Lecture :

Neuromuscular Disorders

Samekto Wibowo
Arstya Dewantara
Neuromuscular Disorders

Nerve
Neuromuscular junction
Muscle
 CNS vs. Neuromuscular

CNS Neuromuscular
Cognitive disturbances Sometimes Never
Long tract signs Frequently Never
Segmental signs Possible Similar
Physical findings
Nerve NMJ Muscle
Reflexes Usually decr. NL or decr. NL or decr.

Atrophy Can be severe Minimal Variable

Fascic. Sometimes None None

Sensory loss Sometimes None None

Disorders of nerve: variety
Cell body, axon & myelin
Fiber size: large, small
Motor, sensory, autonomic
Distribution: focal, multifocal,
generalized...
Course: acute, subacute, chronic, lifelong
Etiology: genetic, toxic, metabolic,
autoimmune, traumatic, vascular,
infectious...
Disorders of Nerve:
Localization
Root radiculopathy
Plexus plexopathy
Single nerve mononeuropathy
Several nerves multiple mononeuropathy,
mononeuritis multiplex
All nerves, polyneuropathy
length-dependent
All nerves, polyradiculoneuropathy
not length-dependent
Root
Segmental loss of
motor
atrophy
weakness
reflexes
sensation
Signs usually minimal; symptoms can be
severe (pain);
Usually only one limb.
Root (cont’d)

Examples C6 S1
weakness biceps gastrocnemius
reflex biceps ankle
sensory loss thumb lateral foot
Common etiologies
herniated disc
herpes zoster
Root (cont’d)
Plexus

Pain
Weakness, atrophy, variable, but
usually more severe than
radiculopathy
Usually restricted to one limb
Etiology:
Brachial: trauma, neoplasm, idiopathic
Lumbosacral: diabetes, neoplasm
Single nerve
(mononeuropathy)
Restricted distribution
Pain, numbness or tingling,
atrophy, weakness
Etiology:
entrapment
trauma
Carpal tunnel syndrome

Pain in hand,
forearm, arm...
Numbness in
median
distribution
Symptoms
aggravated by
wrist flexion
Carpal tunnel syndrome:
electrodiagnosis
Ulnar neuropathy
Numbness
Atrophy of first
dorsal interosseous
Weakness
Compression at
elbow
Entrapment in
cubital tunnel
Distal injury
Radial nerve:
Saturday night palsy

Weakness of wrist
& finger extensors,
brachioradialis
Pressure palsy
Trauma (humerus
fracture)
Peroneal palsy

Crossing legs
Weight loss
Hospitalization
Surgery
Several nerves
(mononeuritis multiplex)

Often painful at onset

Often sudden
Deficits in the distribution of several
peripheral nerves (one at a time)
Etiology: vasculitis
All nerves: Length-dependent
(polyneuropathy)

Lower before upper extremity

Distal first (feet)
Atrophy of intrinsic foot muscles
Decreased ankle jerks
Stocking, then glove sensory loss
Distal motor and sensory findings
always much more severe than
proximal
Polyneuropathy (cont’d)
Polyneuropathy (cont’d)

Most common kind of neuropathy

Etiology
metabolic (diabetes, renal failure)
nutritional (thiamine, B12 deficiency)
toxic (heavy metals, organic solvents,
some drugs)
familial (Charcot-Marie-Tooth)
All nerves, not length-dependent
(polyradiculoneuropathy)

Both proximal and distal weakness

Variable sensory symptoms
Autonomic symptoms (pulse, blood
pressure, urination...)
Can affect respiration, swallowing
Autoimmune
HYPERGLYCEMIA-----NEUROPATHY
Summary of nerve disorders
Root Disk, Herpes zoster
Plexus Autoimmune, trauma,
neoplasm
Mononeuropathy Trauma, entrapment
Multiple
mononeuropathy Vasculitis...
Polyneuropathy Toxic, metabolic,
nutritional
Polyradiculo-
neuropathy Autoimmune
Guillain-Barre
Syndrome
Guillain-Barre syndrome
Progresses over days to <4 weeks
Typically ascending weakness
Reflexes lost early
Motor symptoms predominate, but
can affect sensation and autonomic
function
Respiratory failure requires support
Guillain-Barre syndrome (cont’d)

Etiology: autoimmune
target antigen usually unknown
In some cases: specific gangliosides (GM1,
GQ1d... May correlate with symptoms
Precipitating factors: infection
(campylobacter, CMV), immunization,
surgery, trauma...
Treatment: IVIG, plasma exchange,
support
Pathophysiology: MOLECULAR
MIMICRY
In Half of patients with GBS, serum
antibodies to various gangliosides
have been found in human peripheral
nerves
These gangliosides have a specific
tissue distribution in peripheral
nerves, play a part in the maintenance
of the cell membrane structure
C jejuni isolates from patients
express lipo-oligosaccharides (LOS)
that mimic the carbohydrates of
gangliosides
 Guillain-Barre syndrome is now the most common
cause of acute flaccid paralysis

