 Identify the following signs associated with abnormal motor function.

 Weakness
o Reduction in the power that can be exerted by one or more muscles
 Fatigability
o Inability to sustain the performance of an activity that should be normal for a person of the same age, sex,
and size
 Bradykinesia
o Condition in which increased time is required for full power to be exerted
 Apraxia
o Disorder of planning and initiating a skilled or learned movement unrelated to a significant motor or
sensory deficit
 Paralysis
o Weakness so severe that a muscle cannot be contracted at all
 Paresis
o Less severe weakness; the prefix “hemi-“ refers to one-half of the body, “para-“ to both legs, “quadri-“ to
all four limbs
 Flaccidity
o Refers to a decreased tone of a muscle to passive stretch
 Determine the possible cause of muscle weakness based on the distribution of weakness based on the
distribution of weakness and general clinical presentation:
 The distribution of weakness helps to localize the underlying lesion.
o Weakness from involvement of upper motor neurons occurs particularly in the extensors and abductors
of the upper limb and the flexors of the lower limb.
o Lower motor neuron weakness depends on whether involvement is at the level of the anterior horn cells,
nerve root, limb plexus, or peripheral nerve—only muscles supplied by the affected structure are
weak.
o Myopathic weakness is generally most marked in proximal muscles.
o Weakness from impaired neuromuscular transmission has no specific pattern of involvement.
 Weakness often is accompanied by other neurologic abnormalities that help indicate the site of the responsible
lesion (Table 21-1).
 Upper Motor Neuron Weakness.
o Lesions of the upper motor neurons or their descending axons to the spinal cord produce weakness
through decreased activation of lower motor neurons.
o In general, distal muscle groups are affected more severely than proximal ones, and axial movements are
spared unless the lesion is severe and bilateral.
o Spasticity is typical but may not be present acutely.
o Rapid repetitive movements are slowed and coarse, but normal rhythmicity is maintained.
o With corticobulbar involvement, weakness occurs in the lower face and tongue; extraocular, upper facial,
pharyngeal, and jaw muscles are typically spared.
o Bilateral corticobulbar lesions produce a pseudobulbar palsy: dysarthria, dysphagia, dysphonia, and
emotional lability accompany bilateral facial weakness and a brisk jaw jerk.
o Electromyogram (EMG) shows that with weakness of the upper motor neuron type, motor units have a
diminished maximal discharge frequency.
 Lower Motor Neuron Weakness.
o This pattern results from disorders of lower motor neurons in the brainstem motor nuclei and the anterior
horn of the spinal cord or from dysfunction of the axons of these neurons as they pass to skeletal muscle.
o Weakness is due to a decrease in the number of muscle fibers that can be activated through a loss of α
motor neurons or disruption of their connections to muscle.
o Loss of γ motor neurons does not cause weakness but decreases tension on the muscle spindles, which
decreases muscle tone and attenuates the stretch reflexes.
o An absent stretch reflex suggests involvement of spindle afferent fibers.
 When a motor unit becomes diseased, especially in anterior horn cell diseases, it may discharge spontaneously,
producing fasciculations.
 o When α motor neurons or their axons degenerate, the denervated muscle fibers also may discharge
spontaneously. These single muscle fiber discharges, or fibrillation potentials, cannot be seen but can be
recorded with EMG. Weakness leads to delayed or reduced recruitment of motor units, with fewer than
normal activated at a particular discharge frequency.
 Neuromuscular Junction Weakness.
o Disorders of the neuromuscular junctions produce weakness of variable degree and distribution. The
number of muscle fibers that are activated varies over time, depending on the state of rest of the
neuromuscular junctions. Strength is influenced by preceding activity of the affected muscle.
o In myasthenia gravis, for example, sustained or repeated contractions of affected muscle decline in
strength despite continuing effort. Thus, fatigable weakness is suggestive of disorders of the
neuromuscular junction, which cause functional loss of muscle fibers due to failure of their activation.
 Myopathic Weakness.
o Myopathic weakness is produced by a decrease in the number or contractile force of muscle
fibers activated within motor units.
o With muscular dystrophies, inflammatory myopathies, or myopathies with muscle fiber necrosis, the
number of muscle fibers is reduced within many motor units. On EMG, the size of each motor unit action
potential is decreased, and motor units must be recruited more rapidly than normal to produce the desired
power. Some myopathies produce weakness through loss of contractile force of muscle fibers or through
relatively selective involvement of type II (fast) fibers. These myopathies may not affect the size of
individual motor unit action potentials and are detected by a discrepancy between the electrical activity
and force of a muscle.
 Psychogenic Weakness.
o Weakness may occur without a recognizable organic basis. It tends to be variable, inconsistent, and with
a pattern of distribution that cannot be explained on a neuroanatomic basis. On formal testing,
antagonists may contract when the patient is supposedly activating the agonist muscle. The severity of
weakness is out of keeping with the patient’s daily activities.
 DISTRIBUTION OF WEAKNESS
 Hemiparesis.
o Hemiparesis results from an upper motor neuron lesion above the midcervical spinal cord; most such
lesions are above the foramen magnum. The presence of other neurologic deficits helps localize the
lesion.
o Thus, language disorders, for example, point to a cortical lesion.
o Homonymous visual field defects reflect either a cortical or a subcortical hemispheric lesion.
o A “pure motor” hemiparesis of the face, arm, and leg often is due to a small, discrete lesion in the
posterior limb of the internal capsule, cerebral peduncle in the midbrain, or upper pons.
o Some brainstem lesions produce “crossed paralyses,” consisting of ipsilateral cranial nerve signs and
contralateral hemiparesis. The absence of cranial nerve signs or facial weakness suggests that a
hemiparesis is due to a lesion in the high cervical spinal cord, especially if associated with the Brown-
Séquard syndrome.
 Acute or episodic hemiparesis usually results from focal structural lesions, particularly rapidly expanding lesions,
or an inflammatory process.
o Subacute hemiparesis that evolves over days or weeks may relate to subdural hematoma, infectious or
inflammatory disorders (e.g., cerebral abscess, fungal granuloma or meningitis, parasitic infection,
multiple sclerosis, sarcoidosis), or primary or metastatic neoplasms.
o AIDS may present with subacute hemiparesis due to toxoplasmosis or primary central nervous system
(CNS) lymphoma.
o Chronic hemiparesis that evolves over months usually is due to a neoplasm or vascular malformation, a
chronic subdural hematoma, or a degenerative disease.
 Paraparesis.
o Acute paraparesis is caused most commonly by an intraspinal lesion, but its spinal origin may not
be recognized initially if the legs are flaccid and areflexic.
o Usually, however, there is sensory loss in the legs with an upper level on the trunk, a dissociated sensory
loss suggestive of a central cord syndrome, or hyperreflexia in the legs with normal reflexes in the arms.
