrial disease:

Muscle weakness, exercise intolerance, hearing Muscle weakness, exercise intolerance, hearing impairment, ataxia, seizures, learning disabilities, impairment, ataxia, seizures, learning disabilities, cataracts, heart defects, diabetes and stunted cataracts, heart defects, diabetes and stunted growth are unique to mitochondrial disease. growth are unique to mitochondrial disease.

However a combination of three or more of these However a combination of three or more of these symptoms in one person strongly points to symptoms in one person strongly points to mitochondrial disease, especially when the mitochondrial disease, especially when the symptoms involve more than one organ system.symptoms involve more than one organ system.

Diagnostic tests in mitochondrial Diagnostic tests in mitochondrial diseasesdiseases

1.1. The physical examThe physical exam which can involve activities like which can involve activities like repeatedly making a fist, or climbing up and down a small repeatedly making a fist, or climbing up and down a small flight of stairs. The neurological exam can include tests of flight of stairs. The neurological exam can include tests of reflexes, vision and speech.reflexes, vision and speech.

2.2. The most important of these tests is the The most important of these tests is the muscle biopsymuscle biopsy, , which involves removing a small sample of muscle tissue to which involves removing a small sample of muscle tissue to examine. examine.

3.3. CT scans and MRICT scans and MRI scans can be used to visually inspect the scans can be used to visually inspect the brain for signs of damagebrain for signs of damage

4.4. Genetic testGenetic test can determine whether someone has a genetic can determine whether someone has a genetic mutation that causes mitochondrial disease.mutation that causes mitochondrial disease.

Toxic MyopathiesToxic Myopathies

Alcohol:Alcohol: Binge drinking can produce an Binge drinking can produce an acute toxic syndrome of rhadomyolysis acute toxic syndrome of rhadomyolysis with accompanying myoglobinuria. It with accompanying myoglobinuria. It may lead to renal failuremay lead to renal failure

Steroids:Steroids: Proximal muscle weakness Proximal muscle weakness and atrophy may occur in Cushing and atrophy may occur in Cushing syndrome or during therapeutic syndrome or during therapeutic administration of steroidsadministration of steroids

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