Pathophysiology HSC122 Topic: Disorders of Neuromuscular Function (discussion) Date: July 6th 2011 ASGN: Faculty of Health Science

1. Review key concepts of the organization and control of motor function(Motor unit, Motor cortex, spinal reflexes, the stretch reflex) 2. Question: What are common disorders of Muscle tone and movement? How do they occur? How are they treated? 3. What do these terms mean? (Hypotonia, Hypertonia, Rigidity, Clonus, monoplegia, Hemiplegia/hemiparesis, diplegia/diparesis Quadriplegia/quadriparesis, paraplegia/paraperesis tetany ), 4. understand causes of common disorders of the skeletal muscle, neuromuscular junction and peripheral(Muscular dystrophy, muscle atrophy, Myasthenia Gravis, mononeuropathies, Carpal Tunnel Syndrome, Guillain -Barre' Syndrome) How do they present? How are they treated? 5. Understand causes of Back Pain and herniated intervertebral Disk; treatment Very Important!!! (A word to the Wise!) - know about hypokinetic and hyperkinetic disorders: Understand pathogenesis of Parkinson disease and Spinal cord injuries

1. Key concepts of Motor System Structures which organizes and control or coordinate motor function(e.g.running, walking, finger movements -maintenance and movement of body posture(limb extension, flexion, standing supine, active body resistance Structures located throughout neuromuscular system( motor neurons, ), neuromuscular junction, muscle fibres, spinal cord and brain stem) o Motor unit- composed of motor neurons-control motor functionsupper and lower motor neurons- project from motor strip in cerebral cortex1

Found within CNS

o Motor Cortex- area of the cerebral cortex where impulses from the nerve centers to the muscles originate. (Controls muscles of hands, facial

expression, flexor muscles; controls the actions of voluntary muscles. Different regions of the motor cortex are responsible for controlling different muscle of the body.

o Spinal reflexes- reflex actions mediated through a center of the spinal

cord- are coordinated, involuntary motor responses, initiated by stimulus applied to peripheral receptors

Stretch reflexes-Contraction of muscle fibers that occurs when a muscle is stretched, is essential to the control of muscle tone and maintenance of posture(can be induced for the purpose of routine testing, in many muscles throughout the body( knee- jerk) assessing patella reflex- allows for a series steps- Activation of stretch receptors-integration of the reflex in the spinal cordregulation of reflex sensitivity.

o Muscle tone- residual muscle tension- the continuous and

passive partial contraction of the muscles, or the muscles resistance to passive movement or stretch during resting state (e.g. around the joint)

2. Disorders Of Muscle Tone And Movement Characterised by nervous system pathology Caused by any interruption to the stretch receptors by peripheral nerve injury, pathologic process of the neuromuscular junction, and skeletal muscle fibres, injury to spinal cord or nerve root resulting disturbance of muscle tone A. Words used to describe muscle tone when it is less than normal - Hypotonia(decreased muscle tone) reduced excitability of stretch reflex- ranging from postural weakness to total flaccid paralysis (limbs appear floppy) limbs resistance to passive movement is also decreased caused by decreased function of the descending facilitatory systems which control the gamma lower motor neuron LMN that innervate the muscle spindle damage to the stretch reflex or peripheral nerves innervating the muscle - Hypertonia (spasticity) Abnormal increase in muscle tone Result from increase excitation or loss of inhabitation of the spindles gamma LMN or changes in the segmental spinal cord circuitry controlling the stretch reflex There is hyperactive tendon reflexes There is an increased resistance to rapid muscle stretch 2

