NEUROLOGY  Acquired

MUSCLE AND NEUROMUSCULAR JUNCTION DISORDERS

Proteins & Associated Disease
History
Dystrophin: Duchenne/Becker
 Weakness
Acute/Chronic/Episodic (Neuromuscular junction) Actin, Troponin, α-actinin: Nemaline Myopathy
Proximal (Arm, shoulders, pelvic girdle)(Patient will Myoblin: LGMD1
have no problem walking on smooth surfaces or
reaching out for something but will experience
Titin: LGMD2I
difficulty on combing the hair or climbing up the Sarcoglycans: LGMD2C,D,E,F
stairs)
 Swallowing (Laryngeal muscle)/Speech (Tongue)/EOM Extrajunctional Muscle Membrane
(Diplopia at certain gaze)  These are the specific proteins involved in the various
 Respiratory/Cardiac muscle disease that are found in the muscle
 No Sensory Loss: Involves only the motor fibers membrane:
 Muscle pain/cramps  Dystrophin
 Twitches: Not common in motor fiber disease, Found in the cytoplasm of muscle cell
common only in diseases involving the anterior horn Acts together with F-actin
cells Important for cytoskeletal support
 Abnormal posture: If the problem started much
Duchenne & Becker
younger
 Dystrophin associated glycoprotein: Sarcloglycans,
Family History: important, even if negative there is syntrophins, alpha-dystobrevin, sarcospan
still need for investigation
 Past Medical History: Other problems in the body
Dystroglycan: Congenital myotonic muscle
dystrophies
especially thyroid and/or lung diseases
Drug abuse/Substance abuse: Statins & alcohol can Sarcoglycan: Limb-girdle dystrophy
cause myopathy Laminin & agrin: Connects sarcolemma to outside
portion of basal lamina
Physical Examination
Muscle Disorders Nerve Disorders Histology
Proximal weakness Distal weakness (Difficulty  Normal muscle fibers may stain differently based on
on holding on to things) the type. Type 2 muscle fibers take up more stain.
Normal/ Late loss Early hypo/ areflexia Atrophic fibers appear small angulated. Hypertrophic
Pseudohypertrophy (late Atrophy fibers show variation in fiber size and are thick and
atrophy) splitting. A group of fibers that shrink is termed
Muscle tenderness not Dysesthesias (Really painful “Small Group Atrophy” or “Large group Atrophy”
present all the time, even when not being depending on how much is loss. If the atrophy
tenderness only when being examined) appears only in the center of the fiber, the term use
held by the examiner) is Core Atrophy (Congenital myotonic muscle
No sensory loss Sensory loss dystrophy)
 Ragged red fibers
Diagnostics  Necrotic Fibers
Muscle enzymes: CPK (available in the Philippines), Poorly stained
aldolase Loss of internal structure
Macrophage
Electromyogram/Nerve Conduction tests: Normal NCV  Regenerating Fibers
in muscle disease, or may see fibrillations or positive
Small
waves, small motor units will recruit very fast (Early
Basophilic
recruitment of motor units)
Large Pale nuclei
 Radiologic X-rays, MRI, Neuromuscular series (NMS)
 Muscle biopsy
Duchenne Muscular Dytrophy (1986)
 Disease specific examinations: Tests related to other
 Onset: < 5 years (3-5 y/o)
diseases
 Gene analysis: Analysis for Dystrophin Male > Female
 Progressive weakness of the girdle muscles
Classification of Primary Neuropathies Calf hypertrophy: Hypertrophy of muscle – calf first…
 Inherited becomes weak...later infiltrated w/ fat cells…
Usually called dystrophy (Degenerative & contractures…then scoliosis…then respiratory
progressive) difficulty…finally, cardiac failure
Duchenne & Beckers  IQ not too good, patient not too mobile
Congenital myotonic  Respiratory failure in their 20’s-30’s
Limb girdle  Genotype: Dystrophin deficiency
Fascioscapulohumeral 96% with frameshift mutation

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 30% with new mutation
 Clinical Manifestations:
Weakness
Proximal > Distal
Symmetric
Legs & Arms (Legs first)
Adductor magnus of the legs (most affected)
Gracilis & Sartorius (relatively spared)
Duchenne established the diagnostic criteria:
Weakness with onset on the legs
Hyperlordosis with wide-based gait
Hypertrophy of weak muscles
Progressive course over time
Reduce muscle contractility on electric
stimulation
Absence of bladder/bowel dysfunction
Course
Reduced motor function by 2-3 years
Steady decline in strength after 6-11 years
Gower’s sign: Standing up with the aid of hands
pushing on the knees
Failure to walk: 9-13 years
“Waddle when they walk, straddle when they
stand”
Muscle Hypertrophy evident:
Especially in the calf
May be generalized
Increases with age
Most commonly due to muscle fibrosis
Some relatively spared muscles may have true
hypertrophy
Other Clinical Features
Dilated Cardiomyopathy (> 15 years)
Mental Retardation (Mean IQ ~88)
Night blindness
Altered response to flashes of light in dark
adapted state
ERG: b-wave, reduced amplitude
Dp260: Isoform of dystrophin in retina
Death
Most common between 15-25 years
Respiratory or Cardiac failure
Life prolonged by ~ 6 years to 25 years with
respiratory support
Life shortened by 2 years if cardiomyopathy
appears early.