 Imaging the spinal cord may reveal compressive lesions, infarction (proprioception usually is spared),
arteriovenous fistulas or other vascular anomalies, or transverse myelitis.
o Diseases of the cerebral hemispheres that produce acute paraparesis include anterior cerebral artery
ischemia (shoulder shrug also is affected), superior sagittal sinus or cortical venous thrombosis, and
acute hydrocephalus.
o Paraparesis may result from a cauda equina syndrome, for example, after trauma to the low back, a
midline disk herniation, or an intraspinal tumor. The sphincters are commonly affected, whereas hip
flexion often is spared, as is sensation over the anterolateral thighs.
o Rarely, paraparesis is caused by a rapidly evolving anterior horn cell disease (such as poliovirus or West
Nile virus infection), peripheral neuropathy (such as Guillain-Barré syndrome;), or myopathy.
 Subacute or chronic spastic paraparesis is caused by upper motor neuron disease.
o When associated with lower-limb sensory loss and sphincter involvement, a chronic spinal cord disorder
should be considered. If hemispheric signs are present, a parasagittal meningioma or chronic
hydrocephalus is likely. The absence of spasticity in a long-standing paraparesis suggests a lower motor
neuron or myopathic etiology.
o Investigations typically begin with spinal MRI, but when upper motor neuron signs are associated with
drowsiness, confusion, seizures, or other hemispheric signs, brain MRI should also be performed,
sometimes as the initial investigation.
o Electrophysiologic studies are diagnostically helpful when clinical findings suggest an underlying
neuromuscular disorder.
 Quadriparesis or Generalized Weakness.
o Generalized weakness may be due to disorders of the CNS or the motor unit.
o Although the terms often are used interchangeably, quadriparesis is commonly used when an upper
motor neuron cause is suspected, and generalized weakness is used when a disease of the motor units
is likely.
o Weakness from CNS disorders usually is associated with changes in consciousness or cognition
and accompanied by spasticity, hyperreflexia, and sensory disturbances.
o Most neuromuscular causes of generalized weakness are associated with normal mental function,
hypotonia, and hypoactive muscle stretch reflexes. A patient with generalized fatigability without objective
weakness may have the chronic fatigue syndrome.
 Monoparesis.
o Monoparesis usually is due to lower motor neuron disease, with or without associated sensory
involvement. Upper motor neuron weakness occasionally presents as a monoparesis of distal and
nonantigravity muscles. Myopathic weakness rarely is limited to one limb.
 Distal Weakness.
o Involvement of two or more limbs distally suggests lower motor neuron or peripheral nerve
disease.
o Acute distal lower-limb weakness results occasionally from an acute toxic polyneuropathy or cauda
equina syndrome.
o Distal symmetric weakness usually develops over weeks, months, or years and, when associated with
numbness, is due to peripheral neuropathy.
o Anterior horn cell disease may begin distally but is typically asymmetric and without
accompanying numbness. Rarely, myopathies present with distal weaknes. Electrodiagnostic studies
help localize the disorder.
 Proximal Weakness.
o Myopathy often produces symmetric weakness of the pelvic or shoulder girdle muscles.
o Diseases of the neuromuscular junction, such as myasthenia gravis, may present with symmetric
proximal weakness often associated with ptosis, diplopia, or bulbar weakness and fluctuating in severity
during the day.
o In anterior horn cell disease, proximal weakness is usually asymmetric, but it may be symmetric if familial.
o Numbness does not occur with any of these diseases.
o The evaluation usually begins with determination of the serum creatine kinase level and
electrophysiologic studies.
 Weakness in a Restricted Distribution.
o Weakness may not fit any of these patterns, being limited, for example, to the extraocular, hemifacial,
bulbar, or respiratory muscles.
o If it is unilateral, restricted weakness usually is due to lower motor neuron or peripheral nerve disease,
such as in a facial palsy.
o Weakness of part of a limb is commonly due to a peripheral nerve lesion such as an entrapment
neuropathy.
o Relatively symmetric weakness of extraocular or bulbar muscles frequently is due to a myopathy or
neuromuscular junction disorder.
o Bilateral facial palsy with areflexia suggests Guillain Barré syndrome.
o Worsening of relatively symmetric weakness with fatigue is characteristic of neuromuscular junction
disorders. Asymmetric bulbar weakness usually is due to motor neuron disease.
o Weakness limited to respiratory muscles is uncommon and usually is due to motor neuron disease,
myasthenia gravis, or polymyositis/ dermatomyositis.
 State the various conditions associated with episodic generalized weakness
 Recall the anatomy and physiology of the Neuromuscular Junction.
 The process of chemical transmission can be summarized by the following series of steps (Fig. 8- 2):
o Neurotransmitter molecules are packaged into synaptic vesicles. Specific transport proteins in the vesicle
membrane use the energy of an H+ gradient to energize uptake of the neurotransmitter in the vesicle.
o An action potential, which involves voltage-gated Na- and K+ channels (see Chapter 7), arrives at the
presynaptic nerve terminal.
o Depolarization opens voltage-gated Ca2+ channels, which allows Ca2+ to enter the presynaptic terminal.
The increase in intracellular Ca2+ concentration ([Ca2+]i) triggers the fusion of synaptic vesicles with the
presynaptic membrane.
o As a result, packets (quanta) of transmitter molecules are released into the synaptic cleft. The transmitter
molecules diffuse across the synaptic cleft and bind to specific receptors on the membrane of the
postsynaptic cell. The binding of transmitter activates the receptor, which in turn activates the
postsynaptic cell.
o The process is terminated by (1) enzymatic destruction of the transmitter (e.g., hydrolysis of ACh by
acetylcholinesterase), (2) uptake of transmitter into the presynaptic nerve terminal or into other cells by
Na+-dependent transport systems, or (3) diffusion of the transmitter molecules away from the synapse.
 Describe how to perform a comprehensive neurologic examination with emphasis on cranial nerves and motor
system.
 Three important questions that govern the neurologic examination include:
 Is the mental status intact?
 Are right-sided and left-sided findings symmetric?
 If the findings are asymmetric or otherwise abnormal, does the causative lesion lie in the CNS or PNS?
 THE CRANIAL NERVES
 The examination of the Cranial Nerves (CN) can be summarized as follows:
 CN I – Olfactory. Test the sense of smell by presenting the patient with familiar nonirritating odors.
o Avoid noxious odors like ammonia that might stimulate CN V.
 CN II – Optic. Test visual acuity.
o Inspect the optic fundi with your ophthalmoscope, paying special attention to the optic discs.
o Test the visual fields by confrontation. Test each eye separately, and both eyes together.
o Occasionally, in stroke patients, for example, patients will complain of partial loss of vision, and testing of
both eyes reveals a visual field defect, an abnormality in peripheral vision such as homonymous
hemianopsia.
o Testing only one eye would miss this finding.
