SKELETAL MUSCLE PATHOLOGY Part II

Classification of Muscle Disease Dystrophies Dystrophies –Duchenne’s Muscular Dystrophy –Becker’s Muscular Dystrophy –Myotonic Dystrophy Metabolic Myopathies Metabolic Myopathies -Glycogen Storage Diseases -Glycogen Storage Diseases -Mitochondrial Myopathies -Mitochondrial Myopathies

Inflammatory Myopathies Inflammatory Myopathies –Infectious Myositis –Non-Infectious Myositis (Auto-immune ) 1-Polymyositis2-Dermatomyositis 3-Inclusion body myositis

Endocrine and Toxic Myopathies Endocrine and Toxic Myopathies -Thyrotoxic Myopathy -Alcohol Myopathy -Steroids Myopathy - Hyperparathyroidism -Adrenal insufficiency -Hypokalemia Diseases of the Neuromuscular Junction Diseases of the Neuromuscular Junction -Myasthenia Gravis -Lambert-Eaton Syndrome

Myotonic Dystrophy

Introduction: The word myotonic is the adjective for the word myotonia, an inability to relax muscles at will (delayed relaxation of a muscle after voluntary contraction) The word myotonic is the adjective for the word myotonia, an inability to relax muscles at will (delayed relaxation of a muscle after voluntary contraction) Prevalence: 1 in 8000 Prevalence: 1 in 8000 Cause: Abnormality in a gene on chromosome 19 Cause: Abnormality in a gene on chromosome 19 Adult form: Autosomal dominant inheritance Adult form: Autosomal dominant inheritance

Weakness of the voluntary muscles usually is the most noticeable symptom Weakness of the voluntary muscles usually is the most noticeable symptom Myotonia makes it difficult to relax the fingers after a firm hand grip Myotonia makes it difficult to relax the fingers after a firm hand grip Muscle pain also can occur in MMD Muscle pain also can occur in MMD

Myotonic dystrophy Normal grip Weak grip of MMD

MMD has two forms the adulthood MMD and the congenital MMD Adulthood MMD usually allows people to walk before it becomes a problem and patients are fairly independent throughout their lives. Adulthood MMD usually allows people to walk before it becomes a problem and patients are fairly independent throughout their lives. In the congenital form of MMD there is severe muscle weakness, including weakening of the muscles that control breathing and swallowing. These problems can be life-threatening and need intensive care. In the congenital form of MMD there is severe muscle weakness, including weakening of the muscles that control breathing and swallowing. These problems can be life-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 MMD: Limb muscles Weakness of the voluntary muscles Weakness of the voluntary muscles The distal muscles usually are the first to be affected The distal muscles usually are the first to be affected People with MMD often notice that their grip is weak and that they have trouble using their wrist or hand muscles People with MMD often notice that their grip is weak and that they have trouble using their wrist or hand muscles The foot flops down leading to tripping and falling. This is called foot drop. The foot flops down leading to tripping and falling. This 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 dystrophy

Head, neck and face muscles The muscles of the neck, jaw and parts of the head and face weaken The muscles of the neck, jaw and parts of the head and face weaken Eyelids droop (ptosis) Eyelids droop (ptosis) The chewing muscles can be affected which makes the temples appear hollow and the face look thin The chewing muscles can be affected which makes the temples appear hollow and the face look thin

Myotonic dystrophy

Breathing and swallowing muscles: Respiratory muscles can become weak Respiratory muscles can become weak Weakness of the diaphragm and other breathing muscles lead to symptoms of breathing difficulty Weakness of the diaphragm and other breathing muscles lead to symptoms of breathing difficulty Swallowing muscles, if weakened, can lead to choking with food or liquid going down the trachea Swallowing muscles, if weakened, can lead to choking with food or liquid going down the trachea Myotonia also can affect the muscles of the tongue and jaw causing difficulty with speech and chewing. Myotonia also can affect the muscles of the tongue and jaw causing difficulty with speech and 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 problems Conduction block i.e. block in the electricity signal that keeps the heart beating. Conduction block i.e. block in the electricity signal that keeps the heart 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 involuntary muscles) Abnormal weakness of the digestive tract Abnormal weakness of the digestive tract Crampy pain, constipation and diarrhea can occur. Crampy pain, constipation and diarrhea can occur. The gallbladder: People with MMD probably are likely to develop gallstones. The gallbladder: People with MMD probably are likely to develop gallstones.