 Although modern intensive care facilities have

signicantly reduced the mortality associated with
this monophasic immune mediated neuropathy,
up to 5% of patients to not survive and 10% are
left unable to walk unaided

 Supportive medical care remains the most important

aspect of management but both plasmapheresis
and iv. Immunoglobulin have been shown to
hasten recovery when given in the early stages
of the illness
With the near eradication
of polio. Guillain-Barre
Syndrome (GBS) has
become the most common
cause of acute flaccid paralysis

GBS is an acute monophasic

immune mediated neuropathy
with an incidence of 1-1,5
per 100,000 of population
per year
 GBS is predominantly  Two-thirds of cases
motor neuropathy: may present with
the most common sensory symptoms
initial symptom is at the onset of
weakness, usually the disease,
beginning in the however,
lower limbs and abnormalities on
characteristically sensory examination
involving both proximal are often minimal
and distal muscles
Pain, particularly Complete or partial
low back, buttock loss of reflexes in
or thigh, is an eraly seen in almost
symptom in all patients
approximately
50% of patients

Cranial nerve involvement is seen in

two-thrids of cases, most commonly
facial weakness, opthalmoplegia,
difficulty swallowing or altered taste
 Autonomic nervous system involvement is
present in one third of patients and can
manifest as reduced sinus arrhythmia, sinus
tochycardia, arrhythmias, labile blood pressure,
orthostatic hypotension, abnormal sweating
and pupillary abnormalities
 Autonomic instability, along with respiratory
and bulbar weakness is a major cause of
morbidity and mortality in GBS
 GBS is not a single pathophysiological entity
 GBS and acute inflammatory demyelinating
polyradiculoneuropathy (AIDP) can no longer
be used synonymously as in the past
 AIDP remains the most common form of
GBS in Europe
 A pure motor axonal subtype (acute motor
axonal neuropathy; AMAN) is more common
in developing countries
 The motor-sensory axonal type (AMSAN) is
a more severe form with fewer patients
making a complete recovery

 The Miller Fisher variant (MFS) represents

approximately 5% of cases of GBS

 Electrodiagnostic testing is the single most

useful diagnostic evaluation, providing support
for the clinical diagnostic and useful prognostic
information, however nerve conduction studies
may be normal early in the disease, particularly
within the firs week
 Examination of cerebrospinal
fluid (CSF) is invaluable

 CSF protein is increased in

80-90% of cases, characteristically
without a significant increase in
white cells, although a mild
increase in mononuclear
cells is evident in approximately
10% of patients
 An elevated level of CSF protein does support
the diagnosis but, more importantly, spinal tap
excludes other differential diagnoses,
for instance, a marked increase in white cells
should raise doubt about a diagnosis of
idiopathic GBS

 Antiganglioside serology can provide useful

support for the diagnosis in incomplete forms
and unusual variants of GBS, particularly
when electrodiagnostic testing and CSF
are normal
 Approximately two-thirds of patients give a history
of antecedent illness, usually a respiratory or
diarrheal illness, within the month prior to onset
of neurological symptoms

 Neurologc symptoms usually progress over days

to weeks with a nadir being reached within 14
days in two-thirds of patients and within 4 weeks
in virtually all. Recovery usually begins within
2-4 weeks of this nadir but can be delayed
for several months
 Approximately 20%  The severity of disease
of patients remain increase with age and
ambulant throughout, antecedent infection
but up to half become with Campylobacter or
chair - or bed-bound, CMV has also been
one-third require associated with more
intensive care severe disease
admission and
one-quarter mechanical
ventilation
 Most patieints make a complete functional
recovery over 6-12 months, but 20-30% are
left with significant disability and approximately
10% are unable to walk unaided
 With modern intensive care facilities, the
mortality rate has been significantly reduced
but remains 3-8% in recent series.
Most deaths are the result of cardiac arrest
attributed to autonomic disturbance,
respiratory failure or infection,
or pulmonary embolism
Differential diagnosis

 Diagnosis is based on
a set of defined clinical
and laboratory criteria

 A list of diseases that can

mimic GBS is include
 Prognosis
 The most important determinant of rate and efficiency
of recovery is the degree of axonal degeneration.
Axonal degeneration is usually indicative of slow or
incomplete recovery, except in cases with very distal
axonal degeneration is needed over only short distance
 The outcome is better in children and the presence
of decreased CMAP amplitudes and denervation
potentials may not predict poor outcome in this age
group although a prolonged interval to commencement
of clinical recovery
 Pathophysiology

 Campylobacter jejuni infection has become the most

commonly recognized antecedent event for all forms
of GBS
 Experimental models demonstrate a pathophysiologic
role for antiganglioside antibodies and provide
support for the concept of molecular mimicry
 In demyelinating GBS, there is evidence that both
humoral immune responses and T-cell activation
are important in pathogenesis
 Complement-fixing antibodies directed against
peripheral nerve myelin can be detected in the
serum of GBS patients in immunoglobulin and
complement deposition is evident on Schawan
cell surfaces, suggesting a primary immune attact
directed againts Schawan cells or myelin