 CN II and III. Optic and Oculomotor.
o Inspect the size and shape of the pupils, and compare one side with the other.
o Anisocoria, or a difference of >0.4 mm in the diameter of one pupil compared to the other, is seen in up to
38% of healthy individuals.
 o Test the pupillary reactions to light. Also check the near response, which tests pupillary constriction
(pupillary constrictor muscle), convergence (medial rectus muscles), and accommodation of the lens
(ciliary muscle).
 CN III, IV, and IV – Oculomotor, Trochlear, and Abducens.
o Test the extraocular movements in the six cardinal directions of gaze, and look for loss of conjugate
movements in any of the six directions, which causes diplopia.
o Ask the patient which direction makes the diplopia worse and inspect the eye closely for asymmetric
deviation of movement.
o Determine if the diplopia is monocular or binocular by asking the patient to cover one eye, then the other.
o Check convergence of the eyes. Identify any nystagmus, an involuntary jerking movement of the eyes
with quick and slow components. Note the direction of gaze in which it appears, the plane of the
nystagmus (horizontal, vertical, rotary, or mixed), and the direction of the quick and slow components.
o Nystagmus is named for the direction of the quick component. Ask the patient to fix his or her vision on a
distant object and observe if the nystagmus increases or decreases.
o Look for ptosis (drooping of the upper eyelids). A slight difference in the width of the palpebral fissures is
a normal variant in approximately one third of patients.
 CN V – Trigeminal Motor.
o While palpating the temporal and masseter muscles in turn, ask the patient to firmly clench the teeth.
Note the strength of muscle contraction. Ask the patient to open and move the jaw from side to side.
 CN V – Trigeminal Sensory.
o After explaining what you plan to do, test the forehead, cheeks, and chin on each side for pain sensation
in the circled areas. The patient’s eyes should be closed.
o Use a suitable sharp object such as a pin or cotton swab.
o If you detect sensory loss, confirm it by testing temperature sensation.
o Corneal Reflex. Test the corneal reflex.
 Avoiding the eyelashes, lightly touch the cornea (not just the conjunctiva) with a fine wisp of
cotton. If the patient is apprehensive touching the conjunctiva first may be helpful. Inspect for
blinking of both eyes, the normal reaction to this stimulus.
 The sensory limb of this reflex is carried in CN V, and the motor response in CN VII on both
sides.
 CN VII - Facial.
o Inspect the face both at rest and during conversation with the patient. Note any asymmetry, often visible
in the nasolabial folds, and observe any tics or other abnormal movements.
 CN VIII – Acoustic.
o Assess hearing with the whispered voice test.
o If hearing loss is present, determine if the loss is conductive, from impaired “air through ear” transmission,
or sensorineural, from damage to the cochlear branch of CN VIII.
o Test for air and bone conduction, using the Rinne test, and lateralization, using the Weber test.
o Specific tests of the vestibular function of CN VIII are rarely included in the typical neurologic
examination.
 CN XI and X – Glossopharyngeal and Vagus.
o Listen to the patient’s voice. Is it hoarse, or does it have a nasal quality? Is there difficulty in swallowing?
o Ask the patient to say “ah” or to yawn as you watch the movements of the soft palate and the pharynx.
o The soft palate normally rises symmetrically, the uvula remains in the midline, and each side of the
posterior pharynx moves medially, like a curtain.
o The slightly curved uvula seen occasionally as a normal variation should not be mistaken for a uvula
deviated by a lesion of CN IX or X.
o Warn the patient that you are going to test the gag reflex, which some patients may refuse. This reflex
consists of elevation of the tongue and soft palate and constriction of the pharyngeal muscles. Stimulate
the back of the throat lightly on each side in turn and observe the gag reflex. This reflex is diminished in
many normally healthy people.
 CN XI – Spinal Accessory.
o Standing behind the patient, look for atrophy or fasciculations in the trapezius muscles, and compare one
side with the other.
 o Fasciculations are fine flickering irregular movements in small groups of muscle fibers. Ask the patient to
shrug both shoulders upward against your hands. Note the strength and contraction of the trapezii. Ask
the patient to turn his or her head to each side against your hand.
o Observe the contraction of the opposite sternocleidomastoid (SCM) muscle and note the force of the
movement against your hand.
 CN XII – Hypoglossal.
o Listen to the articulation of the patient’s words. This depends on CNs V, VII, IX, and X, as well as XII.
Inspect the patient’s tongue as it lies on the floor of the mouth.
o Look for any atrophy or fasciculations.
o With the patient’s tongue protruded, look for asymmetry, atrophy, or deviation from the midline. Ask the
patient to move the tongue from side to side, and note the symmetry of the movement.
o In ambiguous cases, ask the patient to push the tongue against the inside of each cheek in turn as you
palpate externally for strength.
 THE MOTOR SYSTEM
 Examination of the motor system should focus on the following:
 Body Position.
o Observe the patient’s body position during movement and at rest.
 Involuntary Movements.
o Watch for involuntary movements such as tremors, tics, chorea, or fasciculations. Note their location,
quality, rate, rhythm, and amplitude, and their relation to posture, activity, fatigue, emotion, and other
factors.
 Muscle Bulk.
o Inspect the size and contours of muscles. Do the muscles look flat or concave, suggesting loss of muscle
bulk from atrophy or wasting?
o When inspecting for atrophy, pay particular attention to the hands, shoulders, thighs, and legs.
o The spaces between the metacarpals, where the dorsal interosseous muscles lie, should be full or only
slightly depressed.
o The thenar and hypothenar eminences of the hands should be full and convex. Atrophy of the hand
muscles occurs in normal aging.
o Inspect for fasciculations in atrophic muscles. If absent, tap on the muscles with a reflex hammer, which
stimulates them.
 Muscle Tone.
o When a normal muscle with an intact nerve supply is relaxed voluntarily, it maintains a slight residual
tension known as muscle tone.
o This is best assessed by feeling the muscle’s resistance to passive stretch.
o Persuade the patient to relax. Hold one hand with yours and, while supporting the elbow, flex and extend
the patient’s fingers, wrist, and elbow, and put the shoulder through a moderate range of motion.
o If you suspect decreased resistance, hold the forearm and shake the hand loosely back and forth.
Normally the hand moves back and forth freely but is not completely floppy.
o If resistance is increased, determine if it varies as you move the limb or persists throughout the range of
movement and in both directions, for example, during both flexion and extension.
o Feel for any jerkiness in the resistance. To assess muscle tone in the legs, support the patient’s thigh with
one hand, grasp the foot with the other, and flex and extend the patient’s knee and ankle on each side.
Note the resistance to moving the limb.
