Unit 3 Week 17- Muscle Weakness

Define myopathy

disease of the muscle tissue

Lower Motor Neuron defects can be symmetrical or asymmetrical and discrete:

*Amyotrophic Lateral Sclerosis* *Guillain-Barré syndrome* *Polio* *Cauda Equina Syndrome* *B12 deficiency peripheral neuropathy* *Diabetic neuropathy* (when involving motor neuron)

A 55-year-old male patient with possible diagnosis of Duchenne muscular dystrophy was being discussed while waiting for his biopsy report. The attending physician focused his attention on the histological basis of this disease, he asked which protein is involved in the pathogenesis of Duchenne muscular dystrophy? A. Myosin B. Dystrophin C. Troponin D. Tropomyosin E. F-Actin

*B. Dystrophin protein* Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the costamere or the dystrophin-associated protein complex. This protein plays a role in keeping cells intact.

A 35-year-old female patient with a complaint of retro-orbital pain following a fall today at home last night, at a joint pre-ground round morning report today. The attending professor of pathology focused on the histology of retro-orbital eye muscles, and asked which of these structures is a component of muscle protein, myosin? A. Troponin B. F-Actin C. Regulatory Light Chain D. Tropomyosin E. G-Actin

*C. Regulatory Light Chain* Myosin is a hexameric proteins with two identical heavy chains and two pairs of different light chains. The two light chains are Essential light chain and Regulatory light chain.

A 45-year-old male patient with medical history significant for rhabdomyosistis of the right calf was discussed, at joint tumor board clinical conference today. The patient appears to be doing well on his current medication. Your professor of histology asked, which of the following connective tissue structures enclose a fascicule? A. Deep fascia B. Superficial fascia C. Endomysium D. Perimysium E. Epimysium

*D. Perimysium* Perimysium is a sheath of connective tissue that groups muscle fibers into bundles (anywhere between 10 and 100 or more) or fascicles. Recent advances in muscle physiology suggest that the perimysium plays a role in transmitting lateral contractile movements

How is Myasthenia Gravis diagnosed and treated?

*Diagnosis:* Electrodiagnostics- Repetitive nerve stimulation with small pulses of electricity. Muscle fibers in myasthenia gravis do not respond well to repeated electrical stimulation. Blood test- *elevated levels of serum antibodies to AChR* *Treatment:* No cure but improvement in strength with treatment Anti-cholinesterase drugs slow the destruction of acetylcholine Immunosuppressive drugs suppress production of autoantibodies Rituximab- B cell depletion Plasmapheresis- removal, treatment, and return or exchange of blood plasma Thymectomy

How is Multiple Sclerosis diagnosed and treated?

*Diagnosis:* Lumbar puncture, analysis of CSF for mildly elevated protein, elevated IgG (high IgG/albumin ratio), oligoclonal bands on protein electrophoresis (90% of patients); gandolinium-enhancing lesions on MRI *Treatment:* No cure, treatment with various agents early in the disease may delay progression Antibody against VLA-4 (integrin) - to inhibit leukocyte migration into the CNS across BBB IFN-β- may decrease differentiation of T cells into TH17 cells; Promotes shedding of adhesion molecules, decreases production of IL-12 and induces secretion of IL-10; may decrease differentiation of T cells into TH17 cells; increases numbers of a newly discovered type of Treg cell, called (FoxA1+) Tregs (stay tuned). B cell depletion using anti CD20 antibodies (Rituximab)

How is Guillain-Barré Syndrome diagnosed and treated?

*Diagnosis:* Lumbar puncture- CSF: increase in CSF protein due to inflammation, oligoclonal bands may be present serum: autoantibodies to gangliosides GM1 or GD1 or GQ1 may be present *Treatment:* Not responsive to steroids Hospitalize if respiratory support is indicated Plasmapheresis or IVIg for severe disease Up to 20% of hospitalized patients have long-term disability

A 47-year-old female patient with past medical history significant rotator cuff syndrome, was discussed today at the post clinic conference. Your professor while discussing the skeletal muscles involved in rotator cuff syndrome, focused his attention on the embryology of skeletal muscle. He asked, from which of these options does skeletal muscle develop? A. Osteoblast B. Endoderm C. Ectoderm D. Osteocyte E. Mesoderm

*E. Mesoderm* The mesoderm is one of the three germinal layers that appears in the third week of embryonic development. It is formed through a process called gastrulation. There are three important components, the paraxial mesoderm, the intermediate mesoderm and the lateral plate mesoderm. Specifically, somites and somitomeres form the musculature of the axial skeleton, body wall, limbs and head.

What skeletal muscle structure binds the fascicles into a single muscle?

*Epimysium*

What skeletal muscle structure provides larger blood vessels and nerves to skeletal muscles?

*Perimysium* Surrounding the individual fasciculi Composed of collagen and through which larger vessels and nerves run

*What are the types of Multiple Sclerosis?*

*Relapsing-remitting MS (RRMS)* recurrent attacks of neurologic dysfunction over days to weeks with or without recovery; between attacks, no progression of neurologic impairment is noted. Accounts for 85% of new-onset MS cases. *Secondary progressive MS (SPMS)* always initially presents as RRMS but evolves in many patients into SPMS (~1-2% each year). *Primary progressive MS (PPMS)* is characterized by gradual progression of disability from onset without discrete attacks; 15% of new-onset MS cases.

*Red Muscle Fiber* Characteristics

*Type I or Slow twitch* muscle fibers Rich vascular supply Small nerve fibers Small fiber diameter Numerous mitochondria Rich in myoglobin High in oxidative enzymes Poor in adenosine triposphatase Slower and weaker contraction, but repetitive; not easily fatigued

*White Muscle Fiber* Characteristics

*Type II or Fast twitch* muscle fibers Poor vascular supply Large nerve fibers Large fiber diameter Few mitochondria Poor in myoglobin Poor in oxidative enzymes Rich in adenosine triposphatase Faster and stronger contraction, but easily fatigued

Weakness and loss of motion can result when there is a defect or injury to the corticospinal tract.

*Weakness* can result from upper motor neuron defects, lower motor neuron defects, neuromuscular junction defects, or muscle defects.