 Lymphocytic infiltrates are evident within nerves and

there is systemic evidence of T-cell activation.
The proinflammatory cytokine TNF- is upregulated
in AIDP and levels correlate with disease severity
and electrophysiological evidence of demyelination
 Other inflammatory markers are also elevated,
including vascular adhesion molecules and matrixs
metalloproteinnases and the expression of B-7
costimulatory molecule is upregulated in the sural
nerve of patients with GBS

 In axonal variants of GBS there is minimal

lymphocytic infiltration of nerve, but immunoglobulin
and complement are deposited on the axolemma,
consistent with the axon being the site of primary
immune attack
 Therapy

 Supportive care
 Ventilatory suppot
 Treatment of autonomic dysfunction
 Dysautonomia is common in patients with GBS.
The resulting arrhythmias and labile blood
pressure can be potentially life-threatening
 Prevention of nosocomial infection,
thromboembolism & other complications
of immobility
 Treatment of pain
 Pain, wheather early radicular pain or later
painful distal dysaesthesia, is often severe
enaough to warrant treatment.
Narcotic analgesics and anticonvulsant
medications are useful drug for radicular
pain and dysaethesias respectively
 Narcotics should be used cautiously in patients
at risk for respiratory compromise
 Immunomodulatory therapy

 Both PE and IVIg have been shown to be effective

if started within the first 2 weeks of neurological
symptoms. Patients who present with mild symptoms,
little recent progression and independent ambulation
probably do not require immunomodulatory therapy
as their recovery is typically rapid and complete
 Due to ease of its administration and patient
acceptability IVIg is now the first line of threatment
for most patients
 Plasma exchange
 Treatment schedules
A variety of PE schedules have benn used, with
a standard approach being to exchange a total
of 200-250 ml/kg of plasma in 4-5 sessions over
7-14 days
 Complications
 The potential complications of PE include transient
hypotension, infections relating to cannulation,
thromboembolism and hypocalcaemia from
citrate in relacement fluids
 Patiens with GBS often have some degree of
cardiovascular instability, as described above.
PE is likely to be more problematic in these patiens
and IVIg should be used in preference, if available

 PE is relatively contraindicated in small children

and IVIg is preferable. In pregnancy, significant
fluid shifts are not desirable and IVIg is
used where possible
 Mechanism of action
The mechanism of action of PE remains uncertain.
Plasma exchange removes a number of potentially
pathogenic ciorculatiing factors including antibodies,
cytokines and complement and can alter
lymphosyte subsets
 Intravenous immunoglobulin
 IVIg has been shown to be as effective as
plasma exchange in the treatment of GBS
 There are no large, randomized studies of IVIg
in chilchood GBS
 However, there are numerous anecdotal reports
and reveral small series which demonstrate
reduced time to improvement, better outcomes
at 1 and 3 months and reduced nedd for intubation
and ventilation in IVIg-treated children compared
to controls receiving supportive care alone
 Administration

The standard total dose of IVIg

given tor treat GBS is 2 g/kg.
In the trials described this
was given over 4 or 5 days
and this has been standard
clinical practice for some years
 Complications

 Overall, adverse reactions are estimates to occur in

up to 10% of patients. The most common are mild-
to-moderate headache, myalgia, fever and childs
 Other potential side-effects of IVIg include: rash,
worsening renal function, meningism and
aseptic meningitis
 Anaphylaxys may occur in patients with severe IgA
deficiency, hence serum IgA levels should be
checked before commencing therapy. In patients
with very low IgA (Gammagard-SD, Baxter) is
recommended
 Mechanism of action

 IVIg is known to bind to and neutralize

autoantibodies. Inhibit autoantibody production,
suppress antibody dependent cellular toxicity,
decrease natural killer cell function, down-regulate
proinflammatory cytokine expression and interfere
with complement activation

 It is also postulated that IVIg may lead to

increased catabolism of endogenous
pathogenic antibodies by saturating
FcRn transport receptors
  IVIg has been shown to reduce the circulating levels
of TNF- and IL-1 and clinical improvement in IVIg-
treated patients is associated with a reduction in
levels of unbound TNF- 

 Treatment of variants
There are no controlled studies of immunomodulatory
therapy in the Miller Fisher and primary axonal
Viariants of GBS, but anecdotal reports indicate that
both PE and IVIg are beneficial
 Corticosteroid

 A recent meta-analysis of all the available

randomized studies has concluded that
corticosteroid treatment is not beneficial
 A pilot study of IVIg 0,4 gm/kg/day combined
with iv. Methylprednisolone 500 mg daily for
5 days has suggested that this combination
regimen may be more effective than IVIg alone
 Expert opinion

 We recommend that all patients suspected of

having GBS be admitted to hospital, unless they
have minimal neurological deficit and have already
reached plateu stage
 Patients without any respiratory impairment or
autonomic instability should be admitted to the
neurology ward and forced vital capacity and
EKG monitored regularly
 If there is respiratory impairment, severe bulbar
weakness or autonomic instability we admit
the patient to ICU