 Muscle Strength.
o Normal strength varies widely, so your standard of normal should allow for factors like age, sex, and
muscular training.
o Test muscle strength by asking the patient to actively resist your movement. Remember that a muscle is
strongest when shortest, and weakest when longest.
o If the muscles are too weak to overcome resistance, test them against gravity alone or with gravity
eliminated. When the forearm rests in a pronated position, for example, dorsiflexion at the wrist can be
tested against gravity alone.
 o When the forearm is midway between pronation and supination, extension at the wrist can be tested with
gravity eliminated. Finally, if the patient fails to move the body part, observe or palpate for weak muscular
contraction.
o Test flexion (C5, C6—biceps and brachioradialis) and extension (C6, C7, C8—triceps) at the elbow by
having the patient pull and push against your hand.
o Test extension at the wrist (C6, C7, C8, radial nerve—extensor carpi radialis longus and brevis) by asking
the patient to make a fist and resist as you press down. Or ask the patient to extend the forearms with
fingers straight and palms up, then press the palms downward.
o Test the grip (C7, C8, T1). Ask the patient to squeeze two of your fingers as hard as possible and not let
them go. To avoid getting hurt by strong grips, place your own middle finger on top of your index finger.
Normally it should be difficult for you to pull your fingers from the patient’s grip. Test both grips
simultaneously with the patient’s arms extended or in the lap to help compare the right handgrip with the
left.
o Test finger abduction (C8, T1, ulnar nerve). Position the patient’s hand with palm down and fingers
spread. Instruct the patient to prevent you from moving any fingers as you try to force them together. Test
opposition of the thumb (C8, T1, median nerve). Ask the patient to touch the tip of the little finger with the
thumb, against your resistance.
 You may already have assessed muscle strength of the trunk during other segments of the examination, namely:
o Flexion, extension, and lateral bending of the spine
o Thoracic expansion and diaphragmatic excursion during respiration
o Test flexion at the hip (L2, L3, L4—iliopsoas) by placing your hand on the patient’s mid-thigh and asking
the patient to raise the leg against your hand.
o Test adduction at the hips (L2, L3, L4—adductors). Place your hands firmly on the bed between the
patient’s knees. Ask the patient to bring both legs together.
o Test abduction at the hips (L4, L5, S1—gluteus medius and minimus). Place your hands firmly outside the
patient’s knees. Ask the patient to spread both legs against your hands.
o Test extension at the hips (S1—gluteus maximus). Have the patient push the mid posterior thigh down
against your hand.
o Test extension at the knee (L2, L3, L4—quadriceps). Support the knee in flexion and ask the patient to
straighten the leg against your hand. The quadriceps is the strongest muscle in the body, so expect a
forceful response.
o Test flexion at the knee (L4, L5, S1, S2—hamstrings) as shown below. Position the patient’s leg so that
the knee is flexed with the foot resting on the bed. Tell the patient to keep the foot down as you try to
straighten the leg.
o Test foot dorsiflexion (mainly L4, L5—tibialis anterior) and plantar flexion (mainly S1— gastrocnemius,
soleus) at the ankle by asking the patient to pull up and push down against your hand. Heel and toe walk
also assess foot dorsiflexion and plantar flexion, respectively.
 Coordination. Coordination of muscle movement requires four areas of the nervous system to function in an
integrated way:
o The motor system, for muscle strength
o The cerebellar system (also part of the motor system), for normal rhythmic movement and steady posture
o The vestibular system, for balance and for coordinating eye, head, and body movements
o The sensory system, for position sense

 Rapid Alternating Movements

o Arms. Show the patient how to strike one hand on the thigh, raise the hand, turn it over, and then strike
the back of the hand down on the same place. Urge the patient to repeat these alternating movements as
rapidly as possible. Observe the speed, rhythm, and smoothness of the movements. Repeat with the
other hand. The nondominant hand may perform less well. Show the patient how to tap the distal joint of
the thumb with the tip of the index finger, again as rapidly as possible. Again, observe the speed, rhythm,
and smoothness of the movements. The nondominant side often performs less well.
o Legs. Ask the patient to tap the ball of each foot in turn as quickly as possible on your hand or the floor.
Note any slowness or awkwardness. Normally the feet do not perform as well as the hands.
 Point-To-Point Movements
 o Arms—Finger-to-Nose Test. Ask the patient to touch your index finger and then his or her nose
alternately several times. Move your finger so that the patient has to change directions and extend the
arm fully to reach your finger. Observe the accuracy and smoothness of movement, and watch for any
tremor. Now hold your finger in one place so that the patient can touch it with one arm and finger
outstretched. Ask the patient to raise the arm overhead and lower it again to touch your finger. After
several repeats, ask the patient to close both eyes and try several more times. Repeat on the other side.
Normally the patient touches the examiner’s finger successfully with eyes open or closed. These
maneuvers test position sense and the function of both the labyrinth of the inner ear and the
cerebellum.
o Legs—Heel-to-Shin Test. Ask the patient to place one heel on the opposite knee, then run it down the
shin to the big toe. Observe this movement for smoothness and accuracy. Repetition with the patient’s
eyes closed tests for position sense. Repeat on the other side. Gait. Ask the patient to: Walk across the
room or down the hall, then turn and come back. Observe posture, balance, swinging of the arms, and
movements of the legs. Normally balance is intact, the arms swing symmetrically at the sides, and turns
are smooth.
 Walk heel-to-toe in a straight line—called tandem walking.
o Walk on the toes, then on the heels—this tests plantar flexion and dorsiflexion of the ankles as well as
balance.
o Hop in place on each foot in turn (if the patient is not too ill)—this tests proximal and distal muscle
strength in the legs and requires both normal position sense and cerebellar function.
o Do a shallow knee bend, first on one leg, then on the other. Steady the patient if you think the patient
might fall.
o Or alternatively, rise from a sitting position without arm support and step up on a sturdy stool—if the
patient is unsteady, neurologically impaired, or frail these tests are more suitable than hopping or knee
bends.
 Stance. The following two tests can often be performed concurrently. They differ only in the patient’s arm position
and in what you are assessing. In each case, stand close enough to the patient to prevent a fall.
o The Romberg Test. This is mainly a test of position sense. The patient should first stand with feet
together and eyes open and then close both eyes for 30 to 60 seconds without support. Note the patient’s
ability to maintain an upright posture. Normally any swaying is minimal.
o Test for Pronator Drift. The patient should stand for 20 to 30 seconds with eyes closed and both arms
held straight forward with palms up. Normally patients hold this arm position well. If necessary,
patients can be tested in the sitting position. Next, instruct the patient to keep the arms out and eyes shut
and tap the arms briskly downward. The arms normally return smoothly to the horizontal position. This
response requires muscular strength, coordination, and good position sense.

 Discuss Myasthenia Gravis (MG).

