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Musculoskeletal and Nervous System Review Felix Hernandez, M.D. Muscle Tissue Skeletal Muscle Cardiac Muscle Smooth Muscle Skeletal Muscle Long cylindrical cells Many nuclei per cell Striated Voluntary Rapid contractions Cardiac Muscle Branching cells One or two nuclei per cell Striated Involuntary Medium speed contractions Smooth Muscle Fusiform cells One nucleus per cell Nonstriated Involuntary Slow, wave-like contractions Microanatomy of Skeletal Muscle Acetylcholine Opens Na+ Channel Muscle Contraction Summary Nerve impulse reaches myoneural junction Acetylcholine is released from motor neuron Ach binds with receptors in the muscle membrane to allow sodium to enter Sodium influx will generate an action potential in the sarcolemma Muscle Contraction Continued Action potential travels down T tubule Sarcoplasmic reticulum releases calcium Calcium binds with troponin to move the troponin, tropomyosin complex Binding sites in the actin filament are exposed Muscle Contraction Continued Myosin head attach to binding sites and create a power stroke ATP detaches myosin heads and energizes them for another contraction When action potentials cease the muscle stop contracting Isometric Contraction Produces no movement Used in Standing Sitting Posture Isotonic Contraction Produces movement Used in Walking Moving any part of the body Neurogenic Atrophy • Transection of the larger nerves can be repaired if the proximal part of the axon is preserved. • The nerve distal to the transection injury degenerates (wallerian degeneration). • Fiber type grouping is seen. Figure 20-06 Myasthenia Gravis • Autoimmune disease involving the neuromuscular junction (NMJ) • More common in women than in men • Cause unknown • In the younger age group, associated with enlargement of the thymus – • Hyperplasia or neoplasia (thymoma) Striated muscles histologically normal Myasthenia Gravis Figure 20-07 Myasthenia Gravis • Reduced number of surface receptor sites for acetylcholine at the motor neural plate • Easy fatigability and muscular weakness • Small extraoccular muscles and facial muscles most often involved • Ptosis, diplopia, easy fatigability on reading, facial muscle weakness, inability to chew; all muscles may become affected Muscular Dystrophies • Genetic defects inherited as mendelian traits • Primary muscle cell pathology • A progressive course and symptoms related to muscle wasting Duchenne-type Muscular Dystrophy • Most common muscular dystrophy • Caused by deficiency of dystrophin • Dystrophin holds together other structural proteins, linking them to the cell membrane Figure 20-08 Duchenne-type Muscular Dystrophy • Degeneration of skeletal muscle cells with ensuing muscle weakness • Sex-linked recessive disease • Occurs only in boys • Mothers asymptomatic • Milder form—Becker’s dystrophy Duchenne-type Muscular Dystrophy • In the early stages, individual muscle cell degeneration and loss occur. • The abnormal muscle cells have an irregular shape, granularity of cytoplasm, and centrally located nuclei. • Muscle cell loss is progressive. • Compensatory hypertrophy of viable fibers occurs. • There is ingrowth of fibrous tissue and fat cells. Duchenne-type Muscular Dystrophy • Appearance of symptoms in preschool children • Weakness of the weight-carrying muscles of the pelvic girdle and lower extremities • Difficulty getting up from a squatting position • Deformed legs, inability to keep legs straight, contractures and deformities of the extremities • Pulmonary infections, heart failure, anemia, reduced intelligence • Early death—usually in late teens or early 20s Tumors of Muscles and Soft Tissues • Rhabdomyosarcoma • Synovial sarcoma • Liposarcoma • Leiomyosarcoma • Angiosarcoma Functions of Skeletal System • SUPPORT: Hard framework that supports and anchors the soft organs of the body. • PROTECTION: Surrounds organs such as the brain and spinal cord. • MOVEMENT: Allows for muscle attachment therefore the bones are used as levers. • STORAGE: Minerals and lipids are stored within bone material. • BLOOD CELL FORMATION: The bone marrow is responsible for blood cell production. Features of a Long Bone: Epiphysis: Ends of the bone. Diaphysis: The shaft of the bone which surrounds the medullary cavity. Articular Cartilage: Cushions the ends of the bones and allows for smooth movement. Epiphyseal Plate: Areas made of cartilage allowing for the growth of the bone. Bone Structure • Periosteum – hard outer