 Laboratory exams
CK is very high
Troponin I: Elevated beyond normal but not to
levels comparable to cardiac ischemia
Liver enzymes: High AST/ALT
Biopsy
NADH Stain: Pale necrotic fibers
H&E Stain: Phagocytosis: Invasion of fibers by
macrophages
Dystrophin stains around the rim of the muscle
fibers
Degeneration & regenerating muscle fibers
 Treated using steroids (Prednisone)
 X-linked disorder
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Becker’s Muscle Dystrophy
 Dystrophin mutation
Deletion: in 70% of patients
Frameshift mutation
New mutations are rare
Worse Cases: Additional mutation in myogenic
factors
 Clinical features
Onset > 7 years old
Weakness
Not as bad as in Duchenne
Symmetric
Proximal > Distal; legs and arms
May be especially prominent in quadriceps or
hamstrings
Slowly progressive
Severity & onset age correlate with muscle
dystrophin levels
Calf pain on exercise
Muscle hypertrophy: prominent in the calves and is
painful after exercise.
Failure to walk: 16-80 years
Systemic Clinical manifestations:
Joint contractures: Ankles & others
Cardiomyopathy: may occur before severe
weakness
Mental retardation
Associated with deletion of Dp140 transcription
unit
Dystrophin deficiency (because it is found also
in the brain tissue)
 Serum CK is very high: 5,00 – 20,000 (Lower levels
with increasing age and disability)
 Muscle Biopsy:
Myopathic
Varied muscle fiber size
Endomysial connective tissue increased
Myopathic grouping: < 12 years of age
Degeneration/Regeneration
Reduced dystrophin (Provides support for muscle
during contraction & relaxation) staining
 Older patients:
Findings are typical of chronic dystrophies
Increased endomysial connective tissue
Variable fiber size: small muscle fibers are rounded
Internal nuclei
The largest muscle fibers are hypertrophied
Occasional fibers: Degeneration; regeneration;
hypocontracting; split
Mosaicism for Dystrophin
Asymptomatic & symptomatic female carriers
Majority are females: Larger calves with overt muscle
weakness
 Female heterozygous carriers
 Increase CK with proximal muscle weakness
Myonuclei capable & dystrophin negative
Sarcoglycanopathy (Limb-Girdle Muscular Dystrophy)
 Shoulder or pelvic weakness
Walton & Nattrass Definition (1954)
  Expression in either male or female sex Older adult (with minimal DM1; onset of > 60)
 Onset usually in the late first or second decade of life present with cataracts
(but also middle age) Age of onset correlates with length of repeat when
Usually autosomal recessive & less frequently CTG number is less than ~ 400
autosomal dominant  Can grasp hand but cannot relax
 Involvement of shoulder or pelvic girdle muscles with  Contraction for a long time on tapping thenar muscle
variable rates of progression  Dive bomber sound??
 Severe disability within 20-30 years  (+)percussion contraction ( depression in the skin
after percussion)
Muscular pseudohypertrophy &/or contractures are
uncommon Hooded eyes, hollowed masseter & temples; inverted
 Basic division of LGMD V mouth
Autosomal Dominant (LGMD 1)  Chronic changes in MD Type 1 (Most common form)
Autosomal Recessive (LGMD 2) H&E stain
Numerous internal nuclei
Classification uses an alphabetical lettering system
Longitudinal chains
spanning A-E in LGMD 1 & A-J in LGMD 2: The letter
Myopathic changes: Fiber size variation
delineates the order in which each LGMD was linked
to a chromosomal locus (ie. LGMD 1A was mapped to Other signs/symptoms: cataracts, endocrine
a chromosome prior to LGMD 1B, etc.) problems like DM, myoglobinuria,
respiratory/cardiac problems
Hip-girdle weakness is most prominent in the gluteus
maximus & hip adductors. Along with abdominal
Congenital Myopathy
weakness, this leads to a wide-based, lordotic gait
 Central Core Disease
 Atrophy is often prominent (Very early)
Nemaline rods
Progression tends to be slow & wheelchair use begins Centronuclear (Myotubular) Myopathy: Infant with
11-28 years after the onset of the symptoms
A long slender body
Fascioscapulohumeral Dystrophy Long fingers & toes
 Autosomal dominant, 4q35 with childhood onset. NL
lifespan Elongated head
Floppy
Facial, neck, proximal shoulder & scapular muscles
involved, rare in cardiac Shifting of bones due to poor muscle tone
 Ankle dorsiflexores Frog-leg posture
 Slowly progressive course Swallowing difficulties
 Histopath similar to Duchenne’s but milder. Shows Very fatal course
muscle fibers of different sizes.