 Potential new specific immunomodulatory therapies

directed at immune effectors implicated in the
pathogenesis of GBS include blockade of the
inflammatory cytokine TNF-  with infiximab
(achimeric monoclonal antibody which neutralizes
the biological activity of human TNF-  ) and
etanercept (TNF dimeric p75 receptor fusion protein
fused to Fc fragment)
 Since typically most of the pathology is localized
in the spinal roots and proximal nerves, axonal
regeneration advances st an approximate rate of
1 inch/month, this recovery is slow

 Delivery of such growth factors to appropriate

sites is another important challenge
 Summary &
conclusion

 The mortality and morbidity of GBS has been

significantly reduced primarily due to advances in
intensive care and the advent of two effective
immunomodulatory therapies
 Both immunomodulatory therapies are equally
effective but IVIg has become the treatment of choice
and standard of care because of ease of administration.
PE still has a role, particularly in patients who have
contraindications to IVIg
Myasthenia Gravis
Myasthenia gravis (MG)
is an otoimmune disease,
which destroys key
components of the
neuromuscular system
responsible for governing
muscular activity
It is a disorder caused by an antibody-
mediated autoimmune attack on the
acetylcholine receptors at the
neuromuscular junction
 The calling card of myasthenia
gravis is fluctuating muscle
weakness that woresens with
exertion and improves with rest

 Ocular manifestations, such as

ptosis and diplopia, are frequently
present at the onset and eventually
in most patients
PATHOPHYSIOLOGY

The source of the autoimmune

response has not been established
Most of patients have thymic
abnormalities, response to
thymectomy
Both T and B cells from the
myasthenic thymus are particularly
responsive to the ACh receptor
Pathophysiology (cont)

Moreover, thymus contains “myoid

cells” (resembling striated muscle)
that bear surface ACh receptors
The thymic myoids cells are the foci
of immunologic stimulation in MG
Pathophysiology (cont)

A virus with a tropism for thymic cells that

have ACh receptors might injury such cells
and induce antibody formation
Thymic lymphocytes of MG can synthesize
anti-Ach receptor antibody, both in culture
and spontaneously
 Epidemiology

MG has a prevalence of approximately one

In 20,000 persons. There is no racial or
Geographic predilection. There does seem
to be a genderrelated age distribution,
with females more likely to experience early
onset disease (under age 50) by a ratio of 7:33
 Signs and
symptoms

Patients with MG typically

present to the practice
with symptoms of variable
ocular fatigue and
weakness
Ocular Examination for Suspected MG

Limitation of adduction

Eyelid drooping (ptosis)

Normal pupil size and reaction
The common ocular findings include ptosis,
droopy eyelids that appear worse at the end
of the day, orbicularis weakness, limitation
of ocular motility, paradoxical lid retraction,
Cogan’s lid twitch (transient eyelid retraction
following an extended period of down gaze),
exposure keratitis and intermittent diplopia
A small percentage of patients possess
a form of the disease known as ocular
myasthenia. Here, the signs and
symtoms remain strictly confined to
the extraocular muscles.
The pupils is never involved in MG.
Systemic symptoms include
intermittent fatigue of the libs,
weakness of the facial muscles
and difficulty breating, chewing,
talking and swallowing (dysphasia)
 In a small percentage of patients,
dysthyroidism may be present, resulting
in the mixture of ptosis and exophthalmos.
Thymic neoplas ‘n (thymoma) is an
associated finding in patients over.

 Associated immunologic disorders such

as diabetes mellitus, lupus erythematosus
and rheumatoid arthritis occur in 20%
of MG patients
 Pathophysiology

MG is characterised by an
autoimmunological
degradation of acetylcholine
receptors in the neuromuscular
junctions of the skeletal
muscles of the body
Thymus
 While poorly understood, these attacks
have been linked to maverick antibodies
that appear to originate in the thymus gland

 Sign and symptoms may be initiated,

exacerbated or mimicked by medications
such as D-penicillamine, antibiotics
(polymyxn B, neomycin, gentamicin,
streptomycin), beta blockers and
anticonvulsants
Bedside Diagnosis of Suspected MG (Awwad, 2001)

Wartenberg Test
Increasing left ptosis
developing upon sustained
upward gaze in a patient
with myasthenia gravis

The Cogan Sign

The lid will be seen to
overshoot in a twitch
before gaining its
initial
ptotic position
1.Edrophonium (Tensilon) Testing
Initially
 Dosing: 2 mg of edrophonium is
administered intravenously as a test
dose
 Monitoring heart rate: Bradycardia or
ventricular fibrillation may develop