covering Cells for growth and repair • Compact bone – hard strong layer Bone cells, blood vessels, protein with Ca and P • Spongy bone – at ends of long bones Has small open spaces to lighten weight Marrow cavity – hollow in middle of long bones Bone Marrow Red marrow – produces blood cells and clotting factors Found in humerus, femur, sternum, ribs, vertebrae, pelvis Produces RBC 2 million per second Yellow marrow – stores fat Found in many bones Bone Structure Haversian System Structure of compact bone Rings of bone tissue with blood vessels and nerves in the center Bone Development Initial skeleton of cartilage in infants Replaced with bone by osteoblasts More than 300 bones at birth – fuse to 206 Always growing and breaking down Osteoblasts – form new bone cells Osteoclasts – break bone cells down Osteoporosis • Multifactorial disease characterized by absolute reduction of the total bone mass • Age related—in those older than 85 years, one third have osteoporosis • Women > men, especially after menopause • Etiologically subdivided into two groups: – Primary osteoporosis—cause unknown – Secondary—related to another disease Pathogenesis of Primary Osteoporosis • Etiology unknown, but certain factors are known to predispose to osteoporosis • Low initial bone mass (“small frame”) • Bad dietary habits, smoking • Hormones (e.g., early menopause) • Age-related changes in the metabolism Causes of Secondary Osteoporosis • Hormonal disturbances—excess of cortisol, deficiency of sex hormones • Dietary disorders—vitamin C or calcium deficiency, malabsorption of food • Immobilization • Drugs—anticonvulsants, anticoagulants (e.g., heparin) • Tumors—breast cancer Osteomalacia • Softening of bones as a result of inadequate mineralization of the organic matrix (osteoid) • Caused by deficiency of vitamin D, inadequate metabolic processing and activation of vitamin D, or disturbances of phosphate metabolism Etiology of Vitamin D Deficiency • Inadequate intake—malnourished children in Africa, food faddists in United States • Inadequate exposure to sunlight—people living above the Arctic Circle • Abnormal intestinal absorption Pathology of Osteomalacia • Excess nonmineralized osteoid • Bone deformities and fractures • Rickets = osteomalacia in children – – Bowlegs Widened costochondral junction (“rachitic rosary”) – Craniotabes – Delayed dentition Paget’s Disease • Common chronic disease of unknown etiology characterized by irregular restructuring of bone and subsequent thickening and deformities of bones • Diagnosis made radiologically • Three phases – Destructive phase – Mixed phase – Osteosclerotic phase Paget’s Disease • (1) In the first stage, there is irregular osteoclastic resorption of bone; • (2) In the second stage, osteoblasts react by actively laying down new bone, which balances the osteolysis and maintains the total bone volume. The disease can be recognized at this stage by the irregular manner in which osteoblasts lay down trabeculae. The new bone is highly vascular; • (3) Finally, there is a sclerotic phase in which osteoblastic activity is greatly in excess of osteoclastic resorption, leading to marked thickening of bony trabeculae and cortex Paget’s Disease Figure 19-07A Fractures Figure 19-08 Bone Tumor • Malignant tumors • Benign tumors – Osteoma – Chondroma – Fibroma – Giant cell tumor (benign in most cases but may recur) – Osteosarcoma – Chondrosarcoma – Ewing’s sarcoma Osteoarthritis—Degenerative Joint Disease (DJD) • Most common joint disease • Disease of old age • Affects weight-bearing big joints but also small joints of hands and feet • Classified as: – Primary—cause unknown or multifactorial – Secondary—related to another disease Osteoarthritis Figure 19-14 Osteoarthritis • Crepitus is a characteristic feature—a grating sound produced by friction between adjacent areas of exposed subchondral bone. • Osteophytes may be visible clinically—as bony masses such as those that occur over affected distal interphalangeal joints (Heberden's nodes) Rheumatoid Arthritis • Chronic systemic disease of unknown etiology characterized by the following: – Chronic, symmetric inflammation of joints • proximal interphalangeal joints • Involved joints are swollen, painful, and stiff. Stiffness is maximal in the morning after the joint has been inactive during the night – Significant, but not diagnostic, laboratory findings indicative of immune disorder – Variable extra-articular findings Rheumatoid Arthritis Figure 19-15 Rheumatoid Arthritis—Clinical