 PE: downward sloping of clavicles, elevated scapula, Metabolic Myopathy
pectoralis is atrophic, no anterior axillary fold,  Myophosphorylase Defect
patient can’t abduct arms w/o help Defect in glycogen metabolism
Diagnosis: Weakness in facial muscles, scapular Absent to reduced muscle phosphorylase
muscles & later in ankle dorsiflexors Exercise intolerance
 Different sizes of muscle fibers Myoglobinuria
Muscle weakness in ~ 70%
Myotonic Dystrophy (Types 1-3) Forearm exercise test: no rise in lactate
 Caused by a defective gene on chromosome 19q13.2 CK: High
 Thyrotoxic Myopathy
The muscle weakness is accompanied by myotonia
Proximal weakness with EMG; abnormalities in 90%
(delayed relaxation of muscles after contraction) &
by a variety of abnormalities in addition to those of Percussion may give fascies associated with
the muscle Myasthenia gravis or PP.
 Other names: Fatty deposit around the eyes create exopthalmos
Steinert’s disease Recti muscles hypertrophies
Dystrophia myotonica Periodic hypokalemic paralysis
 Onset: Neonatal to late adulthood  Hypothyroidism
Congenital onset: Floppy infant, but no myotonia Percussion provokes prolonged contraction with
yet, respiratory weakness slow release (+) percussion contracture
Children: Mental retardation & motor delay Weakness, stiffness, cramps, pseudomyotonia,
increased CPK
Adults
 Periodic Paralysis
Myopathic discharge
Hypo, hyper, euklaemic
Seen on EMG & clinically
Autosomal dominant with male predominance
Especially 2nd to 4th decades Molecular mechanism is a mutation of the voltage
Weakness: Finger flexors, neck flexors & face gated sodium channel
Motonia: Grip Triggered by CHO load, exercise, cold
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 Sudden attacks Vacuolation
In patients w/ hyperthyroidism, can’t move in the Amyloid deposition
morning, signs & symptoms precipitated by high Mitochondiral proliferation
CHO intake, patient is hypokalemic, more common  Etiologies
in males than in females Multifactorial
Treatment: Give potassium supplements Genetic Predisposition
 Alcoholic Myopathy Do not accumulate among family members
Insidious proximal weakness, low CPK HLA-association: A1, B8, DR3, DR5, DR7, HLA-
Acute rhabdomyolysis may accompany binge DRB1*0301-DQA1*0501
drinking with renal failure. Environmental factors/triggers
 Myoglobinuria Infectious: Coxsackie B, HIV, HTLV-1, HBV,
Massive muscle lysis as seen in trauma, burns, Influenza, echovirus, Adenovirus, Toxoplasma,
snake-bites, drug toxicitiy, infections Borrelia
Dramatic CPK elevations U-V Light
Acute tubular necrosis may supervene fatally  Overall clinical features:
1 in 100,000 cases
Inflammatory Muscle Disease Common myopathy
 Most important: polymyositis (PM), dermatomyositis Symmetrical muscle weakness
(DM), inclusion body disease (IBM, sarcoidosis, Subacutely to chronic progression
scleroderma, focal infection) Difficulty in getting up from chair, climbing
Group of muscle disease that cause inflammation & stairs, lifting objects & combing hair
degeneration of the skeletal muscle tissues PM/DM : Affects mostly proximal muscles
Heterogenous group of subacute, chronic & rarely
IBM: Affects distal muscles & proximal legs
acute acquired
(Quadriceps selected weakeness)
 Autoimmune
Distal weakness first (hand flexors), w/ wasting,
Muscle weakness + skin signs & symptoms in later quads become atrophic
dermatomyositis; but signs & symptoms may be Dermatomyositis: Rashes on the shoulder (Shawl
transient.