Myasthenia Gravis Epidemiology

A chronic autoimmune neuromuscular disease that most commonly impacts women under 40 years old and men over 60 years old. 30 cases per 100,00 persons tRisk factors include thymic hyperplasia in 30% (especially in younger patients and thymoma in 10% of patients

Curare

A drug that competes with acetylcholine for receptors on motor end plate Decrease size of EPP (end plate potential) In maximal doses produces paralysis of the respiratory muscles and death

Neostigmine

A drug that inhibits the activity of acetylcholinesterase Prolongs and enhances action of Ach at motor end plate

*Denervation Atrophy*

A peripheral neuropathy in which there is axial degeneration leads to secondary muscle atrophy. Denervation atrophy of skeletal muscle reflects lesions of lower motor neurons. Following denervation, muscle atrophy occurs rapidly and results in presence of *very small, dark fibers that are angular* in cross-section and compressed by adjacent normal myofibers. Two-thirds of the muscle mass will be lost in 2-3 weeks. The angular atrophic fibers are a mixture of Type I and Type II fibers. Denervated muscle fibers may be eventually *reinnervated* by outgrowths from adjacent axons of healthy motor nerves. When this occurs the atrophy is reversed and the reinnervated fibers all adopt the fiber type characteristics of their innervating motor unit,*resulting in "blocks" or groups of a particular fiber type.* This is known as *"fiber type grouping"* and is pathognomonic for denervation followed by reinnervation. This results in weakness and fasciculations (a brief, spontaneous contraction affecting a small number of muscle fibers, often causing a flicker of movement under the skin.)

Define atrophy

A reduction in myofiber diameter due to loss of organelles including myofilaments.

*Dermatomyositis*

A systemic autoimmune disease of unknown cause that causes damage to small blood vessels in muscular tissue resulting in proximal muscle weakness and skin changes (rash). Inflammatory cells (CD4+ T-helper cells and complement) surround the blood vessels and eventually lead to destruction of muscle fibers. Vasculopathic changes can be seen as telangiectasias (dilated capillary loops) in the nail folds, eyelids, and gums, and as dropout of capillary vessels in skeletal muscle A distinctive feature of dermatomyositis is atrophy and degeneration of myofibers at the periphery of fascicles (*perifascicular atrophy*-PFA), which occurs even in absence of inflammation. Segmental fiber necrosis and regeneration may also be seen.

*Amyotrophic Lateral Sclerosis (ALS)*

ALS is a progressive neurological disease that both the upper motor neurons and the lower motor neurons degenerate or die, and stop sending messages to the muscles. Unable to function, the muscles gradually weaken, start to twitch (called fasciculations), and waste away (atrophy). Eventually, the brain loses its ability to initiate and control voluntary movements. *ALS is often called Lou Gehrig's disease*, after the famous baseball player who was diagnosed with it. Doctors usually don't know why ALS occurs. Some cases are inherited. Familial ALS represents 5-10% of the overall disease burden and is usually autosomal dominant pattern. Although the disease can strike at any age, symptoms most commonly develop between the ages of 55 and 75. Usually affecting men more than women and Caucasians and non-hispanics. ALS often begins with muscle twitching and weakness in a limb, or slurred speech. Eventually, ALS affects control of the muscles needed to move, speak, eat and breathe. There is no cure for ALS, and eventually the disease is fatal. ALS often starts in the hands, feet or limbs, and then spreads to other parts of your body. As the disease advances and nerve cells are destroyed, your muscles progressively weaken. This eventually affects chewing, swallowing, speaking and breathing. ALS doesn't usually affect your bowel or bladder control, your senses or your thinking ability. It's possible to remain actively involved with your family and friends. The LMN is destroyed, can start with asymmetry, but ultimately, more destruction and more symmetrical.

Sliding filament theory

According to the sliding filament theory, the myosin (thick) filaments of muscle fibers slide past the actin (thin) filaments during muscle contraction, while the two groups of filaments remain at relatively constant length, in a process that requires ATP.

Actin Filament

Actin is a protein that forms (together with myosin) the contractile filaments of muscle cells The thin myofilament (F-actin, filamentous actin) is made up of two helically intertwined chains of G-actin (globular actin) units. Two proteins that bind to the actin molecules: * Tropomyosin * Troponin complex→ Made up of three members

T-Tubules

Also called *transverse tubules*, these are deep invaginations of the sarcolemma (plasma membrane) found in the skeletal muscle cells. These invaginations allow depolarization of the membrane to quickly penetrate to the interior of the cell. Contraction then occurs by sliding filament mechanisms. Contraction of skeletal muscle is under voluntary control and is initiated via action potentials in alpha motor neurons. Action potentials are transmitted across the neuromuscular junction by the release of acetylcholine which binds to nicotinic receptors , resulting in depolarization of the muscle fiber.

*Myotonic Dystrophy*

Also known as *Steinert's disease,* this form is an autosomal dominant multisystem disorder associated with skeletal muscle weakness, cataracts, endocrinopathy, and cardiomyopathy. It affects about 1 in 10,000 individuals Characterized by an inability to relax muscles at will following contractions. *Myotonia*, a sustained involuntary contraction of muscles, is a key feature of the disease. Myotonic muscular dystrophy is the most common form of adult-onset muscular dystrophy. Facial and neck muscles are usually the first to be affected. Some patients present with "congenital myotonia," marked by severe manifestations in infancy Pathogenesis: Expansions of CTG triplet repeats in the 3′-noncoding region of the myotonic dystrophy protein kinase (DMPK) gene, but precisely how this genetic aberration produces the disease phenotype is unknown

*Guillain-Barré Syndrome (GBS)*

An acute immune-mediated demyelinating neuropathy with ascending paralysis in which peripheral nerves are infiltrated with lymphocytes and macrophages. Up to 70% of GBS occur after an acute infectious illness (C. jejuni, CMV, EBV, Mycoplasma pneumonia, also vaccinations) Neurologic symptoms occur during recovery 1 to 3 cases per 100,000 persons Acute, life threatening disease of peripheral nervous system