Rigidity A greatly decreased resistance to movements in all direction Caused by increased activation of the alpha LMNs innervating the extrafusal muscle fibers Seen in conditions Parkinson disease in which descending CNS of alpha LMNs is impaired - Clonus Rhythmic contraction and alternate relaxation of a limb that is caused by suddenly stretching a muscle and gently maintaining it in the stretched position Seen in the hypertonia of spasticity associated with LMN lesions (e.g spinal injury B. Words used to describe disorders/loss of muscle movement and functions - Paralysis- used to describe the extent an anatomic location of motor damage- leading to loss of movement - Paresis- weakness or incomplete loss of muscle function can be designated as of UMN or LMN origin - Monoparesis/monoplegia-destruction of pyramidal UMN innervations of one limb - Hemiparesis or hemiplagia- both limbs on one side - Diparesis or diplegia/ paraparesis or paraplegia- both upper and lower limbs - Tetraparesis or tetraplegia/quadriparesis or quadriplegia all four limbs C. Upper Motor Neuron Lesions involve the motor cortex or brain structures through which the corticospinal or corticobulbar tracts descend or the spinal cord - Lesions at or above the level of the pyramids results in paralysis on opposite side of body - N.B: in LMN lesions spinal reflexes remain intact but communication and control from higher brain centers are lost UMN disorders involving injury to the lumber (L) 1 level above there is immediate profound weakness and loss of fine skilled voluntary lower limb movement, reduced bowel and bladder control. Diminished sexual functioning followed by an exaggeration of muscle tone UMN damage above cervical(C) level 5- all function below the upper shoulders also is affected D. Lower Motor Neuron Lesions - LMN disorders disrupt communication between the muscle and all neural input and output from spinal cord reflexes - Infection or irritation of the cell body of the LMN or its axon can lead to hyperexcitability causing spontaneous contractions of muscle units(e.g infection by poliomyelitis virus) - These can be observed as twitching and squirming (wriggly) movement on the muscle surface (called fasciculations)- often are followed by death of LMN 3

Tetany(Sustained contraction of of muscles on both sides of joints leading to immobility or tetanic paralysis- and sustained contaction of musclesoccurs when when toxic agents (e.g. tetanus toxin) produce extreme hyper excitability of the LMN With complete LMN- muscles of affected limbs, bowels, bladder, genital areas become atonic and it is impossible to elicit contraction by stretching tendons N.B: Damage to an LMN with or without spinal cord damage referred to as peripheral nerve injury May occur at any level of the spinal cord C7 peripheral nerve injury leads to LMN hand weakness Injury to spinal cord at the lumber(L)1 level or below results in a LMN injury and flaccid paralysis (occurs because spinal cord ends at the L1 to L2 level and from this level the spinal roots of the LMNs continue caudally in the vertebral canal as part of the cauda equina

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Skeletal Muscle, Neuromuscular Junction And Peripheral Disorders E. Skeletal Muscle Disorders Muscle Atrophy A decrease in muscle mass Caused by reduced use of muscle Characterised by a reduction in diameter of muscle fibres due to loss of protein filament (when normally innervated muscle is not used for a long time, the muscle cells shrink in diameter and lose much of their contractile protein, becoming weak Muscular Dystrophy Applied to a number of genetic disorders that produce progressive generation and necrosis of skeletal muscle fibers and eventual replacement with fat and connective tissue Fat and connective tissue replace the muscle fibres cause an increase in muscle size resulting in muscle weakness F. Disorders Of The Neuromuscular Junction Review (A&P)- Neuromuscular junction serves as a synapse between motor neuron and a skeletal muscle fiber- consist of axon terminals of motor neuron- transmission of impulses at that junction is mediated by the release of of the neurotransmitter acetylcholine from axon axon terminal Causes Disorders occur through effects of drugs and chemicals- Number of drugs and agents can alter or block/inhibit neuromuscular function or actions by changing the release, inactivation or receptor binding acetylcholine Toxins from certain organisms (e.g. Clostridium botulinum ) produce paralysis by blocking acetylcholine release Myasthenia Gravis A disorder of transmission at the neuromuscular junction that affects communication between motor neuron and innervated muscle cell. 4

May occur at any age but peaks between 20 and 30 years of age 3 times more common in women than men Smaller second peak occurs in later life and affects more men than women Pathophsiology Autoimmune disease Caused by an antibody-mediated destruction of acetylcholine receptors in neuromuscular junction( thought to be related to abnormal T-lymphocyte function) A thymus tumor or thymic hyperplasia Clinical manifestations Some persons have fewer acetylcholine receptors in post synaptic. Therefore each release of acetylcholine from pre-synaptic membrane results in muscle weakness and fatigability Eyes and periorbital muscles are most area commonly affected Ptosis due to eyelid weakness & diplopia due to weakness of the extraocular muscles (initial symptom in 50% of cases Disease may progress from ocular muscle weakness to generalized weakness including respiratory weakness Chewing and swallowing may be difficult Weakness of lower limb movement-more pronounced in proximal than distal parts of extremities-difficulty in climbing stairs and lifting objects Muscle of lower face are affected as disease progresses- causing speech impairment Symptoms are least evident when arising in the morning but grow worse with effort and as day progresses Diagnosis and Treatment Diagnosis is based on history and physical examination, the antocholinesterase test, nerve stimulation studies and immunoassay test for acetylcholine receptor antibodies Treatment methods include -the use of pharmacologic agents; immunosupprossive therapy, (corticosteroid drugs; Management of myasthetic crises- thymectomy, treat with intravenous immunoglobin Avoid medication that may exacerbate myasthenia gravis (aminogycocide antibiotics) Person is placed on drugs which inhibits the breakdown of acetycholine at neuromuscular junction by acetcholinesterase. Corticosteroid drugs which suppress the immune response- used in cases of poor response to anticholinesterase drugs and thymectomy Immunosurppressant drugs (e.g., azathiopine, cyclosporine) may be used in compination with plasmapheresis (plasmapheresis removes antibodies from the circulation and provides short-term clinical improvement- used primarily to stabilize the condition of persons in myasthenic crises or short-term treatment in persons undergoing thymectomy) Intravenous immunoglobin also produces improvement in persons with myasthenia gravis- effect is temporary- it may last weeks to months 5

