Transcript Slide 1

Presynaptic Neuromuscular
Junction Disorders
Farzad Fatehi,
Neurologist,
Shariati Hospital,
Tehran University of Medical Sciences
Lambert Eaton Myasthenic
Syndrome
Lambert-Eaton myasthenic syndrome
(LEMS)
• A rare presynaptic disorder of neuromuscular
transmission
• Quantal release of acetylcholine (ach) is
impaired, causing a unique set of clinical
characteristics, which include:
– Proximal muscle weakness
– Depressed tendon reflexes
– Post-tetanic potentiation
– Autonomic Changes.
Neuromuscular Junction
Normal NMJ
+++
Ca++
NMJ
Ach
+++
Ca++
Acetyl Choline Esterase
Ach
Ach → Acetyl + Choline Ach
Ca++
m=nXp
+++
m: number of quanta released
p: probability of release
n: the number of quanta in axon
Ca++
NMJ
Ach
+++
Ca++
Ach
Ach
Ca++
In LEMS: p↓
Pathophysiology
• Impaired ACh release from the motor nerve
terminal.
• An autoimmune attack directed against the
voltage-gated calcium channels (VGCCs) on
the presynaptic motor nerve terminal -- >
loss of functional VGCCs at the motor nerve
terminals
LEMS
Ca++
+++
Anti
VGCC
NMJ
Ach
Anti
Ca++ VGCC
+++
Ach
Ach
Ca++
Anti
VGCC
Anti
VGCC
Pathophysiology
• ALSO,
– Parasympathetic
– Sympathetic
– Enteric neurons
• are all affected.
• This ‘post exercise facilitation’ seems likely to
be due to the temporary build up of Ca++ in
the nerve terminal which results in a striking
potentiation of release, temporarily
increasing the safety factor.
• A qualitatively similar potentiation occurs at
normal NMJs.
Epidemiology
• The most common age for the appearance of
symptoms is 60 years.
• It is rare in children however, at least 7
children younger than 17 years are reported
to have had LEMS.
• M:F=1:1
Epidemiology
• An estimated 3% of patients with SCLC have
LEMS.
• The prevalence of SCLC is 5 cases per million
population in the United States.
• Because only 50-70% of patients with LEMS
have an identifiable cancer and because
LEMS goes undiagnosed in many patients,
the true total prevalence of LEMS may be
considerably higher.
Epidemiology
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The overwhelming majority of cancers associated with LEMS are SCLC.
However, many different malignancies may be involved.
A partial list includes
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Non-sclc
Neuroendocrine carcinomas
Lymphosarcoma
Malignant thymoma
Cancers of the breast
Stomach
Colon
Prostate
Bladder
Kidney
Gallbladder
Rectum
Basal cell carcinoma
Leukemia
Lymphoproliferative disorders such as Castleman syndrome and Hodgkin lymphoma.
History
• The initial presentation can be similar to that
of myasthenia gravis (MG), but the
progressions of the 2 diseases have some
important differences.
History
• Symptoms of Lambert-Eaton myasthenic
syndrome (LEMS) usually begin insidiously
and progress slowly.
• Many patients have symptoms for months or
years before the diagnosis is made.
• Weakness is the major symptom.
• Weak muscles may ache and are occasionally
tender.
History
• Proximal muscles > Distal muscle
• Lower extremity > Upper extremity
• Patients typically have difficulty rising from a
chair, climbing stairs, and walking simulating
myopathies.
History
• Increased temperatures may worsen the
weakness.
• The oropharyngeal and ocular muscles are
mildly affected in about 25% of cases of LEMS:
• Ptosis
• Diplopia
• Dysarthria
• Differentiation between the 2 diseases may be
difficult.
History
• Respiratory muscles are not usually affected.
If occurred
– Not as severe as MG.
History
• Most patients have a dry mouth, which
frequently precedes other symptoms of
LEMS.
• Many patients report an unpleasant metallic
taste.
• Some patients have other manifestations of
autonomic dysfunction, including impotence
in males and postural hypotension.
Cancer and LEMS
• Cancer is present or subsequently discovered
in 50-70% of patients with LEMS.
• In the case of lung cancer, the clinical
symptoms of LEMS may precede detection of
the underlying disease.
• Symptoms of the underlying cancer, as well
as the “B” symptoms of cancer, may be
present.
Cancer and LEMS
• Smoking and age at onset are major risk
factors for cancer in patients with LEMS.
• Duration of symptoms is also a factor.
• If a tumor is not found within the first 2 years
after symptom onset, cancer is unlikely.