*Myasthenia Gravis*

An autoimmune disease associated with *anti-acetylcholine receptor antibodies* that block acetylcholine binding to neuromuscular junctions. Type II Hypersensitivity Reaction- The number of receptors is greatly reduced, and those present are often blocked by *IgG* C5-9 complexes. Antibodies to the AChR are present in the serum of 85-90% of patients. About 15% have another autoimmune disorder. 10-30% of the patients have a thymoma, and most of the rest have thymic hyperplasia. Thymus sensitized B cell produce autoantibodies

*Lambert-Eaton Myasthenic Syndrome*

An autoimmune disorder caused by *antibodies that block acetylcholine release by inhibiting a presynaptic calcium channel.* In contrast to myasthenia gravis, rapid repetitive stimulation increases muscle response. Muscle strength is increased after a few seconds of muscle activity. Patients typically present with weakness of their extremities. In about half of cases there is an underlying malignancy, most often neuroendocrine carcinoma of the lung. Treatment consists of drugs that increase acetylcholine release by depolarizing synaptic membranes and immunosuppressive agents, such as those used to treat myasthenia gravis.

How is Multiple Sclerosis a type IV hypersensitivity disorder?

An autoimmune disorder characterized by the *demyelination* of the CNS and *sclerotic plaque* replacement leading to relapsing or chronic progressive paralytic course. There is evidence of link to viral infection (possibly antigenic mimicry) Th1 cells secreting *IFN-gamma*, together with macrophages, penetrate the blood-brain barrier. The *activated macrophages* secrete proteases and cytokines to induce inflammation along the *myelin sheath*, leading to loss of myelin and deposition of sclerotic plaques. This leads to Fas induction and apoptosis of neuronal cells Symptoms- Weakness, Paralysis, and Ocular Symptoms

Myasthenia Gravis is an autoimmune disorder.

Antibody-mediated attack of acetylcholine receptors so less available to open AChR and start depolarization. The post synaptic folds are "flattened" or "simplified" so not only less available receptors, but receptors less efficient. Occurs in Women more than men Women with earlier onset (20-30's versus men in 50-60's). Characterized by weakness and fatigability of muscles reduced by rest. Usually presents in cranial nerves, EOM weakness is classic presentation. Diplopia and ptosis are common initial complaints. Facial weakness produces a "snarling" expression when the patient attempts to smile. Weakness in chewing is most noticeable after prolonged effort, as in chewing meat. In majority of patients, progresses to limb weakness. The limb weakness is proximal and may be asymmetric. Deep tendon reflexes are preserved.

Define denervation

Any loss of nerve supply regardless of the cause. If the nerves lost to denervation are part of the neuronal communication to a specific function in the body then altered or a loss of physiological functioning can occur. Causes of denervation include disease, chemical toxicity, physical injury, or intentional surgical interruption of a nerve.

Lambert-Eaton myasthenic syndrome

Associated with cancer in about 50% of patients. Small Cell lung cancer is strongest cancer association. CN weakness and proximal muscle weakness. Autonomic dysfunction and diminishment of reflexes are distinguishing features. Immune mediated. Treatment of the cancer improves symptoms. Points to complex immune function when cancer cells present.

How is Lambert-Eaton Myasthenic Syndrome a type II hypersensitivity disorder?

Autoantibodies against calcium channels increase their internalization/degradation resulting in: Weakness in extremities, difficulty walking, autonomic disfunction, enhanced neurotransmission after repeated stimulation No improvement in upon administration of anticholinesterase agents Amount of anticholinesterase in synaptic vesicles and response to anticholinesterase is normal Fewer vesicles are released in response to each presynaptic action potential

How is Myasthenia Gravis a type II hypersensitivity disorder?

Autoantibodies specific for the acetylcholine receptor on muscle cells blocks the action of acetylcholine, leading to paralysis Autoantibody against the acetylcholine receptor (AChR) binds to the receptor which may inhibit acetylcholine binding, complement binds (classical pathway) which injures postsynaptic membrane and increases internalization/degradation of AChRs (result is loss of functional AChRs) Symptoms May Include- Muscle weakness, Paralysis, Difficulty, swallowing, Drooping eyelids, Impaired speech (dysarthria), Double vision, Respiratory compromise, and *diminished motor responses after repeated stimulation*

*Becker Muscular Dystrophy*

Becker muscular dystrophy is a second relatively common dystrophinopathy that is characterized by later disease onset and a milder phenotype. Dystrophin is produced but doesn't function normally. Becker muscular dystrophy mutations permit the synthesis of a truncated version of dystrophin which retains some function It is 1/10 as frequent as Duchenne, and is also x-linked. Signs and symptoms are similar to those of Duchenne muscular dystrophy, but tend to be milder and progress more slowly. Symptoms generally begin in the teens but may not occur until the mid-20s or even later. Its course is more slowly progressive often with a near normal life expectancy

Hemicholinium

Blocks reuptake of choline into presynaptic terminal Depletes Ach stores from presynaptic terminal

Duchenne Muscular Dystrophy Clinical Features

Boys with Duchenne muscular dystrophy are normal at birth Very early motor milestones are met, but walking is often delayed First indications of muscle weakness are clumsiness and inability to keep up with peers Weakness begins in the pelvic girdle muscles and then extends to the shoulder girdle Enlargement of the muscles of the lower leg associated with weakness, termed *pseudohypertrophy* Mean age of wheel chair dependence is around 9.5 years Patients develop joint contractures, scoliosis, worsening respiratory reserve, and sleep hypoventilation Dystrophin deficiency in cardiac muscle often leads to the development of cardiomyopathy and arrhythmias, particulary in older patients Frequent falls, Difficulty rising from a lying or sitting up position, Trouble running and jumping, Waddling gait, Walking on the toes, Large calf muscles, Muscle pain and stiffness & Learning disabilities

Cardiac Muscle

Cardiac muscles have Intercalated Discs, which are anchoring structures containing gap junctions These intercalated disks are diagnostic features seen on microscopy of a cardiac tissue Cardiac muscle cells are faintly striated, branching, mononucleated cells, which connect by means of intercalated disks to form a functional network Action potential travels through all cells connected together forming a functional syncytium in which cells function as a unit

*Cauda Equina Syndrome*

Cauda equina syndrome is a rare disorder that usually is a surgical emergency. In patients with cauda equina syndrome, something compresses on the spinal nerve roots (LMN lesion). You may need fast treatment to prevent lasting damage leading to incontinence and possibly permanent paralysis of the legs.