 Myasthenia gravis (MG) is a neuromuscular junction (NMJ) disorder characterized by weakness and fatigability of
skeletal muscles.
o The underlying defect is a decrease in the number of available acetylcholine receptors (AChRs) at NMJs
due to an antibody-mediated autoimmune attack.
o Bimodal age distribution.
o The female to-male ratio is 2:1 in the young adults, but in older adults there is a male predominance. MG
has a prevalence as high as 200 in 100,000. It affects individuals in all age groups, but peak incidences
occur in women in their twenties and thirties and in men in their fifties and sixties. Overall, women are
affected more frequently than men, in a ratio of ~3:2.
 Explain the pathophysiology of MG.
o In MG, the fundamental defect is a decrease in the number of available AChRs at the postsynaptic
muscle membrane. In addition, the postsynaptic folds are flattened, or “simplified.” These changes result
in decreased efficiency of neuromuscular transmission. Therefore, although ACh is released normally, it
produces small end-plate potentials that may fail to trigger muscle action potentials. Failure of
transmission results in weakness of muscle contraction.
o The amount of ACh released per impulse normally declines on repeated activity (termed presynaptic
rundown).
 o In the myasthenic patient, the decreased efficiency of neuromuscular transmission combined with the
normal rundown results in the activation of fewer and fewer muscle fibers by successive nerve impulses
and hence increasing weakness, or myasthenic fatigue. This mechanism also accounts for the
decremental response to repetitive nerve stimulation seen on electrodiagnostic testing.
o MG is an autoimmune disorder most commonly caused by anti- AChR antibodies.
o The anti-AChR antibodies reduce the number of available AChRs at NMJs by three distinct mechanisms:
(1) accelerated turnover of AChRs by a mechanism involving cross-linking and rapid endocytosis of the
receptors; (2) damage to the postsynaptic muscle membrane by the antibody in collaboration with
complement; and (3) blockade of the active site of the AChR (i.e., the site that normally binds Ach).
o An immune response to muscle-specific kinase (MuSK), a protein involved in AChR clustering at the
NMJ, can also result in MG, with reduction of AChRs demonstrated experimentally. Anti-MuSK antibody
occurs in about 10% of patients (about 40% of AChR antibody negative patients), while 1– 3% have
antibodies to another protein at the NMJ—low-density lipoprotein receptor-related protein 4 (LRP4)—that
is also important for clustering of AChRs.
o The pathogenic antibodies are IgG and are T cell dependent.
o Thus, immunotherapeutic strategies directed against either the antibodyproducing B cells or helper T cells
are effective in this antibody-mediated disease.
o How the autoimmune response is initiated and maintained in MG is not completely understood, but the
thymus appears to play a role in this process.
 The thymus is abnormal in ~75% of patients with AChR antibody–positive MG;
o in ~65% the thymus is “hyperplastic,” with the presence of active germinal centers detected histologically,
although the hyperplastic thymus is not necessarily enlarged.
o An additional 10% of patients have thymic tumors (thymomas). Muscle-like cells within the thymus (myoid
cells), which express AChRs on their surface, may serve as a source of autoantigen and trigger the
autoimmune reaction within the thymus gland.
 Describe the pathology of the neuromuscular junction in MG.
o By light microscope examination, muscle biopsy specimens are usually unrevealing.
o In severe cases, type 2 fiber atrophy due to disuse may be found.
o By electron microscopy, the post synaptic membrane is simplified, and there is loss of AChRs from the
region of the synapse. Immune complexes and the complement membrane attack complex (C5-C9) can
be found along the postsynaptic membrane as well.
 Describe the clinical features of MG.
o The cardinal features are weakness and fatigability of muscles.
o The weakness increases during repeated use (fatigue) or late in the day and may improve following rest
or sleep. The course of MG is often variable.
o Exacerbations and remissions may occur, particularly during the first few years after the onset of the
disease. Unrelated infections or systemic disorders can lead to increased myasthenic weakness and may
precipitate “crisis”.
o The distribution of muscle weakness often has a characteristic pattern. The cranial muscles, particularly
the lids and extraocular muscles (EOMs), are typically involved early in the course of MG; diplopia and
ptosis are common initial complaints.
o 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. Speech may have a nasal timbre
caused by weakness of the palate or a dysarthric “mushy” quality due to tongue weakness.
o Difficulty in swallowing may occur as a result of weakness of the palate, tongue, or pharynx, giving rise to
nasal regurgitation or aspiration of liquids or food.
o Bulbar weakness is especially prominent in MuSK antibody– positive MG.
o In ~85% of patients, the weakness becomes generalized, affecting the limb muscles as well. If weakness
remains restricted to the EOMs for 3 years, it is likely that it will not become generalized, and these
patients are said to have ocular MG.
o The limb weakness in MG is often proximal and may be asymmetric.
o Despite the muscle weakness, deep tendon reflexes are preserved.
o If ventilator weakness becomes requires respiratory assistance, the patient is said to be in crisis.
Summarize the salient features needed to diagnose MG.
 The diagnosis is suspected on the basis of weakness and fatigability in the typical distribution described above,
without loss of reflexes or impairment of sensation or other neurologic function.
 The suspected diagnosis should always be confirmed definitively before treatment is undertaken; this is
essential because (1) other treatable conditions may closely resemble MG and (2) the treatment of MG may
involve surgery and the prolonged use of drugs with potentially adverse side effects.
 Identify the role of the laboratory tests in the diagnosis and management of MG and interpret the results.
o Ice-pack Test. If a patient has ptosis, application of a pack of ice over a ptotic eye often results in
improvement if the ptosis is due to an NMJ defect. This is hypothesized to be due to less depletion of
quanta of AChR in the cold and reduced activity of AChE at the NMJ. It is a quick and easy test to do in
the clinic or at the bedside of a hospitalized patient.
 Autoantibodies Associated with MG.
o As previously mentioned, anti-AChR antibodies are detectable in the serum of ~85% of all myasthenic
patients but in only about 50% of patients with weakness confined to the ocular muscles.
o The presence of anti-AChR antibodies is virtually diagnostic of MG, but a negative test does not
exclude the disease.
o The measured level of antiAChR antibody does not correspond well with the severity of MG in
different patients.
o Antibodies to MuSK are present in ~40% of AChR antibody–negative patients with generalized MG.
MuSK antibodies are rarely present in AChR antibody–positive patients or in patients with MG limited to
ocular muscles. These antibodies may interfere with clustering of AChRs at NMJs. A small proportion of
MG patients without antibodies to AChR or MuSK have antibodies to LRP4.
o Interestingly, antibodies against agrin have recently been found in some patients with MG. Agrin is a
protein derived from motor nerves that normally binds to LRP4 and important for normal clustering of
AChRs at NMJ.
o Additionally, anti-striated muscle antibodies directed against titin and other skeletal muscle components
are found in ~30% of myasthenic without thymoma, 24% of thymoma patients without myasthenia, and
70–80% of patients with both myasthenia and thymoma.
o Furthermore, antibodies directed against Netrin-1 receptors and Caspr2 (contactin-associated protein-like
2) often coexist and are associated in patients with thymoma who have MG and neuromyotonia or
Morvan syndrome.