Features Figure 19-16 Gout • Common systemic metabolic disorder often affecting the joints • Hyperuricemia—deposition of urate crystals in tissues; inflammation of joints • Podagra (swelling and pain of first metatarsophalangeal joint of the foot) • Subcutaneous tophi—uric acid nodules • Uric acid urinary stones Gout Clinical Features • Acute gout—acute attack of joint pain, swelling, and inflammation • Chronic gout—tophi, deposits of uric acid crystals in internal organ, urinary stones The Nervous System Major division - Central vs. Peripheral Central or CNS- brain and spinal cord Peripheral- nerves connecting CNS to muscles and organs Central Nervous System Peripheral Nervous System Peripheral Nervous System 3 kinds of neurons connect CNS to the body Brain Spinal Cord sensory motor interneurons Motor - CNS to muscles and organs Sensory - sensory receptors to CNS Interneurons: Connections Within CNS Nerves Peripheral Nervous System Peripheral Nervous System Skeletal (Somatic) Autonomic Sympathetic Parasympathetic Somatic System Brain Nerves to/from spinal cord control muscle movements Sensory Neuron somatosensory inputs Both Voluntary and reflex movements Skin receptors Motor Neuron Interneuron Skeletal Reflexes Muscle simplest is spinal reflex arc Autonomic System Two divisions: sympathetic Parasympatheitic Control involuntary functions heartbeat blood pressure respiration perspiration digestion Can be influenced by thought and emotion Sympathetic CENTRAL NERVOUS SYSTEM “ Fight or flight” response Release adrenaline and noradrenaline SYMPATHETIC Brain Dilates pupil Stimulates salivation Relaxes bronchi Spinal cord Increases heart rate and blood pressure Salivary glands Lungs Accelerates heartbeat Inhibits activity Increases blood flow to skeletal muscles Heart Stomach Pancreas Stimulates glucose Inhibits digestive functions Secretion of adrenaline, nonadrenaline Relaxes bladder Sympathetic ganglia Stimulates ejaculation in male Liver Adrenal gland Kidney Parasympathetic CENTRAL NERVOUS SYSTEM PARASYMPATHETIC Brain Contracts pupil “ Rest and digest ” system Calms body to conserve and maintain energy Lowers heartbeat, breathing rate, blood pressure Stimulates salivation Spinal cord Constricts bronchi Slows heartbeat Stimulates activity Stimulates gallbladder Gallbladder Contracts bladder Stimulates erection of sex organs Summary of autonomic differences Autonomic nervous system controls physiological arousal Sympathetic division (arousing) Pupils dilate Decreases Parasympathetic division (calming) EYES Pupils contract SALVATION Increases Perspires SKIN Dries Increases RESPERATION Decreases Accelerates HEART Slows Inhibits DIGESTION Activates Secrete stress hormones ADRENAL GLANDS Decrease secretion of stress hormones Central Nervous System Brain Spinal Cord Brain and Spinal Cord Brain has 2 Hemispheres Corpus Callosum Left & Right sides are separate Corpus Callosum : major pathway between hemispheres Some functions are ‘lateralized’ Right Hemisphere language on left math, music on right Lateralization is never 100% Left Hemisphere Each hemisphere is divided into 4 lobes Frontal Parietal Occipital Temporal Contralateral Motor Control Movements controled by motor area Right hemisphere controls left side of body Left hemisphere controls right side Motor nerves cross sides in spinal cord Motor Cortex Somatosensory Cortex Corpus Callosum Major ( but not only) pathway between sides Medial surface of right hemisphere Connects comparable structures on each side Permits data received on one side to be processed in both hemispheres Aids motor coordination of left and right side Corpus Callosum Corpus Callosum What happens when the corpus callosum is cut? Sensory inputs are still crossed Motor outputs are still crossed Hemispheres can’t exchange data Occipital Lobe Input from Optic nerve Occipital Lobe Contains primary visual cortex most is on surface inside central fissure Outputs to parietal and temporal lobes Visual Lobe Temporal Lobe Contains primary auditory cortex Inputs are auditory, visual patterns Auditory Cortex speech recognition face recognition word recognition memory formation Outputs to limbic System, basal Ganglia, and brainstem Temporal Lobe Parietal Lobe contains primary Inputs from multiplecortex senses somatosensory borders visual & auditory cortex Outputs to Frontal lobe hand-eye coordination eye movements attention Somatosensory Parietal Cortex Lobe Frontal Lobe No direct sensory input Important planning and