*Ion Channel Myopathies*

Channelopathies are a group of inherited diseases caused by mutations affecting the function of ion channel proteins. Most channelopathies are autosomal dominant disorders with variable penetrance. Depending on the channel that is affected, clinical manifestations may include epilepsy, migraine, movement disorders with cerebellar dysfunction, peripheral nerve disease, and muscle disease. Different ion channel myopathies may cause decreased or increased excitability resulting in hypotonia or hypertonia.

Multiple Sclerosis (MS)

Chronic inflammation and selective destruction of CNS myelin (*UMN lesion*) by autoimmune process (genetic and environmental determinants factor in as well). The multifocal scarred lesions are called plaques (seen on MRI of brain). Diagnosed in Women more than Men Clinically, extremely variable presentations. Can present insidiously (gradual, subtle) or acutely. Sometimes symptoms so subtle, the patient doesn't seek care until more significant symptoms emerge. Classic symptoms include stiff or clumsy limb, abnormal gait, "heavy limb", visual disturbance, etc. Treatment targets reducing immune response/inflammation.

*Botulism*

Clostridium botulinum, an anaerobic spore-forming gram-positive bacterium creates a toxin. Toxin acts to inhibit acetylcholine release at the neuromuscular junction through an enzymatic mechanism. Usually contracted through food but can have a spore contaminated wound. Most cases in US (couple dozen a year) are contracted by home canned food that was not heated sufficiently to kill heat labile toxin. Small amount is extremely toxic so concern for bioterrorism. Presents as symmetric cranial-nerve palsies (diplopia, dysarthria, dysphonia, ptosis, facial paralysis, and/or impaired gag reflex) Followed by symmetric, *descending* flaccid paralysis that may progress to respiratory failure and death. Constipation due to paralytic ileus is almost always present. Anti-toxin is available and can be life saving

*Congenital Myopathies*

Congenital myopathies typically present in infancy with muscle defects that tend to be static or to even improve over time. They are often associated with distinct structural abnormalities of the muscle. Examples include: Central core disease (autosomal dominant), Nemaline rod myopathy, Centronuclear myopathy, and Congenital fiber-type disproportion All present as *floppy infants*, and electron microscopy or special stains are used for differential diagnosis.

Dermatomyositis Summary

Dermatomyositis is immune damage to small blood vessels contributes to muscle injury *Etiology:* Unknown: both environmental and infectious triggers are suspected; 14-24% of adult cases have an associated malignancy *Immune mechanism:* Unclear: possibly mediated by *CD4+ T cells*, antibody and complement; *membrane attack complexes (MAC, C5-9) seen along capillary beds* *Immunodiagnosis:* *Myositis specific autoantibodies: anti-Mi-2 (anti-Mi-2 nuclear helicase antigen).* Also seen are: anti-Jo1; anti-P155/P140 (transcriptional regulators) in juvenile disease *Treatment:* Corticosteroids *Special Features:* Distinctive skin rashes (lavender discoloration of upper eyelids called a heliotrope rash)

*Inclusion body myositis*

Disease of late adulthood that typically affects patients older than 50 years Most common inflammatory myopathy in patients older than age 65 years Presents with slowly progressive muscle weakness that tends to be *most severe in the quadriceps and the distal upper extremity muscles*

Fascicular Architecture in muscular dystrophies

Duchenne and Becker muscular dystrophy are similar, but differ in degree. Both are marked by chronic muscle damage that outpaces the capacity for repair. Muscle biopsies in young boys show ongoing damage in the form of segmental myofiber degeneration and regeneration associated with an admixture of atrophic myofibers The fascicular architecture is preserved at this stage of the disease, and there is usually no inflammation except for the presence of *myophagocytosis* Disease progresses, muscle tissue is replaced by collagen and fat cells ("fatty replacement" or "fatty infiltration") Immunohistochemical studies for dystrophin show absence of the normal sarcolemmal staining pattern in Duchenne muscular dystrophin and reduced staining in Becker muscular dystrophy

Duchenne muscular dystrophy (DMD)

Duchenne muscular dystrophy (DMD) is a Genetic Disorder characterized by progressive muscle degeneration and weakness It is one of 9 types of muscular dystrophy DMD is caused by an Absence of Dystrophin, a protein thathelps keep muscle cells intact

Muscle Relaxation

During Relaxation Process, calcium ions are carried away from myofilaments Myosin- Actin linkages loosen The troponin complex and tropomyosin bind to the myosin binding sites on the F-actin subunits Myosin and F- actin myofilaments return to their original positions

Skeletal Muscle Fascicular Arrangement Histology

Each Fascicle is separated (wrapped) from other fascicles by a connective tissue sheath, Perimysium The entire muscle as a whole is surrounded by another connective tissue layer, Epimysium The Epimysium gradually becomes connective tissue sheaths called *Fascia* Fascia thickens and becomes *Deep Fascia*. Has no fat and lies between adjacent muscles When this even becomes thicker is known as *Superficial fascia*, which lies between muscles and skin. Some regions of the body like buttocks and abdomen is very fatty.

Skeletal Muscle Cell Organization

Each muscle fiber contains: *Sarcolemma*- plasma membrane *Sarcoplasm* - Cytoplasm Has many *myofibrils* (protein bundles)-- actin and myosin Many Mitochondria Has many flattened or sausage shaped nuclei pushed against the plasma membrane

Skeletal Muscle Embryogenesis

Embryologically, mesenchymal cells differentiate into long, mononuclear skeletal muscle precursors called *myoblasts* These proliferate by mitosis Subsequently, the myoblasts fuse end to end forming elongated multinucleate cells called *myotubes.*These may eventually contain up to 100 nuclei. Later in development there could be cross-striation in some of the myotubes Nucleated fetal erythrocytes can be observed Stem cells (myoblast) which remain in adult muscle cells can regenerate if damaged, by proliferation

What skeletal muscle structure provides small blood vessels and nerves to skeletal muscles?