Follow-up
 After observing for about 2 minutes,
if no clear response develops
 Up to 8 additional mg of edrophonium
is injected
Positive test
► Most myasthenic muscles respond in 30 to
45 seconds after injection
► Improvement in strength that may persist
for up to 5 minutes
► Requires objective improvement in muscle
strength.
► Subjective or minor responses, such as
reduction of a sense of fatigue, should not
be over interpreted
Progressive decline in CMAP amplitudes with the first 4
to 5 stimuli.
Positive RNS test features
1. Decrement in CMAP amplitude
Size: More than 10% in reduction in CMAP
amplitude
Measure from 1st to 4th or 5th potential
intrain
Smallest CMAP is often 2nd or 3rd potential in
train
2. Post-exercise exhaustion
Exercising muscle briefly before testing
exacerbates decremental response
Occurs rapidly after initial stimulation
3. Post-tetanic potentiation
Reduction in decrement in minutes after exercise
Occurs after post-exercise exhaustion
www.neuro.wustl.edu
Patofisiologi Myasthenia Gravis (Drachman, 1994)
Blockade of Ach binding site (Cornelio, 2002)
 Bilateral weakness of the upper and lower limbs

Myopathy Neuropathy Neuromuscular junction

Distribution of weakness Proximal Distal (initially) General

Ocular and bulbar muscle weakness Rare Infrequent Common

Muscle pain and/or tenderness +/- - -

Muscle atrophy Late Early -

Reflexes Preserved - early Absent - early Present

Absent- late

Sensory deficit Absent May be present Absent

 Management

 Patients who report neurological signs

or symptoms require a thorough review
of family history, illnesses, systems,
medications and behaviours

 Practitioners should inspect and

measure the palpeoral apertures
of patients with positional
lid anomalies
THERAPY
Aim of treatment (Cornelio, 2002)

1. Optimise neuromuscular transmission

2. Reduce or neutralise the

consequences
of autoimmune reaction

3. Modify the natural history of MG

  The quintessential method of
diagnosing MG is the endophonium
hydrocholide (Tension) injections test

 An additional laboratory test used

for diagnosing MG is the acetylcholine
antibody receptor test (Ach r)
 In-office test for the
optometrist include:

 Asking the pertinent history

 Testing the pupils
 Assessing the orbicularis function by
asking the patient to squeeze their
eyelids shut while one forcibly attempts
to open eliminating
 Attempting to elicit diplopia by eliminating
the occlusive effects of ptosis
 Attempting to elicit superior rectus or
elevator fatigue by asking the patient to
sustaine upgaze while observing for
unexpected eyelid droop
 Attempting to elicit the Cogan’s lid twitch
sign by asking the patient to look into
downgaze for an extended period,
then to upgaze
 Appling an ice pack to eyelid for 20 minutes
and re-evaluating the ptosis for improved
position following its removal
 Asking the patient to close their eyes for 30
minutes (sleep test), and re-evaluating the ptosis
for improved position upon awakening.
Dianosis may also be assisted by evaluating
old photographs for appearance
 Anticholinesterases, which block the degradation
of acetylcholine in the neuromuscular junction
and and oral steroids. Pyridostigmine (Mestinon),
ambenonium (Mytelase) or neostigmine
(Prostigmine) with ephedrine and potassium
chloride are frequent regimens
 Oral prednisone is frequently used to quell
acute episodes
 In recalcitrant cases, immunosuppressive
agents such as azathioprine and
cyclophosphamide have been found to
possess beneficial effects. In extreme cases,
surgical removal of the thymus may be helpful

 Laboratory testing is an important consideration

for patients diagnosed with MG because of
its association with other systemic
autoimune disease
Pertinent studies include fasting blood sugar
(FBS - diabetes), thyroid function test (ASH,
T3, T4), antinuclear antibody (ANA - lupus),
rheumatoid factor (RF - arthritis) and in
suspicious cases, radiological testing,
imaging the thymus gland
A purified protein derivated
(PPD - tuberculosis) should be
completed because steroid
regiments, used to treat MG have
potential to activate or worsen
dormant disease. Patients should
always be educated to report
difficulties with breathing
or swallowing
Neuromuscular junction
Disorders of the neuromusuclar
junction

Release of acetyl choline:

Botulism (toxin = endopeptidase targeting
various proteins mediating exocytosis)
Lambert-Eaton myasthenic syndrome
(antibodies to voltage-gated calcium channel)
Acetylcholine receptor blockade:
Myasthenia gravis (antibodies to ACh receptor)
Myasthenia Gravis
Fluctuating weakness
Eyes: ptosis, diplopia (spares pupils)
Bulbar weakness: dysarthria, dysphagia
Proximal muscle weakness
Respiratory weakness
Normal reflexes
Normal sensation
Assoc w/ thymoma
Assoc w/
other autoimmune d/o
Myasthenia Gravis
Treatment:
acetyl cholinesterase
inhibitors
immunotherapy
steroids
IVIG
plasma exchange
immunosuppressive agents
thymectomy
Prinsip
Therapy
Pascuzzi R M. Myasthenia Gravis and Lambert-Eaton
Syndrome.Ther Apher, Vol. 6, No. 1, 2002
Immunosuppressive therapy

►Indicated when weakness is not adequately

controlled by anticholinesterase drugs and is
sufficiently distressing to outweigh the risks
of possible side effects of
immunosuppressive drugs.