Women with MMD experience difficulties in childbirth that can be serious for both mother and baby. Women with MMD experience difficulties in childbirth that can be serious for both mother and baby. Men with MMD may experience atrophy (shrinking) of the testicles and reduced fertility Fortunately most patients don’t have problems in urinating or holding onto urine in MMD. Fortunately most patients don’t have problems in urinating or holding onto 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 brain MMD patients are slow, dull, uncaring, unenthusiastic or depressed MMD patients are slow, dull, uncaring, unenthusiastic or depressed Children born with the congenital form MMD have a lot of learning problems Children born with the congenital form MMD have a lot of learning problems

The eyes Cataracts — cloudy areas of the lens of the eye that eventually can interfere with vision — are extremely common in MMD Cataracts — cloudy areas of the lens of the eye that eventually can interfere with vision — are extremely common in MMD Surgery can remove the lens that contains a cataract and the surgeon inserts an artificial lens Surgery can remove the lens that contains a cataract and the surgeon inserts an artificial 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 Syndrome

Definition: (“Autoimmune" disease). The attack occurs at the junction between nerve and muscle and interferes with the ability of nerve cells to send signals to muscle cells The attack occurs at the junction between nerve and muscle and interferes with the ability of nerve cells to send signals to muscle cells Associated with some type of cancer in about 60 percent of cases (mostly bronchial small cell carcinoma) Associated with some type of cancer in about 60 percent of cases (mostly bronchial small cell carcinoma) Onset - childhood to adulthood Onset - childhood to adulthood Eaton – Lambert Syndrome

Cause: If LES appears in association with cancer then the cause may be that the body’s attempt to fight the cancer inadvertently causes it to attack nerve fiber endings (specifically, the so-called voltage-gated calcium channels found there) (presynaptic calcium channels) If LES appears in association with cancer then the cause may be that the body’s attempt to fight the cancer inadvertently causes it to attack nerve fiber endings (specifically, the so-called voltage-gated calcium channels found there) (presynaptic calcium channels) The trigger for LES when not associated with cancer is unknown The trigger for LES when not associated with cancer is unknown

Pathogenesis: Nerve impulses in the body are electrical and currents that travel down a nerve fiber. When they reach the end of that nerve fiber, they trigger the release of a chemical neurotransmitter such as acetylcholine. Nerve impulses in the body are electrical and currents that travel down a nerve fiber. When they reach the end of that nerve fiber, they trigger the release of a chemical neurotransmitter such as acetylcholine. Acetylcholine must cross a tiny gap called the synapse in order to stimulate the muscle to contract. Acetylcholine must cross a tiny gap called the synapse in order to stimulate the muscle to contract. In LEMS, antibodies stop the nerve releasing enough acetylcholine to get a strong nerve impulse from the nerve to the muscle – there is not enough acetylcholine released. In LEMS, antibodies stop the nerve releasing enough acetylcholine to get a strong nerve impulse from the nerve to the muscle – there is not enough acetylcholine released.

Symptoms: Initially, leg weakness and difficulty walking; weakness of the eye muscles and those involved in talking, chewing and swallowing may occur later Initially, leg weakness and difficulty walking; weakness of the eye muscles and those involved in talking, chewing and swallowing may occur later Dry mouth, constipation and bladder urgency sometimes occur Dry mouth, constipation and bladder urgency sometimes occur Males are more commonly affected Males are more commonly affected Repeated stimulation to the muscle lead to improved neurotransmission. Repeated stimulation to the muscle lead to improved neurotransmission.