sequencing areas Broca’s area for speech Contains primary motor cortex Prefrontal area for working memory Frontal WorkingLobe Broca’s Memory Area Motor Cortex Frontal Lobe Disorders Broca’s area productive aphasia Prefrontal area lose track of ongoing context fail to inhibit inappropriate responses Often measured with the Wisconsin Card Sorting Task Dysraphic Developmental Disorders Figure 21-04 Cerebrovascular Diseases • Third most common cause of death • Most common crippling disease • Most important clinical manifestation—stroke • Disease of old age (atherosclerosis) • Arterial hypertension • Thromboembolism Cerebrovascular Diseases • Global ischemia • Cerebral infarct • Intracerebral hemorrhage Figure 21-06 Cerebral Infarct • Caused by thrombotic occlusion and thromboemboli • Encephalomalacia • Pale infarct or hemorrhagic infarct • Surrounding brain tissue that is edematous • Fluid-filled cavity (“pseudocyst”) • Clinical presentation as stroke (e.g., contralateral hemiplegia, sensory loss, global aphasia, drowsiness, stupor, coma) Multiple Sclerosis • Demyelinating disease • Women affected twice as often as men • Genetic factors • Oligoclonal T-cell populations in the brain • IgG in CSF composed of oligoclonal bands Multiple Sclerosis • Chronic disease • Episodes of exacerbation and remission of neurologic symptoms • Sensory abnormalities – • Motor abnormalities – • Loss of sensitization of touch Muscle weakness, unsteady gait, incoordination of movements, sphincter abnormalities Unpredictable course Alcoholism • Wernicke-Korsakoff syndrome • Uncoordinated movements • Progressive mental deterioration, loss of memory, inability to concentrate, irritability • Subdural hematoma, pontine myelinolysis Figure 21-13 Alzheimer’s Disease • Unknown etiology • Genetic factors—Down’s syndrome • Atrophy of the cortical parts of the frontal and temporal parts of the brain • Disease of older people (>70 years) • Dementia—progressive loss of cognitive functions and a functional decline (loss of memory predominates) Alzheimer’s Disease • Gross examination – • The brain appears atrophic and shows narrowing of the gyri and a widening of the sulci. Histologic changes – Most prominent in the cortex – Neuritic (senile) plaques – Neurofibrillary tangles – Granulovacuolar degeneration – Deposition of amyloid in the neuritic plaques and the wall of the cerebral vessels Parkinson’s Disease • Subcortical neurodegenerative disorder • Typically affects elderly persons • Cause unknown • Decreased number of dopaminergic neurons in the substantia nigra • Disturbances of movement, primarily tumor, rigidity, bradykinesia, postural instability Parkinson’s Disease • Tremor or twitching of the muscles • Instability while walking • Depression and dementia – • Gross examination – • Significant number of patients become depressed, and about 10% develop dementia. Substantia nigra appears pale. Histologically – Loss of melanin-rich neurons – Lewy bodies Huntington’s Disease • Autosomal dominant neurodegenerative disease • Involuntary, gyrating movements and progressive dementia • Atrophy of the cortex and subcortical nuclei, most prominently the caudate and putamen Huntington’s Disease • Nonspecific histologic changes include: – Atrophy, degeneration, loss of neurons, reactive gliosis • First symptoms usually do not appear before midlife. • Most affected patients become mentally incapacitated by the age of 50 to 60 years. Amyotrophic Lateral Sclerosis • Neurodegenerative disease • Affects older men and women • Motor weakness and progressive wasting of muscles in the extremities (small hand muscles) • Fasciculations (involuntary twitching) • Slurred speech but the intellect is not affected Amyotrophic Lateral Sclerosis • Loss of motor neurons in the spinal cord, midbrain, and cerebral cortex • Loss of the lateral cerebrospinal pathways in the spinal cord • Incurable, progressive disease that leads to death over a period of a few years Glioblastoma Multiforme • Most common CNS tumor • Peak incidence—65 years • Lateral hemispheres • Gross appearance – Parts of the tumor are necrotic and yellow – Parts are hemorrhagic red, and parts are white – Irregularly shaped – Poorly demarcated – Butterfly-like appearance Glioblastoma Multiforme • Histologically – Highly anaplastic astrocytic cells – Cell appearance—may retain a fetal appearance or become enlarged, bizarre shaped, or multinucleated with welldeveloped cytoplasm – Numerous mitotic figures – Proliferative changes of blood