Presynaptic Neuromuscular Junction Disorders

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Presynaptic Neuromuscular Junction Disorders

• Farzad Fatehi,
• Neurologist,
• Shariati Hospital,
• Tehran University of Medical Sciences

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Lambert Eaton Myasthenic Syndrome
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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.

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Neuromuscular Junction
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Normal NMJ
Ca
NMJ
Ach
Ca
Ach
Ach
Ca
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m n X p m number of quanta released p
probability of release n the number of quanta in
axon
Ca
NMJ
Ach
Ca
Ach
Ach
In LEMS p?
Ca
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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 -- gt loss of
  functional VGCCs at the motor nerve terminals

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LEMS
Ca
Anti VGCC
NMJ
Ach
Anti VGCC
Ca
Ach
Anti VGCC
Ach
Anti VGCC
Ca
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Pathophysiology

• ALSO,
• Parasympathetic
• Sympathetic
• Enteric neurons
• are all affected.

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• 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.

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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.
• MF11

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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.

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Epidemiology

• The overwhelming majority of cancers associated
  with LEMS are SCLC.
• However, many different malignancies may be
  involved.
• A partial list includes
• 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.

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History

• The initial presentation can be similar to that
  of myasthenia gravis (MG), but the progressions
  of the 2 diseases have some important differences.

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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.

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History

• Proximal muscles gt Distal muscle
• Lower extremity gt Upper extremity
• Patients typically have difficulty rising from a
  chair, climbing stairs, and walking simulating
  myopathies.

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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.

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History

• Respiratory muscles are not usually affected. If
  occurred
• Not as severe as MG.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Physical Examination

• An increase in DTRs after contraction is a
  hallmark of LEMS.

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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

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Prognosis

• SCLC - LEMS ? Better prognosis than SCLC LEMS
• Due to
• Earlier detection of underlying cancer
• Better response to immunotherapy

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Paraclinics

• Electrodiagnostic tests
• Antibody assays

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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.

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EDx

• CMAPs are usually small
• Often less than 10 of normal
• Fall during 1- to 5-hz RNS (Slow RNS)

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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.

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3 HZ RNS
3 HZ RNS after 10 sec activation
30 HZ RNS
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• A similar increase in CMAP size is seen
  immediately after the patient voluntarily
  contracts the muscle maximally for several
  seconds.

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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.

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Rapid RNS

• Facilitation gt 100 in most muscles tested or gt
  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.

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Electromyography

• Needle electromyography
• Conventional needle EMG in LEMS demonstrates
  markedly unstable motor unit action potentials,
  which vary in shape during voluntary activation.

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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

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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.

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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

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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

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• Treatment Approach

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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.

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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)

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DAP
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Guanidine hydrochloride
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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.

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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.

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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.

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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 Jun20(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 Jun180(2)569-71. Epub 2008 Nov 13.

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Botulism
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Botulism Sausage disease

• Botulism (Latin, botulus, "sausage)

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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

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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.

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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

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Botulism

• Patients with wound botulism typically have a
  history of traumatic injury with wounds that are
  contaminated with soil.

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Pathophysiology

• The mechanism of action
• By inhibiting acetylcholine release at the
  presynaptic clefts.
• By binding acetylcholine itself.

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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.

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Clinical Manifestations

•  Botulism is classically described as the acute
  onset of
• Bilateral cranial neuropathies
• symmetric descending weakness

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The CDC has also suggested that the following be
considered as key features of the botulism
syndrome

• 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.

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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

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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
• Diplopia
• Nystagmus
• Ptosis
• Dysphagia
• Dysarthria
• Facial weakness

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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.

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Clinical Manifestations

• Respiratory difficulties (eg, dyspnea) requiring
  intubation and mechanical ventilation are common.
• CSF is Normal.

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Differential Diagnosis

• NMJ Disorders
• 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

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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.

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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.

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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.

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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.

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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.

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Electrodiagnosis

• EMG studies may be useful in these patients as
  well, but are not generally required.

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Electrodiagnosis

• Patients with botulism may have mild non-specific
  abnormalities on electrocardiography.
• Results from nerve conduction studies are normal.
• NCS CMAP amplitude ?

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Electrodiagnosis

• EMG may be useful in establishing a diagnosis of
  botulism, but the findings can be nonspecific and
  nondiagnostic, even in severe cases.

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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.

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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.

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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.

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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.

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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.

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Treatment

• Antibiotics are useful in wound botulism, but
  they have no role in foodborne botulism.

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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.

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