Distribution of affected muscles Eaton – Lambert Syndrome

Progression - depends on whether it occurs with cancer or not Progression - depends on whether it occurs with cancer or not Treatable in all forms Treatable in all forms Inheritance - There appears to be a genetic predisposition to autoimmune diseases. Inheritance - There appears to be a genetic predisposition to autoimmune diseases.

How Is LEMS Diagnosed? The autonomic symptoms and predominant leg weakness of LEMS help to distinguish it from MG. The autonomic symptoms and predominant leg weakness of LEMS help to distinguish it from MG. Electrodiagnostic testing that shows an increased muscle response to repeated stimulation also favors LEMS rather than MG (in which the response decreases). Electrodiagnostic testing that shows an increased muscle response to repeated stimulation also favors LEMS rather than MG (in which the response decreases). In most cases, LEMS can be confirmed by detection of anti-VGCC antibodies (voltage- gated calcium channel ) in the blood. In most cases, LEMS can be confirmed by detection of anti-VGCC antibodies (voltage- gated calcium channel ) in the blood.

Metabolic Diseases of Muscles

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

What Causes Metabolic Diseases? In normal metabolism, food provides fuel that's processed inside the cells, producing energy for muscle contraction and other cellular functions. In normal metabolism, food provides fuel that's processed inside the cells, producing energy for muscle contraction and other cellular functions. In metabolic myopathies, missing enzymes prevent mitochondria from properly processing fuel and so no energy is produced for muscle function In metabolic myopathies, missing enzymes prevent mitochondria from properly processing fuel and so no energy is produced for muscle function

There are 10 metabolic diseases of muscle. Each one gets its name from the substance that's lacking: 1.Acid maltase deficiency (pompe's disease) Acid maltase deficiencyAcid maltase deficiency 2.Carnitine deficiency Carnitine deficiencyCarnitine deficiency 3.Carnitine palmityl transferase deficiency Carnitine palmityl transferase deficiencyCarnitine palmityl transferase deficiency 4.Debrancher enzyme deficiency (cori's or forbes' disease) Debrancher enzyme deficiencyDebrancher enzyme deficiency 5.Lactate dehydrogenase deficiency Lactate dehydrogenase deficiencyLactate dehydrogenase deficiency 6.Myoadenylate deaminase deficiency Myoadenylate deaminase deficiencyMyoadenylate deaminase deficiency 7.Phosphofructokinase deficiency (tarui's disease) Phosphofructokinase deficiencyPhosphofructokinase deficiency 8.Phosphoglycerate kinase deficiency Phosphoglycerate kinase deficiencyPhosphoglycerate kinase deficiency 9.Phosphoglycerate mutase deficiency Phosphoglycerate mutase deficiencyPhosphoglycerate mutase deficiency 10.Phosphorylase deficiency (McArdle's disease) Phosphorylase deficiencyPhosphorylase deficiency

Acid Maltase Deficiency (Pompe Disease) Definition: - Definition: - One of a group of muscle diseases that interfere with the processing of carbohydrates Cause: Cause: –A defect in the gene for the acid maltase enzyme that prevents the breakdown of glycogen (stored sugar) to glucose Onset: Onset: infancy to adulthood infancy to adulthood

Onset: Onset: infancy to adulthood infancy to adulthoodSymptoms: –Slowly progressive weakness of respiratory muscles and muscles of the hips, upper legs, shoulders and upper arms –Cardiac involvement in infantile-onset form

Inheritance: Inheritance: –Autosomal recessive, meaning caused by the contribution of a defective gene from each parent Progression: –Slowly progressive in adult-onset forms –Infantile form usually leads to death within first year of life unless treated early

Phosphorylase Deficiency (McArdle Disease) Definition: Definition: –One of a group of muscle diseases that interfere with the processing of carbohydrates for energy production Inheritance: Inheritance: –Autosomal recessive, meaning caused by the contribution of a defective gene from each parent