►Steroids are the most commonly used and

most consistently effective
immunosuppressive agents for the treatment
of myasthenia gravis.
Immunotherapy in MG (Drachman, 1994)
 Plasmapheresis

1. Removes antibodies from the circulation and

produces short-term clinical improvement in
patients with myasthenia gravis

2. It is used primarily to stabilize the condition of

patients in myasthenic crisis or for the short-
term treatment of patients undergoing
thymectomy

3. Five exchange treatments of 3 to 4 liters each

are carried out over a two-week period
The effect of plasmapheresis is rapid, with
improvement occurring within days of
treatment.
Improvement correlates roughly with a
reduction in the anti-acetylcholine-
receptor antibody titers
The beneficial effects of plasmapheresis
are temporary, lasting only weeks.
The drawbacks of plasmapheresis include
problems with venous access, the risk of
infection of the indwelling catheter,
hypotension, and pulmonary embolism. The
benefit must be weighed against these
problems and the high cost of the procedure
 intravenous immune globulin

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
Lambert-Eaton Myasthenic Syndrome
Donald B Sanders, MD, Laboratory Director, Professor of Medicine (Neurology), Division of
Neurology, Duke University Medical Center
Last Updated: March 20, 2001

Lambert-Eaton myasthenic syndrome (LEMS) is a rare

condition in which weakness results from an abnormality of
acetylcholine (ACh) release at the neuromuscular junction.
Recent work demonstrates that LEMS results from an
autoimmune attack against voltage-gated calcium channels
(VGCC) on the presynaptic motor nerve terminal.
Cancer is present when the weakness begins or is later
found in 40% of patients with LEMS. This is usually a small
cell lung cancer (SCLC), although LEMS also has been
associated with non-SCLC lung cancer, lymphosarcoma,
malignant thymoma, or carcinoma of breast, stomach,
colon, prostate, bladder, kidney, or gallbladder.
Clinical manifestations frequently precede cancer
identification. In most cases, the cancer is discovered
Pascuzzi R M. Myasthenia Gravis and Lambert-Eaton
Syndrome.Ther Apher, Vol. 6, No. 1, 2002
 The typical patient with LEMS presents with slowly
progressive proximal leg weakness.
 Weak muscles may ache and are occasionally
tender.
 Oropharyngeal and ocular muscles may be
affected mildly.
 Respiratory muscles usually are not affected, but
cases with severe respiratory compromise have
been reported.
 Strength usually is reduced in proximal muscles of the legs
and arms, producing a waddling gait and difficulty elevating
the arms.
 Some degree of eyelid ptosis or diplopia, usually mild, is
found in 25% of patients. Occasionally, difficulty chewing,
dysphagia, or dysarthria is present.
 Tensilon or pyridostigmine may improve strength, but this is
rarely as dramatic as in myasthenia gravis (MG).
Pascuzzi R M. Myasthenia Gravis and Lambert-Eaton
Syndrome.Ther Apher, Vol. 6, No. 1, 2002
Pascuzzi R M. Myasthenia Gravis and Lambert-Eaton
Syndrome.Ther Apher, Vol. 6, No. 1, 2002
Axon
 PRINCIPLES OF CLINICAL MYOLOGY:
DIAGNOSIS AND CLASSIFICATION OF
MUSCLES DISEASE --
GENERAL CONSIDERATIONS
Skeletal, or voluntary, muscle constitutes
the principal organ of locomotion as well as
a vast metabolic reservoir.
Disposed in more than 600 separate muscles,
this tissue makes up as much as 40 percent
of the weight of adult human being
 APPROACH TO THE PATIENT WITH
MUSCLES DISEASE

 The physician is initially put on the tract of

a myopathic disease by elicting complaints of
muscle weakness or fatigue, pain, limpness or
stiffness, spasm, cramp, twitching, or a muscle
mass or change in muscle volume.
Of these, the symptom of weakness is by
far the most frequent and at the same time
the most elusive
 As when speaking of weakness, the patient
often means excessive fatigability.
Although fatigability may be a feature of
muscle disease -- particularly those affecting
the neuromuscular junction, such as
myasthenia gravis -- it is far more frequently
a complaint of patients with chronic systemic
disease or with anxiety and depression
 To distinguish between fatigability
and weakness, one must assess
the patient’s capacity to perform
certain common activities such
as walking, running, climbing stairs,
and arising from a sitting, kneeling,
squatting, or reclining position.
Difficulty in performing these tasks
signifies weakness rather
than fatigue
 The same is true of difficulty in working
with the arms above shoulder level.
Particular complaints may reveal
a localized muscle weakness; e.g.,
drooping of the eyelids, diplopia and
strabismus, change in facial expression
and voice, and difficulty in chewing,
closing the mouth, and swallowing indicate
a paresis of the levator palpebrae,
extraocular, facial, laryngeal, masseter,
and pharyngeal muscles, respectively
 These impairments of muscle
function may be due to
a neuropathic or central nervous
system (CNS) disturbance rather
than to a myopathic one, but usually
these conditions can be separated
by the methods indicated
 Evaluation
of Muscle Weakness
and Paralysis