Sign), hands & neck, dysphagia are common
 Myopathy is a muscle disease
Heliotrope Rash
 Inflammation is a response to cell damage
Red-purple edematous ± erythema
The inflammatory process  Destruction of muscle (maculopapular)
tissue  Weakness & pain  Loss of muscle bulk Distribution: Face & upper eyelids, Symmetric
(Atrophy)
A dark lilac discoloration or is violaceous to dusky
 Classification erythematous rash with or without edema in a
Idiopathic IM: Largest group symmetrical distribution involving the periorbital
Secondary area
In association with other systemic or CTD
This rash may follow the course of myositis or it
In association with bacterial, viral or parasitic
may wax/wane discordantly with the disease
infection
activity
Infantile/Childhood
Gottron’s Sign
Miscellaneous forms
Red-purple keratotic, atrophic erythema, or
 Characterisitic symptom: Muscular Weakness macules
 Frequency: Found on extensor surface of the joints:
Incidence of 0.5-8.4/million especially MCP, PIP and DIP (Knuckles)
Pevalence of 5-10/million  V-neck Sign: Violaceous macular erythema on the
 M:F ratio chest
Polymyositis (PM) 1:1 Mechanic’s Hands/Nailfold lesions: Raised scaly & dry
Dermatomyositis (DM) 1:2 on the extensor surfaces of the finger joints
Inclusion Body Myositis (IBM) 3:1  Electromyography findings
 Age: Fibrillation potentials
DM has a bimodal pattern (3-10 and 45-50 years) Positive sharp waves
PM 45-60 years Complex repetitive discharges
IBM > 50 years Short-duration, small amplitude, polyphasic motor
 Race: More frequent among Afro-Americans units with early recruitment but normal frequency
 Genetic predisposition  Muscle biopsy Findings: H&E stain
 T-Cell mediated myotoxicity Necrotic & regenerating muscle fibers in
 Complement mediated microangiopathy perifascicular regions
IBM: Autoimmune + degenerative features Muscle fiber size is variable
Myonuclear abnormalities  Treatment Options

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 Severe cases: Initiate treatment with IV more juveniles, which bore through the body or
methyprednisolone 20-30 mg. per kg/day or every travel in lymphatic vessels to other organs,
other day for 3-5 days including skeletal muscles where they encyst.
Usual treatment: Prednisone 1.5 mg/kg/day (up to  Bacterial infections
100 mg) in a morning dose. In 2-4 weeks, it can Staphylococcus aureus myositis
often be changes to alternate day regimen
Dose taper: No more than 5 mg every 2-4 weeks Usually focal, unless patient is
Exacerbation: Double the dose of prednisone (up to immunocompromised
1.5 mg/kg or 100 mg.) Fluctuant mass
Calcium: 1000 – 1500 mg/day  Yersinia spp
Vitamin D: 400-800 IU/day  Streptococcus spp
Physical therapy: Axial exercise to reduce the risk  Anaerobes
of osteoporosis.  Bacteria causes a suppurative form of myositis
Exercise also reduces steroid induce myopathy Tropical myyositis
Estrogen therapy in post-menopausal women Pyomyositis
Weight control
Collagen Vacular Diseases
Monitor the BP, glucose, potassium & eyes  Muscle ischemia
(glaucoma & cataract)  Cachexia
Only polymyositis & dermatomyositis respond to  Peripheral nerve involvement
steroids
Musculoskeletal deformities
Secondary Inflammatory Myopathies  Systemic sclerosis (associated with DM)
 Myopathies will get better & patient will be stronger  SLE (PM in 5-8%)
once the infection is better  In Sjogren’s Syndrome (DM and IBM)
 Retroviruses  Same pathological features as that found in the
In humans infected with HIV & HTLV-1 idiopathic forms
Inflammatory myopathy (HIV-polymyositis) can  Treatment: Steroid (However, high doses of steroid
occur as either an isolated clinical phenomenon or can cause myopathy especially in high doses)
concurrently with the other manifestations of HIV
Very weak or early atrophy (Maybe due to poor Miscellaneous Forms
intake with decrease muscle mass)  Granulomatous myopathy
 Other Viral Infections In hypersensitivity vasculitis: Eosinophilic syndromes
They have been associated with acute & chronic  Macrophagic myofascitis
myositis Localized form
Molecular mimicry especially with Coxsackie virus With pipe stem capillaries
to Jo-1 antibody  Drug induced
PCR is unable to detect these viruses  Graft versus host reaction
Examples: Coxsackie, Influenza, Paramyxovirus,  Combined with mitochondrial myopathy
CMV, EBV
 Nonviral Microbial Myositis Drugs causing Drug induced Forms
Parasites  Amiodarone: For arrhythmias
 Protozoa: Toxoplasma, Trypanosoma  Amphetamines
 Cestodes: Cysticerci  Chloroquine
 Nematodes: Trichinae  Cimetidine
 May produce diifuse myositis  Parasitic  Cocaine
polymyositis Colchicine: Anti-gout medications
Trichinosis  Corticosteroids: Even if you have weakness, must still
 Infection derived by eating infected pork continue giving drugs because the weakness may
 Biopsy may reveal the following: disappear
Empty cysts  Cyclosporin
Cyst containing inflammatory cells  Danazol
Cyst containing calcifications  Epsilon amino-caproic acid
Surrounding muscle has no inflammation or  Ethanol
active myopathic changes  Fibric acid derivatives
 Juveniles of the parasitic nematode Trichinella  Heroin
spiralis are exncysted in human muscle tissue  Hydralazine
 Humans acquire the infection by eating  Hydroxychloroquine
undercooked infected pork or other meat with  Hydroxyurea
juvenile worms encysted in the muscle tissue.  Ipecac (emetine)
 Within the human intestine, the juveniles  Levodopa