 Electrodiagnostic Testing.
o Repetitive nerve stimulation may provide helpful diagnostic evidence of MG.
o Anti-AChE medication should be stopped 6–12 h before testing.
o It is best to test weak muscles or proximal muscle groups.
o Electrical stimulation is delivered at a rate of two or three per second to the appropriate nerves, and
action potentials are recorded from the muscles.
o In normal individuals, the amplitude of the evoked muscle action potentials does not change by >10% at
these rates of stimulation.
o However, in myasthenic patients, there is a rapid reduction of >10% in the amplitude of the evoked
responses.
 Anticholinesterase Test.
o Drugs that inhibit the enzyme AChE allow ACh to interact repeatedly with the limited number of AChRs in
MG, producing improvement in muscle strength.
o Edrophonium is used most commonly for diagnostic testing because of the rapid onset (30 s) and
short duration (~5 min) of its effect.
o An objective end point must be selected to evaluate the effect of edrophonium, such as weakness of
EOMs, impairment of speech, or the length of time that the patient can maintain the arms in forward. An
initial IV dose of 2 mg of edrophonium is given.
o If definite improvement occurs, the test is considered positive and is terminated.
o If there is no change, the patient is given an additional 8 mg IV. The dose is administered in two parts
because some patients react to edrophonium with side effects such as nausea, diarrhea, salivation,
fasciculations, and rarely with severe symptoms of syncope or bradycardia.
 o Atropine (0.6 mg) should be drawn up in a syringe and ready for IV administration if these symptoms
become troublesome.
o The edrophonium test is now reserved for patients with clinical findings that are suggestive of MG but
who have negative antibody, electrodiagnostic testing, or ice-pack test.
o False-positive tests occur in occasional patients with other neurologic disorders, such as amyotrophic
lateral sclerosis, and in placebo-reactors. False-negative or equivocal tests may also occur.
 Differentiate MG from the following conditions that cause weakness of the cranial and/or somatic musculature.
o Other conditions that cause weakness of the cranial and/or somatic musculature include the
nonautoimmune congenital myasthenia, drug-induced myasthenia, Lambert-Eaton myasthenic syndrome
(LEMS), neurasthenia, hyperthyroidism (Graves’ disease), botulism, intracranial mass lesions,
oculopharyngeal dystrophy, and mitochondrial myopathy (Kearns-Sayre syndrome, progressive external
ophthalmoplegia).
o Treatment with penicillamine (used for scleroderma or rheumatoid arthritis) and check point inhibitors
for cancer may also result in autoimmune MG.
o Aminoglycoside antibiotics or procainamide can cause exacerbation of weakness in myasthenic
patients; very large doses can cause neuromuscular weakness in normal individuals.
 Congenital Myasthenic Syndrome
o The congenital myasthenic syndromes (CMS) comprise a rare heterogeneous group of disorders of the
NMJ that are not autoimmune but rather are due to genetic mutations in which virtually any component of
the NMJ may be affected.
o Alterations in function of the presynaptic nerve terminal, in the various subunits of the AChR, AChE, or
the other molecules involved in end-plate development or maintenance, have been identified in the
different forms of CMS.
o These disorders share many of the clinical features of autoimmune MG, including weakness and
fatigability of proximal or distal extremity muscles, and often involving EOMs and the eyelids similar to the
distribution in autoimmune MG.
o CMS should be suspected when symptoms of myasthenia have begun in infancy or childhood, but
they can present in early adulthood.
o As in acquired autoimmune MG, repetitive nerve stimulation is associated with a decremental
response.
o Some forms (e.g., AChE deficiency, prolonged open channel syndrome) have a feature of after-
discharges which are not seen in MG.
o An additional clue is the absence of AChR and MuSK antibodies though these are absent in ~10% of
generalized MG patients (so-called double seronegative MG) antibodies.
o The prevalence of CMS is estimated at ~3.8 per 100,000.
o The most common genetic defects occur in the ε subunit of the AChR, accounting for ~50% of CMS
cases, with mutations in the genes encoding for rapsin, COLQ, DOK7, agrin, and GFPT together
accounting for ~40%.
o In most of the recessively inherited forms of CMS, the mutations are heteroallelic; that is, different
mutations affecting each of the two alleles are present.
o Features of the most common forms of CMS are summarized in Table 440-2. Molecular analysis is
required for precise elucidation of the defect; this may lead to helpful treatment as well as genetic
counseling.
o Some forms of CMS improve with AChE inhibitors, while others (e.g., slow channel syndrome, AChE
deficiency, DOK-7 related CMS) actually worsen.
o Fluoxetine and quinidine can be useful for slow channel syndrome, and albuterol for mutations affecting
AChE, DOK- 7, rapsyn, and agrin.
o Additionally, ephedrine and 3,4 diaminopyridine (3,4 DAP) may be of benefit in some forms of CMS.
 Lambert-Eaton Myasthenic Syndromes (LEMS)
o LEMS is a presynaptic disorder of the NMJ that can cause weakness similar to that of MG.
o The proximal muscles of the lower limbs are most commonly affected, but other muscles may be involved
as well. Cranial nerve findings, including ptosis of the eyelids and diplopia, occur in up to 70% of patients
and resemble features of MG.
 o However, the two conditions are usually readily distinguished because patients with LEMS have
depressed or absent reflexes and experience autonomic changes such as dry mouth and impotence.
o Nerve stimulation produces an initial low amplitude compound muscle action potential and, at low rates of
repetitive stimulation (2–3 Hz), a decremental responses as seen in MG; however, at high rates (20–50
Hz), or following brief exercise, incremental responses occur.
o LEMS is caused by autoantibodies directed against P/Qtype calcium channels at the motor nerve
terminals detected in ~85% of LEMS patients. These autoantibodies impair the release of ACh from nerve
terminals.
o In young adults, particularly women, LEMS is not associated with an underlying cancer.
o However, in older adults, most LEMS is associated with malignancy, most commonly small-cell lung
cancer (SCLC) The tumor cells may express calcium channels that stimulate the autoimmune response.
o Treatment of LEMS involves plasmapheresis and immunotherapy, as for MG. 3,4-
o Diaminopyridine (3,4-DAP) and pyridostigmine can also help with symptoms. 3,4-DAP acts by blocking
potassium channels, which results in prolonged depolarization of the motor nerve terminals and thus
enhances ACh release. Pyridostigmine prolongs the action of ACh, allowing repeated interactions with
AChRs.