Thymectomy may be used as a treatment for the disease however because the mechanism whereby surgery exerts its effect is unknown, treatment is controversial E. Peripheral Nerve Disorders Disorders involving neurons located outside the CNS Include disorders of the motor and sensory branches of the somatic and visceral nervous system Can involve single(mononeuropathy) or multiple (polyneuropathy) nerves Results in muscle weakness, with or without atrophy and sensory changes Mononeuropathies Usually caused by localized conditions such as trauma, compression or infection that affect a single nerve, plexus, or peripheral nerve trunk Caused by lacerated or compressed nerves as a result of fractures Caused by excessively tight tourniquets which may injure nerves directly or produce ischemic injury; May be caused by infections such as herpes Zoster affecting a single segmental afferent nerve Recovery of nerve function usually is complete after compression lesions and incomplete or faulty after nerve transaction Carpal Tunnel Syndrome An example of a compression-type mononeuropathy that is very common Effects approx 3% of adults 3 times more common in women than men caused by compression of the median nerve as it travels with the fexor tendons through a carnal made by the carpal bones and transverse carpal ligament caused by a variety of conditions that produces reduction in the capacity of carpal tunnel (bony reduction and ligament changes) can also be a feature of many systemic diseases- rheumatoid arthritis, hyperthyroidism, acromegaly, DM can result from wrist injury can occur during pregnancy use of birth control pills commonly seen in persons with repetitive use of the wriste(i.e. flexionextension movements and stress associated with pinching and gripping motions

Clinical manifestations pain, paresthesia and numbness of the thumb and first two and one half digits of the hands pain in wrist and hand which worsens at nights atrophy of the abductor policies muscle weakness in precision grip inflammation and swelling Diagnosis 6

usually based on sensory disturbances confined to median nerve distribution electromyography and nerve conduction studies to confirm diagnosis Treatment avoidance of movements that cause nerve compression, splinting and anti-inflammatory drugs measures to decrease the cause of repetitive movements should be initiated corticosteroid may be injected in carpal tunnel to reduce inflammation and swelling surgery (last )- division of the volar carpal ligaments as peans of relieving pressure on medial nerve - Polyneuropathies Involve semylination of axonal degeneration of multiple peripheral nerves-leading to symmetric sensory, motor or mixed sensorimotor deficits Longest axons are involved first Symptoms begin the distal part of the extremities If the autonomic nervous system is involve- hypotension, constipation, impotence Common conditions include- polyneuropathies from immune mechanisms- Guillian-Barre Syndrome; from toxic agents- arsenic polyneuropathies; lead P; alcoholic P; metabolic diseases e.g. DM Guillian-Barre Syndrome an acute immune mediated polyneuropathy.(characterized by rapidly progressive limb weakness and loss of tendon reflexes Most common cause of acute, flaccid paralysis Symptoms of parasthenia and numbness often accompany loss of motor function Paralysis may progress to involve respiratory muscles (30% of cases)- requiring ventilator assistance Pain is a common feature-shoulder, back, posterior thighs-occurs with the slightest of movements May have an immune component Linked to infection- cytomegalovirus, Emstein-Barr Virus, Mycoplasma pneumonia Condition is a medical emergency due to rapid development of ventilator failure and autonomic disturbances that threatening circulatory problems Treatment- support for vital functions and prevention of complications such as skin breakdown and thrombophlebitis Plasmapheresis(drugs)- effective in decreasing morbidity and shortening the course of disease Immunoglobulin therapy Approximately 80-90% of persons achieve full and spontaneous recovery in 6-12 months 7