Reduced strength of
muscle contraction

Ascertaining the extent

and severity of muscle
 Qualitative Changes in
the Contractile Process

 In the myasthenic states there is a rapid

failure of contraction in the most affected
muscles during sustained

 In addition to myasthenic weakness, there are

other abnormalities that may be discovered by
observing, during one or a series of maximal
action of a group of muscles, the spreed and
efficiency of contraction and relaxation
 In myxedema, for example, a stiffness and
slowness of contraction in a muscle such as
the quadriceps may be seen on change in
posture (contraction myoedema); often it is
associated with prolonged duration of the
tendon reflexes and myoedema, which can
be ellicited by direct percussion of a muscle
 Topography or Patterns of
Myopathic Weakness

 Ocular palsies presenting more or less

exclusively as ptosis, diplopia, and strabismus,
sometimes in association with exophthalmos
and pupillary change
When weakness of the orbicularis oculi
(muscles of eye closure) is added to weakness
of eye opening (ptosis), it nearly always
signifies a primary disease of musle or of
neuromuscular transmission
 Bifacial palsy presenting as an inability to
smile, expose the teeth, and close the eyes
Varying degrees of bifacial weakness are
observed in myasthenia gravis, usually
conjoined with ptosis and ocular palsies

 Bulbar (oropharyngeal) palsy presenting as

dysphonia, dysarthria, and dysphagia with
or without weakness of jaw or facial muscles
Myasthenia gravis is the most frequent cause of
this syndrome and must also be considered
whenever a patient presents with the solitary
finding of a hanging jaw ar fatigue of the jaw
while eating or talking; usually, however, ptosis
and ocular palsies are conjoined
Dysphagia may be an early and prominent sign
of polymyositis as well as inclussion body
myositis and may appear in patients with
myotonic dystrophy, due to upper
esophageal atonia
 Cervical palsy presenting with inability to hold
the head erect or to lift the head from the pillow
 Weakness of respiratory and trunk muscles
 Bibrachial palsy, sometimes presenting as
a dangling-arm syndrome
Weakness, atrophy, and fasciculations of the
hands, arms, and shoulders characterize the
common form of motor system disease,
namely, amyotrophic lateral sclerosis
 Bicrural palsy presenting as lower leg
weakness with inability to walk on the heels
and toes, or as paralysis of all leg and
thigh muscles
Diabetic polyneuropathy or carcinomatous or
lymphomatous radiculopathy may cause
asymmetrical weakness of thigh and pelvic
muscles, often with pain and little sensory change
Chronic inflammatory demyelinating
polyneuropathy (CIDP) may do the same
 Limb-girdle palsies presenting as inability to
raise the arms or to arise from a squatting,
kneeling, or sitting postion
Polymyositis, inclusion body myositis,
dermatomyositis, and the progressive muscular
dystrophies most often manifest themselves
in this fashion

 Distal bilateral limb palsies presenting usually

as foot drop with steppage gait
 Generalized or universal paralysis: limb (but
usually not cranial) muscles, involved either in
attacks or as part of a persistent, progressive
deterioration
When acute in onset and episodic, this
syndrome is usually a manifestation of familial
hypokalemic or hyperkalemic periodic paralysis

 Paralysis of single muscles or group of muscles

This is usually neuropathic, less often spinal
or myopathic
Muscle Fatigue, Lack of Edurance,
and Exercise Intolerance

 Fatigue is an abstruse symptom, always

needing analysis and interpretation

 When not attended by manifest reduction in

muscle power, it is usually nonmuscular in
origin. It may, or medical investigation, prove
to be a manifestation og infection, metabolic
endocrine disorder, or neoplasia.

Cont….
 Cont….

More often, when expressed as a feeling of

weariness and disinclination to undertake or
sustain mental and physical activity,
it is indicative of neurasthenia, a psychiatric
manifestation common to states of chronic
anxiety and depression or simply to boredom
and lack of purpose
 Muscle Tone
All normal muscles display a slight
resistance to strech when fully relaxed

Changes in Muscle Volume

Diminution or increase in muscle bulk
stands as another feature of disease
that can be observed in all axcept
the most obese patients
Twitches, Spasms, and Cramps

Fascicular twiches a rest (fasciculations),

if pronounced and combined with muscular
weakness and atrophy, usually signify motor
neuron disease (amyotrophic lateral sclerosis,
progressive muscular atrophy, or progressive
bulbar palsy); but they may be seen in other
disease that involve the gray matter of the spinal
cord (e.g., syringomelia or tumor) as well as in
lessions of the anterior roots (e.g., protruded
intervertebral disc) and in certain peripheral
neuropathies
Palpable Abnormalities
of Muscles

Altered structure and function of muscle are not

accurately by palpation. Of course, the difference
between the firm, hypertrophied muscle of a well-
conditioned athlete and the slack muscle of
a sedentary person is as apparent to the palpating
fingers as to the eye, as is also the persistent
contraction in tetanus, cramp, contracture,
and extrapyramidal rigidity
Muscle Pain