Physical Examination
• Strength is usually reduced in proximal
muscles of the legs and arms, producing a
waddling gait and difficulty elevating the
arms.
• The degree of weakness is usually mild,
compared with that reported by the patient.
Physical Examination
• Some degree of eyelid ptosis or diplopia, usually
mild, is found in 25% of patients.
• Occasionally, difficulty chewing, dysphagia, or
dysarthria is present.
• Most patients have a dry mouth, eyes, or skin.
• Constipation, urinary retention, pupillary
constriction, sweating, postural hypotension, or
respiratory muscle weakness may be present.
Physical Examination
• Clinical manifestations of underlying
malignancy (eg, cachexia) may be present.
• Fasciculations, common in diseases of the
anterior horn cell, such as amyotrophic
lateral sclerosis (ALS), are absent.
Physical Examination
• MRC: In some patients, strength may improve
after exercise and then weaken as activity is
sustained. This phenomenon is demonstrable in
approximately half of all patients with LEMS.
• DTRs: Reflexes usually are reduced or absent in
LEMS.
– They can frequently be provoked or increased by
having the patient actively contract the muscle group
in question for 10 seconds prior to reflex testing or
by repeatedly tapping the muscles.
Physical Examination
• An increase in DTRs after contraction is a
hallmark of LEMS.
Prognosis
• The prognosis is largely determined by the
presence and type of
• Underlying Cancer
• The Presence And Severity Of Any Associated
Autoimmune Disease
• Severity and distribution of weakness
Prognosis
• SCLC - LEMS  Better prognosis than SCLC –
LEMS
– Due to:
• Earlier detection of underlying cancer
• Better response to immunotherapy
Paraclinics
• Electrodiagnostic tests
• Antibody assays
EDx
• Repetitive nerve stimulation (RNS):
– confirm the diagnosis
• Compound muscle action potentials
(CMAPs): small, often less than 10% of
normal, and fall during 1- to 5-Hz RNS.
EDx
• CMAPs are usually small
• Often less than 10% of normal
• Fall during 1- to 5-hz RNS (Slow RNS)
Rapid RNS
• During stimulation at 20-50 Hz, the CMAP
increases in size (ie, facilitation) and
characteristically becomes at least twice
(200%) the size of the initial response.
3 HZ RNS
3 HZ RNS after 10 sec activation
30 HZ RNS
• A similar increase in CMAP size is seen
immediately after the patient voluntarily
contracts the muscle maximally for several
seconds.
EDx
• In LEMS, the CMAP amplitude is low in most
muscles tested.
• This finding is also non-specific and is
commonly observed in other neuromuscular
diseases.
Rapid RNS
• Facilitation > 100% in most muscles tested or
> 400% in any muscle, the patient almost
certainly has LEMS.
• If facilitation is less than 50% in all muscles
tested → the patient still may have LEMS,
especially if weakness has been present for
only a short time or the patient has been
partially treated.
Electromyography
• Needle electromyography
– Conventional needle EMG in LEMS demonstrates
markedly unstable motor unit action potentials,
which vary in shape during voluntary activation.
Anti VGCC
• Antibodies to voltage-gated calcium channels (VGCCs)
have been reported
– in 75-100% of LEMS patients + small cell lung cancer
– In 50-90% of LEMS patients who do not have underlying
cancer.
• 5% of patients with myasthenia gravis (MG)
• in up to 25% of patients with lung cancer without
LEMS
• some patients who do not have LEMS but have high
levels of circulating immunoglobulins
– SLE
– RA
Edrophonium Test
• Testing with edrophonium (Tensilon) may be
performed to help differentiate LEMS from
MG.
• The test may produce an improvement in
strength, but rarely is the response in
patients with LEMS as noticeable as the
typical response in patients with MG.
Differentials
• Acute Inflammatory Demyelinating Polyradiculoneuropathy
(AIDP)
• Amyotrophic Lateral Sclerosis (ALS)
• Chronic Inflammatory Demyelinating Polyradiculoneuropathy
(CIDP)
• Dermatomyositis
• Inclusion Body Myositis
• Multiple Sclerosis
• Myasthenia Gravis
• Polymyalgia Rheumatica
• Polymyositis
• Spinal Muscular Atrophy
Workup
• Screening strategies may help to detect SCLC:
imaging
• Imaging negative with a substantial risk of
lung cancer 
– bronchoscopy
• If both negative and risk factors for lung
cancer are present,
– PET scanning should be considered.
• If all negative  periodic reassessment
Treatment Approach
Treating underlying cancer
• In patients with cancer, the primary concern is
the cancer.