Back Pain and Herniated Intervertebral Disk Back pain Can result from a number of interrelated problems involving the structures of the vertebral column, the spinal roots or muscle and ligament structures of the back Most common- musculoligamentous injuries and age- related degenerative changes in intervertebral disks and joints Men and women equally affected (onset between 30 and 50 yers) Most common forms of work related disabilities Risk factors(heavy lifting, twisting, bodily vibration, obesity, and poor conditioning (may also affect persons without such risks) Commonly are attributed to herniated disk although most acute back problems may result from other causes( tumors, compression fractures) Diagnosis Based on history and physical examination Radiographs of back; MRI (to r/o the possibility of tumors or impending neurologic infections

Treatment Usually conservative Analgesics, (NSAIDs) or anti-inflammatory drugs; muscle relaxants Instruction in the correct mechanic for lifting and methods of protecting back Bedrest- although research shows it is not as effective for acute back pain Herniated Intervertebral Disk Considered the most critical component of load-bearing structures of the spinal column Caused when the nucleus pulponsus within the intervertebral disk is squeezed out of place and herniate through the annulus fibrosus (a condition referred to as a herniated or slipped disk Can become dysfunctional because of trauma(accounts of 50%), aging(wear and tear of its elasticity), degenerative disorders of the spine(osteoarthritis or ankylosin spondylitis predispose to mal alignment of vertebral column) Results from activities of lifting while in flexed position, slipping, falling on buttocks or back or suppressing Cervical and lumbar regions are the most flexible areas of the spine and those most often involved disk herniations Usually occurs at the lower levels of the lumbar spine Clinical manifestation Localized to the area innervated by the nerve roots Motor and sensory manifestations Pain (first and most common symptoms 8

 Diagnosis

Back pain that spread to back of the leg and over the sole of the foot Pain intensified with coughing and sneezing, straining, stooping, standing and jarring motions that occur during walking or riding Slight motor weakness may occur although major weakness is rare Spinal nerve root compression(sensory deficits) numbness and paresthesias of leg and foot Include history and physical examinations Neurologic assessment- testing of muscle strength and reflexes( straight leg test- done in supine position and is performed by passively raising the persons leg to see if leg can be raised by 90 degrees without pain X-rays, CT scans, MRI Treatment similar to that for back pain

4. Disorders of the Basal Ganglia Review structural component of Basal Ganglia - A group of deep, interrelated subcortical nuclei that constitute an accessory motor system that functions in close association with the motor cortex - Made up of some key structural components however 2 key components subthalmic nucleus of the dicephalon and substantia nigra of the midbrain. - Dorsal part of substantia nigra contain cells that synthesize the neurotransmitter dopamine and are rich in black pigment called melanin. The high concentration of melanin gives the structure a black color- hence the name substantia nigra. The axons of the substantia nigra form the nigrostrial pathway which supplies dopamine to the striatum. This dopamine which is released regulates the overall excitability of the striatum and release of other neurotransmitters. Movement disorders come about as a result of disorders of the basal ganglia leading to motor disturbances characterized by tremors, and other involuntary movements, changes in posture and muscle tone , poverty and slowness of movements- tremors, tics, hypokenetic disorders, hyperkinetic disorders Parkinson disease (PD) Caused by generative changes in the basal ganglia function leading to a deficiency in dopaminergic projection usually begins after 50 years of age most cases diagnosed in 6th and 7th decades of life characterised by progressive destruction of the nigrostriatal pathway depletion in levels of dopamine concentration due to degeneration of dopamine- producing neurons of substantia nigra symptoms may be accompanied by other conditions e.g. CVA, brain tumors, repeated head traumas, degenerative neurologic disease 9

could follow high doses of certain antipsychotic drugs due to genetic factors- may run in families

Clinical manifestations tremor (hands, feet, face, neck, lips, tongue & jaw) rigidity (resistance to movement of flexor and extensor muscles bradykinesia (slowness of movement) falling due to loss of postural reflexes fluctuations in motor functions difficulty speaking lean forward to maintain centre of gravity when walking limited emotional and voluntary facial movements and expressions rigidity of palate, tongue and throat muscles drooling because of difficulty moving saliva to back of mouth