 Botulism
o Botulism is due to potent bacterial toxins produced by any of eight different strains of Clostridium
botulinum.
o The toxins enzymatically cleave specific proteins essential for the release of ACh from the motor nerve
terminal, thereby interfering with neuromuscular transmission.
o Most commonly, botulism is caused by ingestion of improperly prepared food containing toxin.
o Rarely, the nearly ubiquitous spores of C. botulinum may germinate in wounds.
o In infants, the spores may germinate in the gastrointestinal (GI) tract and release toxin, causing muscle
weakness. Patients present with myasthenia-like bulbar weakness (e.g., diplopia, dysarthria, dysphagia)
and lack sensory symptoms and signs.
o Weakness may generalize to the limbs and may result in respiratory failure.
o Reflexes are present early, but they may be diminished as the disease progresses.
o Mentation is normal.
o Autonomic findings include paralytic ileus, constipation, urinary retention, dilated or poorly reactive
pupils, and dry mouth.
o The demonstration of toxin in serum by bioassay is definitive, but the results usually take a
relatively long time to be completed and may be negative.
o Nerve stimulation studies reveal reduced compound muscle action potential (CMAP) amplitudes that
increase following high frequency repetitive stimulation.
o Treatment includes ventilatory support and aggressive inpatient supportive care (e.g., nutrition, deep
vein thrombosis prophylaxis) as needed.
o Antitoxin should be given as early as possible to be effective and can be obtained through the
Centers for Disease
o Control and Prevention. A preventive vaccine is available for laboratory workers or other highly exposed
individuals.
 Neurasthenia
o Neurasthenia is the historic term for a myasthenia-like fatigue syndrome without an organic basis.
o These patients may present with subjective symptoms of weakness and fatigue, but muscle testing
usually reveals the “give-away weakness” characteristic of nonorganic disorders; the complaint of fatigue
in these patients means tiredness or apathy rather than decreasing muscle power on repeated effort.
 Hyperthyroidism (Graves’ Disease)
o Hyperthyroidism is readily diagnosed or excluded by tests of thyroid function, which should be carried out
routinely in patients with suspected MG.
o Abnormalities of thyroid function (hyper- or hypothyroidism) may increase myasthenic weakness.
o Diplopia resembling that in MG may occasionally be due to an intracranial mass lesion that compresses
nerves to the EOMs (e.g., sphenoid ridge meningioma), but magnetic resonance imaging (MRI) of the
head and orbits usually reveals the lesion.
 Progressive External Ophthalmoplegia
 o Progressive external ophthalmoplegia is a rare condition resulting in weakness of the EOMs, which may
be accompanied by weakness of the proximal muscles of the limbs and other systemic features.
o Most patients with this condition have mitochondrial disorders that can be detected on muscle
biopsy.
 Discuss the Management of MG.
 Justify the need to search for associated disorders
o Myasthenic patients have an increased incidence of several associated disorders.
o Thymic abnormalities occur in ~75% of AChR antibody–positive patients, as noted above.
o Neoplastic change (thymoma) may produce enlargement of the thymus, which is detected by chest
computed tomography (CT).
o A thymic shadow on CT scan may normally be present through young adulthood, but enlargement of the
thymus in a patient age >40 years is highly suspicious of thymoma.
o Hyperthyroidism occurs in 3–8% of patients and may aggravate the myasthenic weakness.
o Thyroid function tests should be obtained in all patients with suspected MG.
o Other autoimmune disorders, most commonly systemic lupus erythematosus and rheumatoid arthritis,
can coexist with MG; associations also occur with neuromyelitis optica, neuromyotonia, Morvan’s
syndrome (encephalitis, insomnia, confusion, hallucinations, autonomic dysfunction, and neuromyotonia),
rippling muscle disease, granulomatous myositis/myocarditis, and chronic inflammatory demyelinating
polyneuropathy.
o An infection of any kind can exacerbate typical MG, and should be sought carefully in patients with
relapses. Because of the side effects of glucocorticoids and other immunotherapies used in the treatment
of MG, a thorough medical investigation should be undertaken, searching specifically for evidence of
chronic or latent infection (such as tuberculosis or hepatitis), hypertension, diabetes, renal disease, and
glaucoma.
 Choose the appropriate pharmacological intervention for MG. Describe the pharmacology of these medications.
o The prognosis has improved strikingly as a result of advances in treatment. Nearly all myasthenic patients
can be returned to full productive lives with proper therapy.
o The most useful treatments for MG include anticholinesterase medications, immunosuppressive agents,
thymectomy, plasmapheresis, and intravenous immunoglobulin (IVIg) (Fig. 440-2).
 Anticholinesterase Agents – Pyridostigmine
o Action: Prevents hydrolysis of ACh by AChE at sites of cholinergic transmission.
o Pyridostigmine is the most widely used anticholinesterase drug
o and is initiated at a dosage of 30–60 mg three to four times daily.
o The beneficial action of oral pyridostigmine begins within 15–30 min and lasts for 3–4 h,
o Long-acting pyridostigmine may occasionally be useful to get the patient through the night but should not
be used for daytime medication because of variable absorption.
o The maximum useful dose of pyridostigmine rarely exceeds 300 mg daily.
o Overdosage with anticholinesterase medication may cause increased weakness and other side
effects.
o Atropine/diphenoxylate or loperamide is useful for the treatment of GI symptoms.
 Immunosuppresants
o Glucocorticoids, when used properly, produce improvement in myasthenic weakness in the great majority
of patients.
o To minimize adverse side effects, prednisone should be given in a single dose rather than in divided
doses throughout the day.
o In patients with only mild or moderate weakness, the initial dose should be relatively low (15–25 mg/d) to
avoid the early weakening that occurs in perhaps 10–15% of patients treated initially with a high-dose
regimen.
o The dose is increased stepwise, as tolerated by the patient (usually by 5 mg/d at 2–3 day intervals), until
there is marked clinical improvement or a dose of 50–60 mg/d is reached.
o Patients on long-term glucocorticoid therapy must be followed carefully to prevent or treat adverse side
effects.
 o The most common errors in glucocorticoid treatment of myasthenic patients include (1) insufficient
persistence— improvement may be delayed and gradual; (2) tapering the dosage too early, too rapidly, or
excessively; and (3) lack of attention to prevention and treatment of side effects.
 Azathioprine has long been used for MG and a randomized, clinical trial demonstrated that it was effective in
reducing the dosage of prednisone necessary to control symptoms. However, the beneficial effect of azathioprine
can take a year or more to become evident.
o Approximately 10–15% of patients are unable to tolerate azathioprine because of idiosyncratic reactions
consisting of flulike symptoms of fever and malaise, bone marrow suppression, or abnormalities of
liver function.
o An initial dose of 50 mg/d is given for about a week to test for these side effects. If this dose is
tolerated, it is increased gradually to about 2–3 mg/kg of total body weight, or until the white blood count
falls to 3000–4000/μL.
o In patients taking azathioprine, allopurinol should never be used in combination with azathioprine
because the two drugs share a common degradation pathway; the result may be severe bone marrow
depression due to increased effects of AZA.