develop into sexually mature adults. Females  Nicotinic acid
burrow into the intestinal muscles and produce
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  Pancuronium
 Penicillamine
 Pentazone
 Phenylbutazone
 Phenytoin
 Procainamide
 Rifampin
 Statin drugs
Newer statins causes more myopathy (Atorvastatin)
Older statins (Simvastatin) causes myopathy as well
but at a lesser rate than the newer statins
 Sulfonamides
 Tiopronin
 Vecuronium bromide
 Vincristine
 Zidovudine (AZT)
Toxic Myopathies
 Mitochondrial
 Myosin Deficiency Myopathies
Critical illness myopathy
 Given steroids & neuromuscular blockers
 Improved but quadriplegic due to muscle necrosis
 Sometimes the reason why the patient cannot be
removed from the respiratory
 Rhabdomyolysis
 Muscle overactivity syndrome
Drug & toxin induced
Neuroleptic Malignant Syndrome
 Precipitated by succinylcholine
Introduction
 Neuromuscular Transmission
Process by which action potential in a motor nerve
axon leads to an action potential in the relevant
twitch fiber of a vertebrate skeletal muscle
Particularly relevant to a range of different
diseases
NMJ is the target for many neurotoxins
Envenomation: Cause of neuromuscular failure (Due
to specificity for NMJ proteins, many of the toxins
have been helpful in the study of neuromuscular
transmissions and its disorders)
 Neuromuscular Junction
A chemical synapse
Transmission depends on release of Ach from the
motor nerve terminal & its interaction with AchR’s
on the postsynaptic muscle surface
End-Plate Potential (EPP)
 Generation of a local potential change in the
post-synaptic membrane
 Induces a regenerating action potential by
activating voltage-gated sodium channels
When sufficient VGSCs are opened, resulting
depolarization leads to a regenerative action
potential that can propagate along the muscle fiber
Nature and Development of the NMJ (Microscopic
Structure)
A special structure of the nerve muscle synapse
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Motor nerve unit consists of:
 Motor neuron cell body in the spinal cord
 Motor nerve axon that arises from it
Branches when it reaches the surface of the
muscle, and each branch loses its myelin sheath
just before forming the motor nerve terminals that
synapse on the surface of each muscle fiber.
The NMJ:
 Oval in shape
 30-50 µm in its largest dimension
 Runs parallel to the length of the fiber
 Easily demonstrated in muscle tissue by fixing &
staining for AchE
Each nerve terminal expansion (bouton) is a thin
extension of a Schwann Cells
Schwann cell extension express high levels of
proteins: NCAM & S-100 (Covers the axon & appears
to protect & nourish the axon before it reaches the
muscle)
Muscle surface at the point of contact between the
nerve & muscle is often raised, but the terminal
branches are sunk into synaptic depressions where
the sarcolemma forms post-synaptic folds
In between the muscle and the nerve terminal, the
basal lamina (a distance of ~50 nm) can be seen.
Basal Lamina
 Extends as a double layer into each of the folds
 Appears to be amorphous but contains many
essential molecules:
Collagen IV
Laminins
Heparan SO4 proteoglycans
 At the NMJ, it forms a network or scaffold that
anchors the NMJ-specific proteins:
AchE
S-laminin (synapse-specific laminin)
Agrin (AchR-aggregating molecule)
Neuroregulin
 All are involved in the development,
maintenance & function of the NMJ.
On EM, you can see a large number of small synaptic
vesicles concentrated on the membrane opposite to
the post-synaptic folds
 Active Zones (Cytoplasmic densities)
Cluster along the nerve terminal opposite the
entrance to the folds
Where the voltage-gated Calcium Channels are
located & where the synaptic vesicles fuse with the
plasma membrane to release their contents
α-bungarotoxin: snake toxin
Binds specifically & irreversibly to the AchR’s,
increased density corresponds to the location of
AchR’s, present at > 10,000/µm2 post-synaptic
membrane
In contras, AchR’ density outside the NMJ in mature
muscle falls to ~10/ µm2
VGSCs & NCAM are located in the lower 2/3 of the
post-synaptic folds
 Below the post-synaptic folds, within the cytoplasm
of the myofibril, are several nuclei, which are
responsible for producing the proteins involved in
post-synaptic structure & function
Molecular Architecture of the Post-synaptic Nerve
Terminal
 Receptors are on the trough
 AchR’s purified from the electric fish Torpedo
marmorata were associated with a 43kDa protein that
was qubsequently called RAPsyn (Receptor
aggregating proteins at the synapse)
Synapsin binds to actin, before releasing
acetylcholine, synapsin must 1st release actin
 RAPsyn:
Cytoplasmic protein of ~400 aa residues that
appears to be essential for the localization of
AchR’s & many other NMJ-specific proteins
Highly concentrated at the tops of the folds,
beneath the AchR’s
Important for aggregation of AchR on the junctional
folds
Protein involved on congenital myasthenic
syndrome
 Utrophin
Protein that shows extensive homology to the
dytrophin but which in normal muscle is highly
concentrated at the NMJ at the tops of the
junctional folds, with a similar distribution to the
AchR’s & RAPsyn
Thought to link the AchR/α-dystrobrevin complex
to actin filaments
α-dystrobrevin 1: Col-localizes with AchR’s
 Dystrophin
Present at the base of the folds & throughout the
sarcolemma
At the NMJ, it associates with α-dystrobrevin 2,
ankyrin and β-spectrin.