• Initial treatment should be aimed at the
neoplasm because weakness frequently
improves with effective cancer therapy.
– No further LEMS treatment may be necessary in
some patients.
• Immunotherapy of LEMS without effective
treatment of the underlying cancer usually
produces little or no improvement in strength.
Pharmacotherapy
• The initial pharmacotherapy for LEMS is with
agents that increase the transmission of
acetylcholine (ACh) across the neuromuscular
junction
– either by increasing the release of ACh (eg, DAP,
Guanidine hydrochloride) or
– by decreasing the action of acetylcholinesterase
(eg, pyridostigmine)
DAP
Guanidine hydrochloride
Severe Weakness
• When such therapy is warranted, plasma
exchange (PEX) or high-dose IVIg may be
used initially to induce rapid, albeit
transitory, improvement.
• Immunosuppressants should be added for
more sustained improvement.
PLEX
• PLEX may be performed 4-6 times over 7-10
days.
• IVIg, given in a course of 2 g/kg over 2-5 days.
Immunosuppressants
• Prednisone and azathioprine, the most
frequently used immunosuppressants, can be
used alone or in combination.
• Cyclosporine may benefit patients with LEMS
who are candidates for immunosuppression but
cannot take or do not respond well to
azathioprine.
• Improvement may be seen within 1-2 month
after initiation of cyclosporine, with the
maximum response usually observed in 3-4
months.
Latest Case Reports
• Lambert-Eaton myasthenic syndrome associated with intravascular
uterine leiomyoma. Galassi G, Ariatti A, Agnoletto V, Rivasi F. Eur J Obstet
Gynecol Reprod Biol. 2011 Jul 7.
• Lambert-Eaton myasthenic syndrome and follicular thymic hyperplasia in
systemic lupus erythematosus.Pasqualoni E, Aubart F, Brihaye B, Sacré K,
Maisonobe T, Laissy JP, Lidove O, Papo T. Lupus. 2011 Jun;20(7):745-8.
Epub 2011 Mar 22.
• Unusual paraneoplastic syndromes of breast carcinoma: a combination
of cerebellar degeneration and Lambert-Eaton Myasthenic
Syndrome.Romics L Jr, McNamara B, Cronin PA, O'Brien ME, Relihan N,
Redmond HP.Ir J Med Sci. 2011 Jun;180(2):569-71. Epub 2008 Nov 13.
Botulism
Botulism= Sausage disease
• Botulism (Latin, botulus, "sausage“)
Botulism
• Eight distinct C. botulinum toxin types have
been described:
– A, B, C1, C2, D, E, F, and G. Of these eight, types
•A, B, E, and rarely F and
G cause human disease
Botulism
• Botulinum toxin is the most potent bacterial
toxin, and perhaps the most potent known
poison.
• The MLD (minimum lethal dose in
experimental mice) of botulinum toxin is
0.0003 mcg/kg.
• It is estimated that
• 1 gram kills 1.5 million people.
TYPES OF BOTULISM
• Foodborne botulism — Ingestion of food contaminated by
preformed botulinum toxin.
• Infant botulism — The ingestion of clostridial spores that
then colonize the host's gastrointestinal (GI) tract and
release toxin produced in vivo.
• Wound botulism — Infection of a wound by Clostridium
botulinum with subsequent in vivo production of neurotoxin
• Adult enteric infectious botulism or adult infectious botulism
of unknown source — Similar to infant botulism in that toxin
is produced in vivo in the GI tract of an infected adult host.
• Inhalational botulism
Botulism
• Patients with wound botulism typically have
a history of traumatic injury with wounds
that are contaminated with soil.
Pathophysiology
• The mechanism of action :
– By inhibiting acetylcholine release at the
presynaptic clefts.
– By binding acetylcholine itself.
DIAGNOSIS
• The most important issue in the diagnosis of
any of the four syndromes of botulism is the
initial consideration of the disease.
• A careful history and physical examination
are essential.
Clinical Manifestations
• Botulism is classically described as the acute
onset of
– Bilateral cranial neuropathies
+
– symmetric descending weakness
The CDC has also suggested that the following be
considered as key features of the botulism
syndrome:
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Absence of fever
Symmetric neurologic deficits
The patient remains responsive
Normal or slow heart rate and normal blood pressure
No sensory deficits with the exception of blurred vision
Nonspecific gastrointestinal symptoms also may be seen and
are occasionally the predominant manifestations.
Clinical Manifestations
• The onset of symptoms: 12 to 36 hours after toxin
ingestion.