vessels Meningioma • Arise from the meninges • Mostly benign • Located in the midline, at the base of the brain, and along the spinal cord • Epileptic seizures or motor deficits • Excellent prognosis Tricyclic Antidepressants MOA: Block the reuptake of monoamine NT (Dopamine) thus increasing their levels in the synapse. Possible that a subsequent downregulation of the receptors is the actual MOA Interactions: Potentiate the effects of other CNS depressants and anticholinergic drugs Amitriptyline Indications: major depressive disorder, enuresis, agoraphobia, OCD, migraines Side Effects: severe anticholinergic effects, sedation Imipramine Indications: Enuresis in children. Was the TCA DOC but is no longer used due to its side effects Side Effects: similar to others but can induce arrhythmias Selective Serotonin Reuptake Inhibitors Mechanism of action: Selectively inhibit the reuptake of serotonin Used for depression, OCD and Panic disorder Fluoxetine (Prozac) Sertraline (Zoloft) Paroxetine (Paxil) Stimulants D-Amphetamine (Adderall and Dexedrine) MOA: releases biogenic amines (NE, dopamine and serotonin) from storage vesicles Indications: narcolepsy, ADD Side Effects: restlessness, insomnia, HTN, arrhythmia, anorexia, psychotic episodes Interactions: TCA potentiates the CNS effects by inhibiting the metabolism of amphetamine Special Notes: to treat OD you acidify the urine, give chlorpromazine (Thorazine-sedation) to reduce CNS effects and an alpha blocker for the HTN Methylphenidate (Ritalin) Same thing but milder stimulation Parkinson’s Disease Drugs Levodopa MOA: (L-Dopa) is decarboxylated to dopamine (DA) Improves neuro, motor and psych s/sx of parkinson’s Indications: parkinson’s disease Side Effects: N&V, modest ortho hypo, arrhythmias in elderly, involuntary movements, increased sexual activity Interactions: pyridoxine (B6) reduces its effects, antipsychotics block dopamine receptors, anticholinergics delay absorption Special notes: always used with carbidopa Parkinson’s Disease Drugs Carbidopa MOA: deminishes the decarboxylation of L-Dopa in peripheral tissues therefore increasing the effect of L-Dopa Indications: Parkinson’s Dz Side Effects: reduces the N&V associated with L-dopa Interactions: None Has no MOA when given alone Amantadine MOA: releases dopamine from intact terminals Side Effects: at high doses hallucinations, confucion and nightmares Interactions: anticholinergic drugs enhances the CNS side effects Is less effective than L-Dopa but more effective than anticholinergics Parkinson’s Disease Drugs Bromocriptine MOA: powerful dopamine receptor agonist Indications: Parkinson’s with tolerance to LDopa, hyperprolactinemia, pituitary tumors Side Effects: N, hallucinations, hypotension Interactions: carbidopa can be used with L-Dopa and Opioid Analgesics Morphine MOA: opiate receptor agonist. Induces analgesia, sedation, respiratory depression Indications: severe pain not alleviated by non-narcotics. DOC for severe pain in MI Side Effects: respiratory depression, constipation, orthostatic hypotension, cholestasis, constipation Tolerance can develop to the analgesic effects but not the constipating effects Analgesia is threefold: Increased threshold, unpleasant psych response is reduced, sleep is induced Opioid Analgesics Oxycodone (Oxycontin) MOA: Same as morphine Indications: Side moderate to severe pain Effects: same as morphine Used because it has a better oral absorption than morphine Benzodiazepines MOA: bind to GABA receptors and enhances GABA mediated neuronal inhibition. Causes sedation, skeletal muscle relaxation and barbiturate fast waves on EEG Indications: anxiety, DT’s, seizures, relaxation of Skeletal muscles Side Effects: drowsiness, clouding of consciousness, ataxia, behavioral disinhibition, dermatitis Interactions: effects are additive with ETOH Benzodiazepines Diazepam (Valium) Is long acting Indicated for anxiety disorder Midazolam (Versed) Is short acting Used in anesthesia Alprazolam (Xanax) Short acting Used as an antidepressant and an anxiolytic Used to treat panic attacks Does not cause daytime drowsiness Migraine Headache Therapy Sumatriptan (Imitrex) MOA: serotonin receptor agonists Causes vasoconstriction of the basilar artery and dura matter vessels Onset of relief is 10 minutes – two hours Side Effects: dizziness, tingling, flushing, chest discomfort, weakness and neck pain Used to treat a migraine that is already occurring Propranolol migraine and timilol are used to prevent the onset of a