NM junction disorders

Myasthenia Gravis
1. Pathogenesis
  1. Clear relationship with thymic pathologies, especially tumors or hypertrophy
    1. Possibly involved in cytokines mutations
      1. IRF8
        responsible for depletion of auto- reactive T-cells, therefore resulting in accumulation of such cells
      2. IL-10
        responsible for directly inhibiting Th1 function, resulting once more in excessive stimulation of T cells
  2. Some patients have anti-AchR antibodies, while 5-7% of cases have antibodies anti-MuSK
    1. responsible for modification and organization of the Ach-R
    2. Different types of MGs
      1. Ach-R antibodies, 35% prevalence, thymus hyperplasia and age of onset <45 years
      2. Ach-R antibodies, 10% prevalence, thymomas and age of onset is generally more advanced
      3. Anti-MuSK antibodies, 7%, normal thymus and any age of onset
  3. 3 different types of autoantibodies anti-AchR
    1. Activating the complement
      Annotations:
      - Most dramatic effect: capable of inducing the activation of the complement cascade at the level of the muscle membrane causing massive destruction of Ach-R
    2. Blockers
      1. simply bind to the Ach-binding site (alpha-subunit)
    3. Cross-linking
      Annotations:
      - bind to the Ach-binding site but they are capable of cross-linking with one another causing internalization of the entire membrane expressing with receptors
  4. There seems to be a strong association with HLA genes
    1. HLA-DRB1-3, HLA-DQA and HLA-DQB
2. Clinical presentation
  1. NO sensory abnormalities and the deep tendon reflexes are preserved
  2. Other clinical forms of myasthenia
    1. Seroegative Myasthenia
    2. Neonatal myasthenia
    3. Infant myasthenia gravis
      1. Important to make ddx with congenital myasthenia
      2. No treatment is necessary
    4. Familial myasthenia
  3. The real risk of generalized myasthenia is the involvement of respiratory muscles or bulbar involvement
  4. Ocular level in 50% of cases
  5. Oropharyngeal or facial muscles in 20% of cases
  6. Limb fatigability in 10% of cases
  7. No pain is felt
  8. Initial performance that is very close to normal, but there will be an immediate exhaustion of the movement
3. Myasthenic crisis
  1. Sudden
  2. Often triggered by an infection (50% from respiratory tract)
  3. Can also be casued by excess of treatment with AChEI (15% iatrogenic cause)
  4. 35% have no apparent casue
  5. Symptoms and signs
    1. Respiratory
    2. Anxiety
    3. Fever
    4. Hyperhydrosis
    5. Cardiocirculatory collapse
  6. Therapy
    1. Plasmapheresis (plasma exchange)
    2. ivIg
4. DDx
  1. Eaton-Lambert syndrome
  2. Oculopharyngeal dystrophy
  3. Kearns-Sayre Syndrome
  4. Guillan-Barrè
  5. Botulism
5. Favorable prognosis if
  1. Early diagnosis (<1y)
  2. Younger age of onset (<40y)
  3. Early remission
6. Therapy
  1. Thymectomy
    1. If a thymoma or an enlarged thymus is present, removal is mandatory
  2. Symptomatic
    1. Anticholinesterasic
      1. More effective at beginning
      2. Piridostigmine
      3. Pay attention to overdose
  3. Disease-modifying treatment
    1. Immunosuppressive
      1. Corticosteroids
        They can be used togheter with AChEI to provide a better balance
    2. Immunomodulatory
      1. Rituximab
    3. Other immunotherapies
7. Incidence: 3-4 cases/million/year
8. Evolution
  1. Majority of patients, 85%, will have an evolution of the disease to a generalized form of myasthenia gravis
  2. 15%, especially those with an initial ocular onset, will most probably remain stable with only the ocular symptomatology
Inflammatory myopathies
1. Causes
  1. Infective
    1. Viral
    2. Bacterial
    3. Parasitic
  2. Idiopathic
    1. Polymyositis