 The calcineurin inhibitors cyclosporine and tacrolimus seem to be effective in MG and appear to work more
rapidly than azathioprine and mycophenolate.
o However, they are associated with more frequent severe side effects including hypertension and
nephrotoxicity.
o The usual dose of cyclosporine is 4–5 mg/kg per d, given in two equally divided doses (to minimize side
effects, and the average dose of tacrolimus is 0.07–0.1 mg/kg per d,).
o Side effects of cyclosporine include hypertension and nephrotoxicity, which must be closely monitored.
o “Trough” blood levels are measured 12 h after the evening dose.
o The therapeutic range for the trough level of cyclosporine is 150–200 ng/L, and for tacrolimus, it is 5–15
ng/L.
 Mycophenolate mofetil has become one of the most widely used drug for long-term treatment of MG
because of its effectiveness and relative lack of side effects.
o A dose of 1 g to 1.5 g bid is recommended.
o Mechanism of action: inhibition of purine synthesis by the de novo pathway.
o Since lymphocytes have only the de novo pathway, but lack the alternative salvage pathway that is
present in all other cells, mycophenolate inhibits proliferation of lymphocytes but not proliferation of other
cells.
o It does not kill or eliminate preexisting autoreactive lymphocytes, and therefore clinical improvement
may be delayed for many months to a year, until the preexisting autoreactive lymphocytes die
spontaneously.
o The advantage of mycophenolate mofetil lies in its relative lack of adverse side effects, with only
occasional production of GI symptoms, rare development of leukopenia and very small risks of
malignancy or progressive multifocal leukoencephalopathy.
 Rituximab (Rituxan)
o MOA: is a monoclonal antibody that binds to the CD20 molecule on B lymphocytes.
o It appears particularly effective in MuSK antibody–positive MG, although some patients with AChR
antibody MG also respond. A large NIH sponsored trial is underway in AChRpositive MG.
o The usual dose is 1 g IV on two occasions 2 weeks apart.
 Cyclophosphamide
o For the rare refractory MG patient, a course of high-dose cyclophosphamide may induce long-lasting
benefit by “rebooting” the immune system.
o At high doses, cyclophosphamide eliminates mature lymphocytes but spares hematopoietic
precursors (stem cells), because they express the enzyme aldehyde dehydrogenase, which hydrolyzes
cyclophosphamide.
o This procedure is reserved for refractory patients and should be administered only in a facility fully familiar
with this approach.
o Maintenance immunotherapy after rebooting is usually required to sustain the beneficial effect.
o
 Eculizumab
o Eculizumab is a monoclonal antibody that binds membrane attack complex and was beneficial in a
small pilot study of MG patients.
o The drug is administered intravenously every 2 weeks.
 Describe the role of non-pharmacologic interventions in the management of MG
 Thymectomy
o Two separate issues should be distinguished, (1) surgical removal of thymoma; and (2) thymectomy as a
treatment for MG.
o Surgical removal of a thymoma is necessary because of the possibility of local tumor spread,
although most thymomas are histologically benign.
o Until recently there was a debate regarding the role of thymectomy in non-thymotous MG, but a recent
large international trial of extended transternal thymectomy in non-thymomatous AChR antibody positive,
generalized MG demonstrated that participants who underwent thymectomy had improved strength and
function, required less prednisone and additions of second line agents (e.g., azathioprine), and fewer
hospitalizations for exacerbations.
o Whether or not less invasive thymectomy may be beneficial is unknown.
o Thymectomy should never be carried out as an emergency procedure, but only when the patient is
adequately prepared. If necessary, treatment with IVIg or plasmapheresis may be used before surgery to
maximize strength in weak patients.
 Plasmapheresis and Intravenous Immunoglobulin
o Plasmapheresis has been used therapeutically in MG.
o Plasma, which contains the pathogenic antibodies, is mechanically separated from the blood cells, which
are returned to the patient.
o A course of five exchanges (3–4 L per exchange) is generally administered over a 10- to 14-day
period.
o Plasmapheresis produces a short-term reduction in anti-AChR antibodies, with clinical improvement in
many patients. It is useful as a temporary expedient in seriously affected patients or to improve the
patient’s condition prior to surgery (e.g., thymectomy).
o The indications for the use of IVIg are the same as those for plasma exchange: to produce rapid
improvement to help the patient through a difficult period of myasthenic weakness or prior to surgery.
o This treatment has the advantages of not requiring special equipment or large-bore venous access. The
usual dose is 2 g/kg, which is typically administered >2–5 days. Improvement occurs in ~70% of patients,
beginning during treatment or within a week, and continuing for weeks to months.
o The mechanism of action of IVIg is not known; the treatment has no consistent effect on the measurable
amount of circulating AChR antibody. Adverse reactions are generally not serious but may include
headache, fluid overload, and rarely aseptic meningitis or renal failure.
o IVIg or plasma exchange is occasionally used in combination with other immunosuppressive therapy for
maintenance treatment of difficult MG.
 Idenitfy myesthenic crisis and describe its corresponding treatment
o Myasthenic crisis is defined as an exacerbation of weakness sufficient to endanger life; it usually includes
ventilatory failure caused by diaphragmatic and intercostal muscle weakness.
o Treatment should be carried out in intensive care units staffed with teams experienced in the
management of MG. The possibility that deterioration could be due to excessive anticholinesterase
medication (“cholinergic crisis”) is best excluded by temporarily stopping anticholinesterase drugs.
o The most common cause of crisis is intercurrent infection. This should be treated immediately
because the mechanical and immunologic defenses of the patient can be assumed to be compromised.
o The myasthenic patient with fever and early infection should be treated like other immunocompromised
patients. Early and effective antibiotic therapy, ventilatory assistance, and pulmonary physiotherapy are
essentials of the treatment program. As discussed above, plasmapheresis or IVIg is frequently helpful in
hastening recovery.
 Identify the drugs that may exacerbate MG symptoms
 Identify the prognosis of MG.
o Approximately 20% of patients with MG can be tapered off all immunotherapies and achieve a sustained
remission. There does not appear to be a correlation with maximal disease severity and chance for
remission.
o Thymectomy may increase the likelihood of achieving remission in anti-AChR MG, but the large
randomized trial was too short in duration to examine this endpoint; rather, the results revealed only that
thymectomy was efficacious and led to less use of glucocorticoids and second line agents.
o Anti-MuSK patients typically do not experience myasthenic crises, but are generally more difficult
to treat than anti-AChR MG. However, as noted above, recent series suggest that rituximab is effective
in this subgroup.
o Non-paraneoplastic LEMS is usually responsive to immunotherapy and symptomatic treatment with
pyridostigmine and 3,4 DAP.
o In older adults, LEMS is most often paraneoplastic, and screening for an underlying tumor is
indicated. Recent studies suggest that survival in patients with LEMS has improved, for uncertain
reasons and likely not due to earlier diagnosis and treatment of the tumor. There is wide variability in age
of onset, severity, and prognosis of the many types of CMS.