Endomysium Consists mainly of reticulin fibers and a small amount of collagen, conveys numerous small blood vessels, lymphatics and nerves throughout the muscle Barely visible as the delicate support tissue surrounding each muscle fiber

Guillain-Barré Syndrome

Guillain-Barre syndrome is a rare disorder in which your body's immune system attacks your nerves. Weakness and tingling in your extremities are usually the first symptoms. These sensations can quickly spread, eventually paralyzing your whole body. In its most severe form Guillain-Barre syndrome is a medical emergency. Most people with the condition must be hospitalized to receive treatment. Ascending paralysis (starts distal in the Lower Extremity and moves proximally) Areflexia, motor paralysis, and elevated CSF total protein without pleocytosis (increased cell count=protein is not coming from cells) Usually occurs after GI or Acute URI infections Reach maximum paralysis in 2 weeks 1/3 of patients will need ventilator support during illness 85% patients fully recover Treatment: IVIg improves outcomes (IVIg=blood product immune factors from hundreds of donors, providing wide assortment of antibodies) but glucocorticoids do not.

Babinski Reflex

Important as can be early clue of UMN lesion Normal in infants with entire leg contracting (flexing at the hip) with firm stimulation of plantar surface of foot. Positive is a dorsoflexed great toe with simultaneous contracture of flexor muscles of LE, not movement of the foot away from stimuli. Specificity is 100%, Sensitivity is 90% (meaning 10% of those with UMN lesions still do not have a +Babinski). The other toes do not have to fan to be positive and the stimuli does not need to be painful.

*Chronic inflammatory demyelinating polyneuropathy (CIDP)*

Immune mechanism is the same as GBS, except history of infection is uncommon CIDP has been regarded as a chronic form of GBS but there are differences- T cells are implicated and complement-fixing antibodies are found on the myelin sheath Autoantibodies and oligoclonal bands are not regularly found during immuno-diagnosis Responsive to steroids

How is Guillain-Barré Syndrome a type IV hypersensitivity disorder?

Infection (Campylobacter jejuni, CMV, EBV, Mycoplasma pneumoniae, vaccination) may trigger Type IV hypersensitivity Myelin-specific CD4+ TH1 cells produce IFN-g and activate macrophages which cause demyelination Autoantibodies from B cells may also contribute to disease process (Type II hypersensitivity)

Type II Hypersensitivity

Mediated by IgM and IgG antibodies binding to surface antigens on normal or altered cell membrane determinants Their binding can directly damage the cell or alter is physiology Mechanisms: Enhance phagocytosis by opsonization, activation of complement, or ADCC

Polymyositis Summary

Polymyositis is adult-onset inflammatory myopathy *Etiology:* Unknown: both environmental and infectious triggers are suspected *Immune mechanism:* Unclear: muscle damage may be caused by CD8+ CTLs *Immunodiagnosis:* *Myositis specific autoantibodies: anti-Jo1 (anti-histidyl transfer RNA synthetase)* *Treatment:* Corticosteroids *Special Features:* Skin is not involved; occurs mainly in adults

Muscle Contraction

Muscle contraction obeys the all or none law and is followed by muscle relaxation. It involves thick and thin filaments, along with their associated myofibril proteins, are responsible for muscle contraction *1.* There is an influx of calcium ions in the skeletal muscle cell in response to nerve impulse *2.* Troponin-complex pulls tropomyosin molecules away from the G-actin subunits, exposing the myosin binding sites *3.* The heads of the myosin molecules can bind to the actin subunits, forming cross bridges. The active sites in each myosin head disrupts the high- energy bond of ATP molecules and releases energy. *4.* Release of energy moves the myosin head towards the F- actins *5.*When contact is made with the actin subunits, the F- actin is pulled along, causing the myofilament to contract The coordinated contraction of all the myofilaments of all the muscle cells, causes the entire muscle to contract

What are the signs of defects in *Upper Motor Neurons*?

Muscle is still innervated, but there is no regulation from the brain so there is disorganized muscle activity. Spasticity (early) Hypertonic Hyperreflexive Disuse Atrophy (late) Positive Babinski reflex

Muscle Spindle

Muscle spindles are stretch receptors within the body of a muscle that primarily detect changes in the length of the muscle They convey length information to the central nervous system via afferent nerve fibers The brain then processes the information to determine the position of body parts The specialized fibers that constitute the muscle spindle are known as *Intrafusal Muscle Fibers* (as they are present within the spindle) and are located within the belly of muscles, between *Extrafusal Muscle Fibers*

Dermatomyositis Symptoms

Muscle weakness is slow in onset, symmetric, and often accompanied by myalgias (muscle pains) in children and adults Progressive muscle weakness involves the muscles closest to the trunk, such as those in your hips, thighs, shoulders, upper arms and neck (*the proximal muscles first*). Tasks such as getting up from a chair and climbing steps become increasingly difficult A violet-colored or dusky red rash develops, most commonly on the face and eyelids and on knuckles, elbows, knees, chest and back. The rash, which can be itchy and painful, is *often the first sign of dermatomyositis.*

Muscular dystrophy

Muscular dystrophy involves weakness and wasting of muscles due to a defect in one of the proteins involved in muscle function Gene mutations affecting proteins of the membrane linkage complex are an important cause of the group of muscular dystrophies Other genes coding for contractile and other structural proteins may also cause muscular dystrophy Some people have a mutation in the gene for dystrophin that results in inefficient linking of contractile forces to the support tissues in muscle. Muscle does not function correctly, and fibers undergo progressive damage with repeated contraction, ultimately leading to death of muscle cells.

Muscular Dystrophies

Muscular dystrophy is a group of diseases that cause progressive weakness and loss of muscle mass that typically manifests itself between childhood and adulthood. In muscular dystrophy, abnormal genes (mutations) interfere with the production of proteins needed to form healthy muscle. The most common muscular dystrophies are X-linked and stem from mutations that disrupt the function of a large structural protein called *dystrophin.* *Creatine phosphokinase is elevated* Sarcolemma means cell membrane

*Myasthenia Gravis Symptoms*

Myasthenia gravis usually presents as weakness and fatigability of ocular muscles, and later involves muscles producing dysphagia and dysarthria. In late stages trunk and limb muscles are affected. There is a less than 5% of mortality rate because of involvement of respiratory muscles. *Muscle weakness* *Ptosis* (eye drooping) Difficulty swallowing and breathing *thymoma* (thymus tumor) Some patients respond well to anticholinesterase drugs.