Notably, few of the primary muscle diseases are

painful. When pain is prominent and continuous
during rest and activity, there will usually be
evidence of disease of the peripheral nerves,
as in alcoholic-nutritional neuropathy, or of
adjacent joints and ligaments (rheumatoid
arthritis, polymyalgia rheumatica, etc.)
Nonmuscular Abnormalities
in Muscular Disease

Clinical studies have divulged the involvement

of many organs in certain disease formerly
thought to be purely myopathic.
Some of the nonmuscular abnormalities,
such as dislocation of the hips in several of the
congenital myopathies, are probably secondary
to the inadequate action of immature muscles
DIAGNOSIS OF MUSCLE DISEASE

 The aforementioned symptoms and signs

are most helpful when considered in connection
with the age of the patient at the time of onset,
their mode of evolution and cource, and the
presence or absence of familial occurance

 Since many diseases of muscle are hereditary,

a careful familial history is important. Stated
differently, the familial occurrence of a muscle
disease practically always indicates
a genetic causation
Summary

The clinical recognition of

myopathic diseases in facilitated
by a prior knowledge of a few
syndromes, of the age onset
of the illness, of a familial
occurrence of the same or
similar illnesses, and of the
medical setting in which
weakness evolves
NEUROMUSCULAR DISEASE

PRESENT WITH WEAKNESS

&/OR WASTING OF MUSCLE

Ismail Setyopranoto
Dept. of Neurology School of
Medicine Gadjah Mada University
NEUROMUSCULAR DISEASE
DISORDERS OF MOTOR NEURONE
neuropathic process
NON-PROGRESSIVE (eg. Polio)
PROGRESSIVE (eg. MND, SMA)
DISORDERS OF MUSCLE
myopathic process
PRIMARY (eg. Muscular dystrophy)
SECONDARY (eg. Alcohol)
DISORDERS OF NEUROMUSCULAR
JUNCTION
NEUROMUSCULAR DISEASE

WHY WORRY ABOUT A

SPECIFIC DIAGNOSIS

SOME ARE CURABLE

SOME ARE TREATABLE
SOME ARE NON- OR ONLY SLOWLY
PROGRESSIVE
GENETIC COUNCELLING
 NEUROGENIC DISORDERS
RESULT FROM DAMAGE TO
MUSCLE INNERVATION

MOTOR NEURONE DISEASE (MND)

SPINAL MUSCULAR ATROPHY (SMA)
PERIPHERAL NEUROPATHY

PROGRESSIVE DAMAGE AND

CONCOMMITANT RE-INNERVATION
RESULTS IN CHARACTERISTIC
HISTOLOGY IF APPROPRIATE STAINS
DONE
NEUROGENIC DISORDERS

NORMAL
MYOPATHIC DISORDERS

MYOPATHIES
DYSTROPHIC MYOPATHIES
eg. Duchenne’s muscular dystrophy
CONGENITAL MYOPATHIES
floppy infant
METABOLIC MYOPATHIES
INFLAMMATORY MYOPATHIS
eg. polymyositis
TOXIC MYOPATHIES
eg. alcohol
 DUCHENNE DYSTROPHY

Genetically determined (X-linked)

Deficiency of DYSTROPHIN
(normally present in muscle cell
membrane) - Raised CPK
Presents males 2-4 years
Weakness
Pseudohypertophy of the calves
Die by age 20 years
DUCHENNE DYSTROPHY
DYSTROPHIN STAIN
CONGENITAL MYOPATHIES

Uncommon, inherited disorders

Hypotonia & floppiness in infancy
(hypotonia has OTHER causes as well)
Reflect abnormal maturation fibres
Often only slowly progressive
Muscle biopsy ESSENTIAL
MITOCHONDRIAL MYOPATHY
 MUSCLE BIOPSY

REQUIRES SPECIAL
TECHNIQUES AND SAMPLE
MUST NOT BE PUT INTO
FORMALIN - THUS PRIOR
CONSULTATION
ESSENTIAL
SECONDARY MYOPATHIES

Cachetic atrophy
Endocrine disorders
Vitamin deficiency
Alcohol & other drugs
THUS CLINICAL ASSESSMENT
REQUIRES INVESTIGATION OF
ALL THESE PARAMETERS
Diseases of Muscle
(myopathy)
Symmetrical proximal weakness
Reflexes normal (sometimes
depressed)
No sensory loss
Myopathy (cont’d)
Inherited
dystrophies
congenital myopathies
channelopathies
Acquired
endocrine
inflammatory, including autoimmune
toxic (drugs...)
Inflammatory myopathies

Polymyositis
isolated
with collagen vascular disease
Dermatomyositis
childhood
adult: association with cancer
others
Summary
Neuromuscular disorders have no
suprasegmental symptoms or signs
Nerve disorders can be more easily
diagnosed if localized first to root, plexus,
single or multiple nerves, polyneuropathy,
or polyradiculoneuropathy.
Disorders of NMJ: MG can have a
characteristic presentation
Myopathies present with symmetric
proximal weakness, and many are treatable
MATUR NUWUN