Myasthenia Gravis
 History of Myasthenia Gravis
Thomas Willis: first written description
myasthenia gravis
English physician (1621-1675)
Wrote about a woman who temporarily lost her
power of speech & became mute as a fish.
This has been interpreted as being the first written
description of myasthenia gravis
 Is the most common primary disorder of
neuromuscular transmission
The usual cause is an acquired immunological
abnormality
A chronic autoimmune neuromuscular disease
characterized by varying degrees of weakness of the
skeletal (voluntary) muscles of the body (but may also
involve cardiac & smooth muscle). The name
myasthenia gravis, which is Latin & Greek in origin,
literally means “grave muscle weakness”
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The hallmark of myasthenia gravis is a muscle
weakness that increases during periods of activity &
improves after periods of rest
Certain muscles such as those that control eye &
eyelid movement, facila expression, chewing, talking
& swallowing are often, but not always, involved in
the disorder
The muscles that control breathing & neck & limb
movements may also be affected
 Clinical Presentation
Ocular motor disturbances, ptosis or diplopia
(double-vision), are the initial symptom of MG in
2/3’s of patients, almost all had both symptoms
within 2 years
Levator palpebra is involved, but other muscles
supplied by cranial nerve 3 is not affected
Involvement from rostrocaudal direction: Lid →
muscles for extraocular eye movement → facial
muscle → Respiratory muscles → Leg muscles
Ptosis is initially one-sided & only partially
involved, then becomes complete, after a few
months it becomes bilateral
Ptosis is described as “No ptosis in the morning,
ptosis only apparent at the end of the day”
Size & reactivity of the pupils is normal
Oropharyngeal muscle weakness, difficulty
chewing, swallowing, or talking, is the initial
symptom in 1/6 of the patients.
Limb weakness in only 10%
Initial weakness is rarely limited to single muscle
groups such as neck or finger extensors or hips
flexors (Spotty involvement of the muscle)
The severity of weakness fluctuates during the day,
usually being least severe in the morning & worse
as the day progresses, especially after prolonged
use of affected muscles
Facial weakness is obvious, in that the corners of
the mouth do not rise, the eyebrows are raised &
the forehead is wrinkled in an effort to compensate
for partial right-sided ptosis & almost incomplete
left-sided ptosis
of
Masseter: Manifested as difficulty chewing & jaw
will open if not held up
The course of the disease is variable but usually
progressive
Weakness is restricted to the ocular mscules in
about 10% of cases
The rest have progressive weakness during the first
2 years that involved the oropharyngeal & limb
muscles
Maximum weakness occurs during the first year in
2/3 of patients
In the era before corticosteroids were used for
treatment, approximately 1/3 of patients improved
spontaneously, 1/3 became worse & 1/3 died of the
disease
Spontaneous improvement frequently occurred
early in the course (During the active phase, can do
a lot for the patient)
 During the inactive stage or fixed stage, patient
may not need to take medications
Onset is bimodal
 Females have earlier onset
 Male: Peak happens later in life
Factors that worsen MG symptoms:
 Emotional upset
 Systemic illness (especially respiratory infections)
 Hypothyroidism or Hyperthyroidism
 Pregnancy
 The menstrual cycle
 Drugs affecting the neuromuscular transmission
 Increase body temperature
Symptoms fluctuated over a relatively short period
of time & then became progressively severe for
several years (active stage)
The active stage is followed by an inactive state in
which fluctuations in strength still occurred but are
attributable to fatigue, intercurrent illness, or
other identifiable factors.
After 15-20 years, weakness often becomes fixed &
the most severely involved muscles are frequently
atrophic (burnt-out stage)
Deep tendon reflexes are present even if weakness
is severe as long as there is no muscle atrophy (In
muscle & neuromuscular junction disorders, deep
tendon reflexes are normal)
 Pathophysiology of MG
Problem is post synaptic
The normal NMJ releases acetylcholine (Ach) from
the motor nerve terminal in discrete packlages
(quanta)
The Ach quanta diffuse accross the synaptic cleft &
bind to receptors on the folded muscle end-plate
membrane
Stimulation of the motor nerve releases many Ach
quanta that depolarize the muscle end plate region
& then the muscle membrane causing muscle
contraction
In acquired myasthenia gravis, the post-synaptic
muscle membrane is distorted & simplified, having
lost its normal folded shape
The concentration of Ach receptors on the mscule
end-plate membrane is reduced & antibodies are
attached to the membrane
Ach is released normally, but its effect on the post-
synaptic membrane is reduced.