*Multiple Sclerosis*

Neuroinflammatory autoimmune disease of the central nervous system (CNS). Most common demyelinating disorder (1 case/1000 persons) Onset age:10-50 2X more common in women Relapsing/remitting episodes, but often steady neurologic deterioration Genetic Susceptibility- HLA-DR2 alleles

Inclusion body myositis morphology

Patchy often endomysial mononuclear inflammatory cell infiltrates rich in CD8+ T-cells Focal invasion of normal appearing myofibers by inflammatory cells Admixed degenerating and regenerating myofibers Abnormal cytoplasmic inclusions described as *"rimmed vacuoles*

Defects in Neuromuscular junctions results in what diseases?

Pathology can occur by: Preventing acetylcholine release Blocking acetylcholine receptors Dumping all the acetylcholine and other receptors all at once, depleting the supply of neurotransmitters Diseases: Botulism Myasthenia Gravis Lambert-Eaton myasthenia syndrome (LEMS) Black Widow Toxin

Peripheral neuropathies

Peripheral Neuropathies include B12 deficiency peripheral neuropathy and Diabetic neuropathy LMN involvement causes weakness, gait disturbance Nerve to muscle is impaired/damaged Many other causes, including idiopathic

*Polio*

Polio is a contagious viral illness that in its most severe form causes nerve injury leading to paralysis, difficulty breathing and sometimes death. In the U.S., the last case of naturally occurring polio was in 1979. Today, despite a worldwide effort to wipe out polio, poliovirus continues to affect children and adults in parts of Asia and Africa. Most of the infected are asymptomatic. About 5% have fever, malaise, sore throat, myalgias, and headache, that usually resolves within 3 days. Less the 1% have paralysis: Weakness usually starts asymmetrically, proximally, and in the Lower Extremities. Physical examination reveals weakness, fasciculation, decreased muscle tone, and reduced or absent reflexes in affected areas; hyperreflexia may precede the loss of reflexes. Most recover some function. Estimated the live virus vaccine causes polio in 1 in 25 million doses, much more common in immune compromised.

*Polymyositis*

Polymyositis is an adult-onset inflammatory myopathy with myalgia and weakness The body's immune system turns against its own muscles and damages muscle tissue in an autoimmune process, it is believed to have an immunologic basis with CD8-positive cytotoxic T cells are prominent part of the inflammatory infiltrate in affected muscle Sometimes myofibers with otherwise normal morphology appear to be invaded by mononuclear inflammatory cells Degenerating necrotic, regenerating, and atrophic myofibers are typically found in a random or patchy distribution More common in females than males and usually begins after age 20. Over a period of weeks or months, several muscles become weak and gradually get weaker. Most affected are the muscles of the hips and thighs, the upper arms, the top part of the back, the shoulder area and the muscles that move the neck.

*Primary Lateral Sclerosis*

Primary lateral sclerosis is a type of motor neuron disease that causes muscle nerve cells to slowly break down, causing weakness. Primary lateral sclerosis (PLS) causes weakness in your voluntary muscles, such as those you use to control your legs, arms and tongue. *Death of the UM neurons is irreversible* Primary lateral sclerosis can happen at any age, but it usually occurs between ages 40 and 60. A subtype of primary lateral sclerosis, known as juvenile primary lateral sclerosis, begins in early childhood and is caused by an abnormal gene passed from parents to children. Primary lateral sclerosis is often mistaken for another, more common motor neuron disease called amyotrophic lateral sclerosis (ALS). However, primary lateral sclerosis progresses more slowly than ALS, and in most cases isn't fatal (survival is longer than ALS). *Stiffness is a key feature* and usually the presenting symptom. Other symptoms include weakness and spasticity in your legs, Tripping, difficulty with balance and clumsiness as the leg muscles weaken, weakness and stiffness progressing to your trunk, then your arms, hands, tongue and jaw, hoarseness, reduced rate of speaking, slurred speech and drooling as the facial muscles weaken, difficulties with swallowing and breathing late in the disease.*Limb wasting is rare*

What is the function of skeletal muscle?

Produce skeletal movement Maintain posture and body position Maintain body temperature Support soft tissues Guard entrances and exits Store nutrient reserves

*Huntington's Disease*

Progressive, fatal, autosomal dominant disorder characterized by motor, behavioral, and cognitive dysfunction due to the progressive breakdown (degeneration) of nerve cells in the brain. Expanded CAG repeat in the huntingtin (HTT) gene, located in the short arm of chromosome 4 which codes abnormally long polyglutamine repeat in the huntingtin protein. Onset between age 25-45 Multiple brain regions affected with UMN impact seen in rigidity, involuntary movements. Progressive destruction of UMN can lead to spasticity and rigidity.

Complications of C. jejuni

Reactive arthritis - joint pain and swelling involving hands, ankles and knees (weeks/months) Guillain-Barré syndrome is an autoimmune disorder, mediated demyelinating neuropathy with ascending paralysis

Myosin Filament

Referred to as *thick myofilament,* a fibrous protein that forms (together with actin) the contractile filaments of muscle cells Consists of a large bundled myosin molecules aligned end to end. Hexameric proteins with two identical heavy chains and two pairs of different light chains (Regulatory light chain (RLC) or Essential light chain (ELC))

*Tetanus*

Refers to sustained contraction Occurs when skeletal muscle is repeatedly stimulated Intracellular Ca +2 concentration remains high with continued cross-bridge cycling Buildup of tetanus toxin from Clostridium tetani bacterial infection Tetanus toxin blocks the release of γ-aminobutyric acid (GABA), a neurotransmitter that inhibits motor neurons Results in sustained contraction (spastic paralysis) and hypertonia

Neuromuscular Junction

Skeletal muscle cells and the single motor neuron that innervates them constitute a motor unit Observe the terminal button of a neuron, the synaptic cleft and the motor endplate plus related structures Impulse is transmitted from the motor neuron to the skeletal muscle fiber at the myoneural junction leading to muscle contraction