Treatment includes nonpharmacologic, pharmacologic and surgical methods if indicated Nonpharmacologic- (group support, education, daily exercise, adequate nutrition..) Pharmacologic- usually determined by severity of symptoms Anti Parkinson drugs(acts to increase the functional ability of the underactive dopaminergic system or reduce the excessive influence of excitatory cholinergic neurons( drugs that increase dopamine levels or augment the release of dopamine-fuctions as a dopamine agonist and stimulate dopamine receptors Because dopamine transmission is disrupted in PD there is a preponderance which may be treated with anticholinergic drugs which restores a balance between reduced dopamine and uninhibited cholinergic neurons in the striatum 10

Surgical treatment includes thalamotomy or pallidectomy

Multiple Sclerosis (for personal reading) Spinal Cord Injury Represents damage in the neural elements of the spinal cord Primarily a disorder of young adults 53% occurring in the age group 16-30 years Cause by MVAs, falls, gunshot wounds, recreational sporting activities injury to the vertebral column fractures, dislocations, subluxations vertebral body become displaced and override another preventing correct alignment of vertebral column Damage to ligaments or bony vertebrae may make the spine unstable Most injuries result from some combination of compressive force or bending movement Flexion injuries occur when forward bending of the spinal column exceeds the limits of normal movement Typical flexion injuries occurs when the heads is struck behind as in a fall with the back of the head as the point of impact(i.e. hyperextension) of the spine backward; Typical extension injury- involves a fall in which the chin or face is the point of impact, causing hyperextension of the neck Injuries of flexion and extension occur more commonly in cervical spine (C4 to C6) than in any other area A compression injury causing the vertebral bones to shatter, squash or even burst occurs when there is spinal loading from a high velocity blow to the top of the head or forceful landing on the feet.. Falling from a distance and landing on feet can cause compression injuries Diving injuries Compression injuries may also occur when the vertebrae are weakened by conditions such as osteoporosis and cancer with bone metastasis Acute Spinal Cord Injury (SCI) Involves damage to the neural elements of the spinal cord Damage may result from direct trauma to the cord such as occurs with penetrating wounds or from indirect injury resulting from vertebral fractures, fracture-dislocation or subluxation of spine Spinal cord may be contused, not only at the site of injury but above and below the trauma site Traumatic injury may be complicated by loss of blood flow to spinal cord Sudden complete transaction of the spinal cord results in complete loss of motor, sensory, reflex and autonomic function below level of injury Pathophysiologic process can be divided into two types: primary and secondary Primary neurologic injury Occurs at the time of mechanical injury and is irreversible 11

Characterized by small hemorrhages in the gray matter of the cord, followed by edematous changes in the white matter that lead to necrosis of neural tissue Type of lesion results from the forces of compression, stretch, and shear associated with fracture or compression of spinal vertebrae; dislocation of vertebrae(e.g. flexion, extension, subluxation) and contusion due to jarring of cord in spinal canal Penetrating injuries produce lacerations and direct trauma to the cord and may occur with or without spinal column damage Lacerations occur when there is cutting or tearing of the spinal cord which injures nerve tissue and causes bleeding and edema Secondary injuries Follow the primary injury and promote the spread of injury The tissue destruction that occurs ends in progressive neurologic damage Leads to several pathologic mechanisms- vascular damage, neuronal injury which leads to loss of reflexes vessel damage, hemorrhage , ischemia, increased vascular permeability edema, Blood flow to spinal cord may be compromised by spinal shock, Loss of vasomotor function and neural reflexes etc. etc. Management Goal is to reduce the neurologic deficit and prevent any additional loss of neurologic function Stabilization and immobilization use of cervical collars and backboards and limiting the movement of the person Management depends on extent of the injury In unstable injuries of cervical spine- cervical traction improves or restores spinal alignment, decompresses neural structures and facilitates recovery Fractures and dislocations of the thoracic and lumbar vertebrae may be initially stabilized by restricting the person to bed rest and turning him or her in a log-rolling manner to keep spine rigid Gunshot or stab wounds of the spinal cord may not produce structural instability and may not require immobilization The goal of early surgical internal intervention for an unstable spine is to provide internal skeletal stabilization so that early mobilization and rehabilitation can occur One important goal of care is to prevent and/ or treat any spinal shock and hypoxia associated with compromised respiration Correcting hypotension or hypoxia is essential to maintaining circulation to the injured cord. Bibliography Porth, M.C (2007). Essentials of Pathophysiology. Concepts of Altered Health States (2nd Edition). Philadelphia: Lippincott Williams & Wikins

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