• Prodromal symptoms often include:
– Nausea
– Vomiting
– Abdominal pain
– Diarrhea
– Dry mouth with sore throat
Clinical Manifestations
• Cranial nerve involvement most
commonly marks the onset of
symptomatic illness and can include:
• Blurred vision
– Secondary to fixed pupillary dilation and palsies of cranial nerves III, IV, and
VI
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Diplopia
Nystagmus
Ptosis
Dysphagia
Dysarthria
Facial weakness
Clinical Manifestations
• Descending muscle weakness usually
progresses to the trunk and upper
extremities, followed by the lower
extremities.
• Urinary retention and constipation are
common resulting from smooth muscle
paralysis.
• Occasionally paresthesias and asymmetric
limb weakness are seen.
Clinical Manifestations
• Respiratory difficulties (eg, dyspnea)
requiring intubation and mechanical
ventilation are common.
• CSF is Normal.
Differential Diagnosis
• NMJ Disorders
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Myasthenia Gravis
Lambert-eaton Myasthenic Syndrome (LEMS)
Tick Paralysis
Tetrodotoxin intoxication
Shellfish Poisoning
• Neuropathies
– Guillain-barré Syndrome
• Especially Miller Fisher Syndrome
• Anterior Horn Cell Disorders
– Poliomyelitis
• Stroke
• Heavy Metal Intoxication
R/O Other diagnoses
• Myasthenia gravis
– lacks autonomic symptoms: salivation and
erectile dysfunction, are common in LEMS
– Pupils spared in MG.
• Tensilon (edrophonium) tests to rule out
myasthenia gravis should not be conducted,
as they are often falsely positive in patients
with botulism.
R/O Other diagnoses
• Guillain-Barré syndrome
– Ascending paralysis,
– Sensory findings
– Elevated CSF protein
• WBCs counts, CSF studies, and ESRs are all
normal in patients with botulism.
R/O Other diagnoses
• Tic paralysis:
– A tick check should be performed as part of the
physical examination since the ticks transmitting
tick paralysis may still be attached when the
patient presents.
Diagnosis
• The most important issue in the diagnosis of
any of the four syndromes of botulism is the
initial consideration of the disease.
• A careful history and physical examination
are essential.
Paraclinical Diagnosis
• Patients presenting with clinical signs and
symptoms of food-borne botulism should
have serum analysis for toxin by bioassay in
mice.
• Demonstration of toxin in the blood is
diagnostic.
• Analysis of stool, vomitus, and suspected
food items may also reveal toxin, which is
diagnostic when coupled with the
appropriate clinical and neurologic findings.
Electrodiagnosis
• EMG studies may be useful in these patients
as well, but are not generally required.
Electrodiagnosis
• Patients with botulism may have mild nonspecific abnormalities on
electrocardiography.
• Results from nerve conduction studies are
normal.
• NCS: CMAP amplitude ↓
Electrodiagnosis
• EMG may be useful in
establishing a diagnosis of
botulism, but the findings can be
nonspecific and nondiagnostic,
even in severe cases.
Electrodiagnosis
• Characteristic findings in patients with
botulism include:
– Brief Low-voltage CMAPs
– Positive rapid RNS but not as high as LEMS.
• The increments are usually between 40% and 100%.
Electrodiagnosis
• The results of the edrophonium chloride, or
Tensilon, test for myasthenia gravis may be
falsely positive in patients with botulism.
• If positive, it is typically much less
dramatically positive than in patients with
myasthenia gravis.
Treatment
• Rigorous and supportive care is essential in
patients with botulism.
• Meticulous airway management
• Patients with symptoms of botulism or
known exposure should be hospitalized and
closely observed.
Treatment
• Spirometry, pulse oximetry, vital capacity,
and arterial blood gases should be evaluated
sequentially.
• Respiratory failure can occur with
unexpected rapidity.
• Stress ulcer prophylaxis is also a standard
component of intensive care management.
Treatment
• If an ileus is present, nasogastric suction and
intravenous hyperalimentation are very
helpful supportive measures.
• A Foley catheter is often used to treat
bladder incontinence.
• Deep venous thrombosis (DVT) prophylaxis is
also a standard component of intensive care
management.
Treatment
• Antibiotics are useful in wound botulism, but
they have no role in foodborne botulism.
Antitoxins
• Investigational antitoxin indicated for
naturally occurring noninfant botulism.
Equine-derived antitoxin that elicits passive
antibody (ie, immediate immunity) against
Clostridium botulinum toxins A, B, C, D, E, F,
and G.