Skeletal Muscle

Skeletal muscles are muscles are attached to the skeleton They account for *40%* of human body mass Skeletal muscles are mainly responsible for locomotion, as well as, voluntary contraction and relaxation Under light microscopy Skeletal muscles are composed of *long, cylindrical, multinucleated cells that undergo voluntary contraction. Nuclei are located at the periphery.* Skeletal muscle is further divided into two broad types: slow twitch and fast twitch

Smooth Muscle

Smooth muscles are spindle- shaped, nonstriated fibers with centrally located nuclei They are located in the walls of hollow internal structures such as blood vessels, airways to the lungs, stomach, intestines and uterus Has a slow speed of contraction Nervous control is Involuntary and Auto-rhythmic

*Subacute combined degeneration*

Subacute combined degeneration of spinal cord, also known as Lichtheim's disease, refers to degeneration of the posterior and lateral columns of the spinal cord as a result of *severe vitamin B12 deficiency* (most common), vitamin E deficiency, and copper deficiency. It is usually associated with pernicious anemia. Treatable myelopathy presents with subacute paresthesia in the hands and feet. Progressive spastic and ataxic weakness *Positive Babinski;* May also have LMN symptoms but the positive Babinski signals UMN involvement. Reversible with B12 administration.

Fascicular Arrangement of Skeletal Muscle

The *Endomysium* (En) consists mainly of reticulin fibers and a small amount of collagen, conveys numerous small blood vessels, lymphatics and nerves throughout the muscle; barely visible as the delicate support tissue surrounding each muscle fiber The *Perimysium* (P) surrounding the individual *fasciculi* (F) is composed of collagen and through which larger vessels and nerves run The *Epimysium* (E) is a collagenous sheath that binds the fascicles into a single muscle

Tensilon Test

The Tensilon test uses the drug Tensilon (edrophonium) to help your doctor diagnose myasthenia gravis. Tensilon prevents the breakdown of the chemical acetylcholine, a neurotransmitter that nerve cells release to stimulate your muscles. People with the chronic disease myasthenia gravis don't have normal reactions to acetylcholine. Antibodies attack their acetylcholine receptors. This prevents muscles from being stimulated and makes muscles easy to tire. A person tests positive for myasthenia gravis if their muscles get stronger after being injected with Tensilon. Muscle weakness improves after injection of Edrophonium [Tensilon]. This is a short acting anticholinesterase inhibitor

Sarcomere

The basic unit of striated muscle tissue. It is the repeating unit between two Z lines. Skeletal muscles are composed of tubular muscle cells (myocytes called muscle fibers or myofibers) which are formed in a process known as myogenesis. Muscle fibers contain numerous tubular myofibrils. Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as alternating dark and light bands. Sarcomeres are composed of long, fibrous proteins as filaments that slide past each other when a muscle contracts or relaxes. Two of the important proteins are myosin, which forms the thick filament, and actin, which forms the thin filament. Myosin has a long, fibrous tail and a globular head, which binds to actin. The myosin head also binds to ATP, which is the source of energy for muscle movement. Myosin can only bind to actin when the binding sites on actin are exposed by calcium ions. Actin molecules are bound to the Z line, which forms the borders of the sarcomere. Other bands appear when the sarcomere is relaxed. A muscle fiber from a biceps muscle may contain 100,000 sarcomeres.The myofibrils of smooth muscle cells are not arranged into sarcomeres.

Treatment for Inflammatory Myopathies

The chronic inflammatory myopathies can't be cured in most adults but many of the symptoms can be treated. Options include medication, physical therapy, exercise, heat therapy (including microwave and ultrasound), orthotics and assistive devices, and rest. Polymyositis and dermatomyositis are first treated with high doses of prednisone or another corticosteroid drug. This is most often given as an oral medication but can be delivered intravenously. Immunosuppressant drugs, such as azathioprine and methotrexate, may reduce inflammation in people who do not respond well to prednisone. IBM has no standard course of treatment. The disease is generally unresponsive to corticosteroids and immunosuppressive drugs.

Corticospinal Tract

The corticospinal tract is a major tract that carries movement-related information from the motor cortex to the spinal cord. The neurons that travel in the corticospinal tract are called *upper motor neurons,* they form connections with neurons called* lower motor neurons*, which carry movement-related impulses to muscle itself, causing it to contract. The upper motor neurons of the corticospinal tract leave the motor cortex and descend to the brainstem, entering the midbrain in large fiber bundles called the cerebral peduncles. The tract continues down into the medulla where the fibers form two bundles, known as the pyramids, which create visible ridges on the exterior surface of the brainstem. At the base of the pyramids, about 90% of the fibers in the corticospinal tract decussate, or cross to the other side of the brainstem in a bundle called the pyramidal decussation. The decussating fibers will then enter the spinal cord on the opposite side of the body from where they originated as part of the *lateral corticospinal tract.* The other 10% of the fibers will continue into the spinal cord on the same side of the body where they originated as part of the ventral or *anterior corticospinal tract* and only cross over when they reach the level of the spinal cord where they will synapse on a lower motor neuron. It is thought that the lateral and anterior corticospinal tract fibers have slightly different specializations, with the lateral corticospinal tract controlling the movement of more distal muscles like those of the hands, and the anterior corticospinal tract controlling the movement of more proximal muscles like those of the trunk. Damage to the corticospinal tract can lead to a collection of symptoms known as upper motor neuron syndrome, which involves symptoms like weakness or paralysis, hyperactive reflexes, decreased motor control, and either increased or decreased muscle tone. Over time patients may regain the ability to make crude movements but fine finger movements like writing or typing may remain impaired, suggesting the corticospinal tract is especially important for these types of movements.

Inflammatory Myopathies

The inflammatory myopathies are a group of diseases, with no known cause, that involve chronic muscle inflammation accompanied by muscle weakness. Non-infectious and immunologically mediated The three main types of chronic, or persistent, inflammatory myopathy are polymyositis, dermatomyositis, and inclusion body myositis (IBM).