Cause: Cause: –A genetic defect in the phosphorylase enzyme, which affects the breakdown of glycogen, the stored form of glucose (sugar) Onset Onset - Usually before age 15 - Usually before age 15

Symptoms: Symptoms: –Exercise intolerance; cramps, muscle pain and weakness shortly after beginning exercise Progression: Progression: –Generally not progressive

How Are the Metabloic Diseases of Muscle Diagnosed? Blood tests can be used to detect the presence of certain chemicals in the blood that may indicate some metabolic diseases. Blood tests can be used to detect the presence of certain chemicals in the blood that may indicate some metabolic diseases. An exercise test is used to monitor a person's response to intense or moderate exercise. An exercise test is used to monitor a person's response to intense or moderate exercise. Electromyography (EMG) uses small needle electrodes to measure the electrical currents in a muscle as it contracts. Electromyography (EMG) uses small needle electrodes to measure the electrical currents in a muscle as it contracts.

A muscle biopsy requires the removal of a small piece of muscle tissue for microscopic analysis.. A muscle biopsy requires the removal of a small piece of muscle tissue for microscopic analysis.. Genetic tests using a blood sample can analyze the person's genes for particular defects that cause metabolic disease. Genetic tests using a blood sample can analyze the person's genes for particular defects that cause metabolic disease. Other tests that may be needed include an electrocardiogram to test heart function and brain imaging studies such as CT or MRI scans. Other tests that may be needed include an electrocardiogram to test heart function and brain imaging studies such as CT or MRI scans.

Mitochondrial Myopathies

Definition: Diseases that affect the mitochondria (tiny energy factories found inside all cells) and interfere with the function of muscles Diseases that affect the mitochondria (tiny energy factories found inside all cells) and interfere with the function of muscles Onset: Onset: –Varies according to disease

Cause: Cause: –A defect in a mitochondrial gene that affects the function of the mitochondria Pathological Findings: Pathological Findings: 1-Increased numbers of mitochondria with abnormalities in their sizes and shapes causing irregular muscle fiber contour 2-May contain inclusion bodies (parking lot) or alterations in the structure of the cristae

Normal Muscle Irregular Muscle Contour Normal Muscle Irregular Muscle Contour

Normal Muscle Parking lot

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

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

How are mitochondrial diseases diagnosed? The symptoms of mitochondrial disease: The symptoms of mitochondrial disease: Muscle weakness, exercise intolerance, hearing impairment, ataxia, seizures, learning disabilities, cataracts, heart defects, diabetes and stunted growth are unique to mitochondrial disease. However a combination of three or more of these symptoms in one person strongly points to mitochondrial disease, especially when the symptoms involve more than one organ system. However a combination of three or more of these symptoms in one person strongly points to mitochondrial disease, especially when the symptoms involve more than one organ system.

Diagnostic tests in mitochondrial diseases 1. The physical exam which can involve activities like repeatedly making a fist, or climbing up and down a small flight of stairs. The neurological exam can include tests of reflexes, vision and speech. 2. The most important of these tests is the muscle biopsy, which involves removing a small sample of muscle tissue to examine. 3. CT scans and MRI scans can be used to visually inspect the brain for signs of damage 4. Genetic test can determine whether someone has a genetic mutation that causes mitochondrial disease.

Toxic Myopathies Alcohol: Binge drinking can produce an acute toxic syndrome of rhadomyolysis with accompanying myoglobinuria. It may lead to renal failure Alcohol: Binge drinking can produce an acute toxic syndrome of rhadomyolysis with accompanying myoglobinuria. It may lead to renal failure Steroids: Proximal muscle weakness and atrophy may occur in Cushing syndrome or during therapeutic administration of steroids Steroids: Proximal muscle weakness and atrophy may occur in Cushing syndrome or during therapeutic administration of steroids

THANK YOU