The post-juctional membrane is less sensitive to
applied Ach, & the probability that any nerve
impulse will cause a muscle action potential is
reduced
MuSK: Muscle specific… tyrosine kinase protein:
Sometimes affected in MG
 The Thymus in MG
The thymus contains all the necessary elements for
the pathogenesis of MG:
 Myoid cells that express AchR antigens
 Antigen presenting cells
 Immunocompetent T-cells
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Thymic abnormalities are clearly associated with
myasthenia gravis but the nature of the association
is uncertain
10% of patients with MG have a thymic tumor & 70%
have hyperplastic changes (germinal centers) that
indicate an active immune response.
These are areas within the lymphoid tissue where
B-cells interact with helper T-cells to produce
antibodies
Because the thymus is the central organ for
immunological self-tolerance, it is reasonable to
suspect that thymic abnormalities cause the
breakdown in tolerance that causes an immune
mediated attack on AchR in MG.
Patients with thymoma usually have more severe
disease, higher levels of AchR’s antibodies & more
severe EMG abnormalities than patients without
thymoma
Almost 20% of patients with MG whose symptoms
began between the ages of 30 & 60 years have
thymoma, the frequency is much lower when
symptom onset is after age of 60
Even in patients without thymoma, treatment is
still thymectomy to remove antibody source
 Diagnostic Procedures
The Endrophonium Chloride (Tensilon) Test:
Weakness caused by abnormal neuromuscular
transmission characteristically improves after IV
administration of endrophonium chloride.
Antibodies against AchR
 Gold standard
 74% of patients with acquired generalized MG &
54% with ocular myatshenia have serum
antibodies that bind human AchR
 The serum concentration of AchR antibody varied
widely among patients with similar degrees of
weakness & cannot predict the severity of
disease in individual patients.
Repetitive Nerve Stimulation
 Decrementing response (Decrease in amplitude)
 Significant > 10% - consitient with neuromuscular
transmission defect.
Single Fiber EMG
 Action potential of motor fiber supplied by 1
motor nerve
 Most sensitive clinical test of neuromuscular
transmission & shows increased jitter
 Jitteris greatest in weak muscles but may be
abnormal even in muscles with normal strength
 Patients with mild of purely ocular muscle
weakness may have increased jitter only in facial
muscles
RNS vs SFEMG in MG
 In generalized MG, RNS is sensitive
 In ocular MG, RNS is not so sensitive depending
on the muscle tested.
 SFEMG is indicated & helpful in patients with
normal RNS
  IfRNS is abnormal, practically, SFEMG is not
needed because it will almost always be
abnormal
 Treatment
Treatment decisions should be based on knowledge
of the natural history of disease in each patient &
the predicted response to a specific form of
therapy
Treatment goals must be individualized according
to the severity of the disease, the patient’s age &
sex & the degree of functional impairment
Cholinesterase inhibitors (pyridostigmine: Mestinon)
 Mainstay
 Adverse effects of ChE inhibitors may result from
Ach accumulation at muscarinic receptors on
smooth muscle & autonomic glands & at nicotinic
receptors or skeletal muscle (Salivation, cramps,
diarrhea & bradycardia)
 Frank muscle weakness: Difficult to depolarize
 GI complaints are common
 Increased bronchial & oral secretions are a
serious problem in patients with swallowing or
respiratory insufficiency
 Symptoms of muscarinic overdose may indicate
that nicotinic overdosage (weakness) is also
occurring
Corticosteroid Therapy
 Marked improvement or complete relief of
symptoms occurs in more than 75% of patients
treated with prednisone & same improvement
occurs with most of the rest
 Much of the improvement occurs in the first 6-8
weeks, but strength may increase to total
remission in the months that follow
 The best response occurs in patients with recent
onset of symptoms, but patients with chronic
disease may also respond.
 Patients with thymoma have an excellent
response to prednisone before or after removal
of the tumor
 The most predictable response to prednisone
occurs when treatment begins with a daily dose
of 1.5-2 mg/kg/day
 About 1/3 of patients become weaker
temporarily after starting prednisone, usually
within the first 7-10 days & lasting for up to 6
days
 Treatment can be started at low dose to
minimize exarcebations; the dose is then slowly
increased until improvement occurs.
 Exacerbations may also occur with this approach
& the response is less predictable.