Sarcoplasmic Reticulum

The sarcoplasmic reticulum is a specialized type of smooth ER that regulates the calcium ion concentration in the cytoplasm of striated muscle cells.

Type IV Hypersensitivity

These reaction are cell mediated by *Th1 cells* who complete immune recognition, as well as *macrophages* and *CD8 T cells* which are the effector cells. There are two types: *Delayed-Type Hypersensitivity (DTH)* and *Contact Hypersensitivity* Delayed reactions occurring 24-48 hours after exposure to antigen Reactions are also based on memory, meaning pathology results from previous sensitization Disorders: Multiple Sclerosis, Insulin-Dependent Diabetes Mellitys (IDDM), Hashimoto's Thyroiditis, Rheumatoid Arthritis, Sjogren's Syndrome, Celiac Disease

Campylobacter

Thin, long, curved, Rods, Gram negative Transmission- fecal-oral route- ingestion of contaminated food/water or unpasteurized milk C. jejuni is responsible for most gastroenteritis infections *Campylobacter jejuni has epitopes in common with peripheral myelin* (also, CMV shares epitopes with peripheral nerves) leading to molecular mimicry complications Symptoms include- acute enteritis with diarrhea, malaise, fever and abdominal pain (may mimic appendicitis), septicemia, Diarrhea can be bloody Most recover fully either spontaneously or after antibiotic treatment

What are the signs of defects in *Lower Motor Neurons*?

Think of LMN lesions as brain is sending signal, but the "circuit"(anterior horn cells) or the "plug" (synapse at muscle) or the muscle itself cannot respond to signal. Flaccid Hypotonic Denervation Atropy Hyporeflexive Negative Babinki (UMN control is still exerted on the pathway)

Myasthenia Gravis (MG)

This is one of the most common disorders of neuromuscular signaling It has a prevalence of 13 to 21 per 100,000 in the United States Symptoms experienced by people with MG include Muscle weakness, Ptosis, Diplopia, and Generalized muscle fatigue In healthy patients, the presynaptic terminals release acetylcholine (ACH) from the motor nerve terminal in quanta, this diffuses across the synaptic cleft and binds to receptors on the post synaptic membrane of the muscle, the resultant effect is membrane depolarization and muscle contraction. In patients with MG, post synaptic ACH membrane receptors are destroyed due to immunologic or genetic abnormalities. Thymic tumors are commonly seen in patients with MG.

*Duchenne Muscular Dystrophy*

This is the most common form of muscular dystrophy. Although girls can be carriers and mildly affected, it's much more common in boys (Incidence of 1 per 3500 live male births). On the short arm of the X chromosome loss-of-function mutations in the dystrophin genes leads to a deficiency in dystrophin. Deletions or frame shift mutations that result in total absence of dystrophin. About one-third of boys with Duchenne muscular dystrophy (DMD) don't have a family history of the disease, possibly because the gene involved may be subject to sudden abnormal change (spontaneous mutation). Death occurs by young adulthood

*Toxic Myopathies*

Toxic myopathies can be caused by prescription or recreational drugs, or by certain hormonal imbalances. Among prescription drugs, *statins are among the leading culprits of toxic myopathies.* Statins are cholesterol-lowering drugs that are widely used to reduce the risks of acute ischemic cardiac events and stroke. Myopathy is the most common complication of statins. *Chloroquine and hydroxychloroquine* are antimalarial agents and currently given as long-term therapy to some patients with systemic autoimmune diseases. These drugs interfere with normal lysosomal function and can cause a *drug-induced lysosomal storage myopathy* that presents with slowly progressive muscle weakness. The muscle tissue shows myopathic changes including vacuolation that *predominantly affects type I fibers.* *ICU myopathy or myosin deficient myopathy* is a neuromuscular disorder seen in patients during the course of treatment for critical illness (usually in an intensive care unit) especially with corticosteroid therapy. Selective *degradation of sarcomeric myosin thick filaments*, producing profound weakness that can complicate the clinical course. *Thyrotoxic myopathy* presents as an acute or chronic proximal muscle weakness that may precede other signs of hyperthyroidism. Also present with exophthalmic ophthalmoplegia, characterized by swelling of the eyelids, edema of the conjunctiva, and diplopia. *Alcohol can also be myopathic.* Binge drinking may produce an acute toxic syndrome of rhabdomyolysis, myoglobinuria, and renal failure. Affected individual may complain of acute myalgias that are generalized or confined to a single muscle group.

Excitation-Contraction in Skeletal Muscle

Translation of the action potential in muscle fibers into the production of force or tension. *1.* Action Potential in muscle membrane *2a.* Depolarization of T tubules *2b.* Opens SR Ca2+ release channels (ryanodine receptors) *3.* Increase in intracellular calcium concentration *4.* Calcium binds to troponin C *5.* Tropomyosin moves and allows interaction of actin and myosin *6.* Cross-bridge cycling and force-generation *7.* Calcium re accumulated by SR and muscle relaxation

What are the three types of muscle?

Types of Muscle include Skeletal (Striated & Voluntary), Smooth (Involuntary), and Cardiac (Heart) Skeletal muscle are mesodermal derivative, mostly from somatic mesoderm Skeletal muscle appears striped under a microscope. The word striped means striated.

Upper Motor Neuron defects can be symmetrical or asymmetrical (and/or segmental):

UMNs tend to involve extensors and abductors of the upper limb and the flexors of the lower limb. Any pathology that damages the UMN pathway, i.e. CVA, traumatic brain injury (can be asymmetrical), spinal cord injury (usually symmetrical) can result in the following conditions: *Primary Lateral Sclerosis* (symmetrical) Amyotrophic Lateral Sclerosis (can be asymmetrical early and involves both UMN and LMN) *Multiple sclerosis* *Huntington disease* *Subacute combined degeneration* (Vitamin B12 deficiency)

*Black Widow Toxin*

α-Latrotoxin is the toxin. Venom binds irreversibly to presynaptic nerve terminals with neurotransmitter "dump" and depletes the neurotransmitters. (Cause an explosive release of Ach at the neuromuscular junction at really high levels) Painful cramps and extreme muscle rigidity ensue. Black Widows are common in Tennessee. Supportive treatment! Most survive.