    2. Myasthenia gravis
    3. Granulomatous myositis
    4. Inclusion body myositis
2. Dermatomyositis
  1. Clinical frame
    1. Around 1/3 has an onset in the first decade and about 50% before 20 years of age
    2. Female predominance 3:1
    3. Acute onset and rapid progression
    4. Cutaneous manifestation
  2. Skin abnormalities
    1. Gottron's sign
    2. Gottron's papulae
    3. Heliotrope eythema
    4. Poikiloderma atrophicans vasculare
    5. Enter text here
  3. Pathological aspects
    1. Necrosis of capillaries
    2. Inflammatory infiltrates in septal, perivascular and perifascicular regions
    3. Perifascicular atrophy of myocytes
    4. Perivascular deposits of complement
    5. Presence in the infiltrates of B lymphocytes, dendritic cells, plasmacytoid
    6. Upregulation of chemokines and adhesion molecules
3. Polimyositis
  1. Pathological aspects
    1. Triad: inflammation,degeneration, necrosis
      1. Endomysial infiltrates of CD8 T lymphocytes clonally expanded forming a synapse with monocytes, plus a small B cell contribution
      2. Overexpression of adhesion molecules
      3. Inflammatory invasion of monocytes
      4. Cytokines production, IFNgamma, IL1beta, TNFalfa
      5. Antibodies against cytoplasmic ribonucleoproteins
      6. Necrotic or degenerating fibers are scattered
4. Diagnosis
  1. Serum enzymes (CPK, aldolase, GOT, GPT, LDH)
  2. Myoglobinuria (not frequent)
  3. Imaging (CT and MRI)
    1. Show damage but not pathogenesis
  4. Electromyography
    1. Insertion activity is increased
    2. Fibrillation potentials and positive sharp waves at rest
    3. Short, polyphasic MU potentials
    4. Very early interference pattern of reduced amplitude
  5. Muscular biopsy
    1. Only way to show the inflammatory pathogenesis
5. Therapy
  1. As in MG except for plasma exchange (abs in PM and DM play a very minor role)
    1. Steroids
    2. Immunosuppressants
    3. Iv immunoglobulins
    4. Total body irradiation
  2. For inclusion body myositis there is no effective treatment
6. Inclusion body myositis
  1. The most frequent inflammatory myopathy in old patients
  2. Male predominance
  3. Primary pathogenesis unknown
  4. Peculiar aspects
    1. Subsarcolemmal or central vacuoles
    2. Amyloid deposits
  5. Clinical aspects
    1. Insidious onset at any age, but more frequent after 50 y old
    2. Asymmetric hyposthenia, more often distal
    3. Wrist flexors and extensors of fingers, leg and foot electively affected
    4. Slow evolution, severe disability after 50 y.o.
    5. Resistance to treatment: no real treatment exists
  6. Treatment (future perspectives)
    1. Alemtuzumab
      1. MAB against CD52
Eaton Lambert's myasthenic syndrome
1. Therapy
  1. Guanidine
  2. Diaminopyridine
  3. Plasmapheresis-IVIg
2. Only 1 case every 100 cases of myasthenia gravis
3. Weakness is mostly proximal
4. Caused by IgG antibodies against presynaptic calcium channels
  1. Differently from MG, this is a presynaptic disease (post-synaptic receptors are perfectly functional)
  2. Decreased calcium input
  3. Decreased Ach release
  4. In 70% of cases these auto-Abs are casued by cancer (most fequently small call lung carcinoma)
5. It could be the first sign of a tumor
6. The pattern at EMG is the exact opposite of that seen for MG
  1. The 1st AP in MG is normal while it is reduced in ELS
The Acetylcholine-Receptor is a transmembrane channel composed of 5 subunits
1. The subunits responsible for binding Ach are the α subunits
2. To detect the NMJ one can perform staining with α-bungarotoxin

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NM junction disorders

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	Created by LewisLewis over 10 years ago