 The major disadvantages of chronic steroid
therapy are the side effects (Diabetes,
hypertension, hypokalemia & osteoporosis)
Immunosuppressive drugs (azathioprine,
cyclosporine, mycophenolate, methotrexate)
IVIG
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 Several groups have reported a favorable
response to high-dose (2 g/kg infused over 2-5
days) of IVIG.
 Possible mechanisms of action include donw-
regulation of antibodies directed against AchR &
the introduction of anti-idiotypic antibodies.
Improvement occurs in 50-100% of patients,
usually beginning within 1 week & lasting for
several weeks or months.
Plasmapheresis: Plasma exchange is used as a
short-term intervention for patients with sudden
worsening of MG symptoms for any reason, to
rapidly improve strength before surgery & as a
chronic intermittent treatment for patients who
are refractory to all other treatments (Maybe
stabilized after 5 treatments)
Thymectomy
 Very invasive procedure
 Because of variable course, not sure if resolution
is due to thymectomy or because of remission
Avoid aminoglycosides & tetracycline which can
cause myasthenia crises
Congenital Myasthenic Syndromes
 Electrophysiology
Decrement on RNS
 Common at 2Hz stimulation
 Absent with CMG with episodic apnea when
asymptomatic.
Repetitive CMPA to single stimulus
Patients taking high doses of AchE inhibitors
 Decrement on RNS not corrected by endrophonium
 Syndromes are differentiated by anatomic location of
mutated protein
Presynaptic
 Defects in evolved release of Ach aunta or Ach
resynthesis (ChAT mutations)
 Frequency 8%
Synaptic Basal Lamina
 Defect caused by mutations in collagen tail of
AchE
 Frequency 16%
Postsynaptic
 Most caused by mutations in subunits of AchRs
 Other: Syndromes caused by plectin ort RAPsyn
mutations
 Frequency: 76%
Neonatal Myasthenia Gravis
 Mother has myasthenia gravis: Antibody will go to the
placenta & cause transient fetal myasthenia
 This is different from congenital myasthenia gravis in
which the mother has no myasthenia & the problem
last for life
Myasthenic Syndromes (Lambert-Eaton)
 Epidemiology
Prevalence: 1 in 100,000
Males slightly more common than females
Age: 17-75 years; onset younger without associated
neoplasm.
 Clinical features
 Onset  Results in long lasting severe muscle paralysis
 Weakness (82%), epsecially legs  Symptoms
 Age: Range = 7-80 years Nausea & vomiting are the 1st symptoms
 Usually precedes CA: >80% Neuromuscular features appear in 12-36 hours
Weakness
Initial symptoms: Blurring of vision, dysphagia,
 Proximal > Distal
dysarthia
 Legs (98%) & Arms (82%)
Dilated pupils: Descending weakness progresses for
 Neck (30%)
4-5 days then plateaus (As compared to GBS, in
 Respiratory (15%): Rarely severe.
which the paralysis is ascending)
 Bulbar: Dysphagia (22-56%); Dystarthia (up to
Respiratrory paralysis may occur rapidly
80%)
Most havve autonomic dyysfunction
 Improves with: Brief sustained exercise
 Treatment
 May worsen with: Sustained exercise; heat or
Trivalent (A,B,E) antitoxin
fever
Antibiotics are not effective
 Fatigability (33%)
Supportive therapy increase respiratory assistance
Extraocular muscles
ChE inhibitors are NOT BENEFICIAL
 Not involved at presentation
Guanidine or DAP may improve strength
 Rarely involved on examination
 Occassional ptosis (30-50%) Recovery takes many months but it is usually
 Symptomatic diplopia in ~40% (transient) complete (Weakness can last for a while)
Muscle pain – occasional
VINCE
Sensory neuropathy: Distal/ symmetric (Limb CHRABI
muscles)
Autonomic neuropathy
 Association stronger with cancer than with LEMS
 Dry mouth > eyes
 Impotence among males
 Other (10-50%): Bladder/ Constipation/
Hyperhydrosis
 Diagnosis
Electrophysiology (RNS)
 Increment
After rapid (50Hz) RNS or
Sustained muscle contraction
Prolonged by cooling
Muscles with most increment after 10 seconds
manximal voluntary contracture
Most specific test for LEMS when > 100% in
several muscles or >400% in one muscle
Abductor digiti minimi; abductor policis brevis;
anconeus
 Decrement on slow (5 Hz) RNS: especially in
small band muscles.
 Pathophysiology
Usually related with a malignancy: Small cell
carcinoma of the lung: may manifest even prior to
symptoms of lung malignancy)
Presynaptic disorder
 Reduced numbers of P/Q Ca++ channels on
presynaptic terminals
 Ultrastructure: active zone presynaptic terminals
reduced
 Physiology
Reduced K+ stimulated Ca++ influx into presynaptic
terminals
Reduced Ca++ dependennt quantal Ach release

Botulism
 Intoxication usually follows food ingestion, some
cases follow wound inoculation

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