Myasthenia Gravis - Pathophysiology, Cl. Features, DD

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  • Onset from mild to maximal weakness is less than 36 months in 83% of patients

Transcript

  • 1. PATHOPHYSIOLOGY CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSES Myasthenia gravis Dr JISHANTH M Prof Dr A Gowrishankar’s Unit Dept. of Internal Medicine
  • 2. INTRODUCTION
    • The most significant development:
    • The demonstration of An Immunologic Mechanism operative at the neuromuscular junction
    • Result is a failure of effective neuromuscular transmission on the postsynaptic side
  • 3. THE NEUROMUSCULAR JUNCTION
  • 4. PATHOPHYSIOLOGY
    • Antibodies to AChR protein :
    • 85 % of patients with generalized myasthenia and 60% of those with ocular myasthenia shows AChR Antibodies
    • Anti-MuSK Ab (40% of seronegative cases)
    • An immune response to muscle-specific kinase (MuSK) can also result in myasthenia gravis, possibly by interfering with “ AChR clustering”
    • How do these antibodies act?
    • Blocks the binding of ACh to the AChR.
    • INCREASES THE DEGRADATION rate of AChR ANTIBODIES-> CROSS LINKING OF RECEPTORS -> ->CLUSTERING -> ENDOCYTOEIS -> DEGRADATION
    • A complement-mediated destruction of the postsynaptic folds.
    • The latter two mechanisms would be expected to reduce the number of AChR at the synapse.
  • 5.  
  • 6. Myasthenia Gravis
        • AChRs
    Antibodies Simplified Motor Endplates
  • 7. PATHOLOGY
    • The muscle fibers are generally intact
    • In fatal cases with extensive paralysis,
    • “ Segmental necrosis with variable regeneration”
    • Scattered aggregates of lymphocytes, “Lymphorrhages” especially associated with thymomas
    • MOTOR END PLATE:
    • a reduction in the area of the nerve terminal,
    • a simplification of the postsynaptic region (sparse, shallow, abnormally wide or absent secondary synaptic clefts)
    • a widening of the primary synaptic cleft
    • PRESYNAPTIC VESICLES AND NERVE TERMINALS ARE NORMAL
  • 8. THYMIC AND OTHER ASSOCIATED DISORDERS
    • Thymus is abnormal in ~75% of patients with MG
    • In ~65% the thymus is " hyperplastic ,"
      • (a nonneoplastic lymphofollicular hyperplasia of the thymic medulla) with the presence of active germinal centers detected histologically
    • 10% of patients have thymic tumors (“ neoplastic” )
    • Thymomas with malignant characteristics may spread locally
    • Upon distant spread, the lungs and liver are usually affected.
    • Muscle-like cells within the thymus (myoid cells) which bear AChRs on their surface may trigger immune response
  • 9. Pathologic Features of the Thymus
    • Hyperplasia of the medulla characterized by lymphoid follicles with active germinal centers. The cells in the centers of the follicles are histiocytes;
    • Immunoglobulin G (IgG) is elaborated in the germinal follicles.
    • These resemble the cellular reaction that is observed in the thyroid of Hashimoto thyroiditis .
    • THYMOMAS
    • Two forms have been described:
    • Composed of histiocytic cells like the reticulum cells in the center of the follicles
    • Predominantly lymphocytic and considered to be lymphosarcomatous
  • 10.
    • The immune effector cells in myasthenia gravis are both T and B cells.
    • Sensitized T cells and complement play a role in continued stimulation of B cells and in cell mediated post synaptic destruction
  • 11. CLINICAL FEATURES
    • Prevalence: 1-7 in 10,000
    • Affect all age groups
    • Usual age at onset: BIMODAL PEAK
    • 20-30 yrs(young women), 50-60 yrs(older men)
    • < 10% occur in children <10 yrs
    • When <40 yrs f:m = 2-3:1, males more affected in elderly(3:2)
    • Overall F:M = 3:2
    • Familial occurrence is known, but rare
    • More common is a family history of one or the other autoimmune diseases , and suggests partial genetic predisposition
    • Reports of the concurrence of myasthenia and MULTIPLE SCLEROSIS
  • 12. CLINICAL PRESENTATION
    • Repeated or persistent activity of a muscle group exhausts its contractile power( fatigability ), leading to a progressive paresis, and rest partially restores strength
    • There is special vulnerability of certain muscles
      • ( the eyelids and the muscles of the eyes, face, jaws, throat, and neck, are the first to be affected )
    • Limb muscle weakness as the initial complaint is less frequent.
  • 13. CLINICAL PRESENTATION
    • Fluctuating weakness increased by exertion
      • Weakness increases during the day and improves with rest
    • Levator palpebrae &Extraocular muscle weakness
      • Ptosis/diplopia is presenting symptom in 50% of patients and ↑ during the course of disease in 90%
      • If associated with weakness of closure—almost diagnostic if “PUPILS ARE SPARED”
    • Head extension and flexion weakness
      • More sensitive in demonstrating generalised disease
  • 14. OSSERMAN Classification
    • Class I Any ocular muscle weakness
    • ClassII Mild weakness other than ocular
      • IIa Predominantly limb,axial, or both
      • IIb Predominantly orpharyngeal/respiratory
    • Class III Moderate weakness other than ocular
      • IIIa Predominantly limb,axial, or both
      • IIIb Predominantly orpharyngeal/respiratory
    • Class IV Severe weakness other than ocular
      • IVa Predominantly limb,axial, or both
      • IVb Predominantly orpharyngeal/respiratory
    • Class V Intubation with/without ventilation
  • 15. PROGRESSION OF DISEASE
    • Mild to severe…..over weeks to months
      • Spreads from ocular to facial to bulbar to truncal and limb muscles
      • Symptoms may remain limited to EOM and eyelid muscles for yrs
      • The disease remains ocular in 16% of patients
  • 16. REMISSIONS
      • Spontaneous remissions rare, most remissions with treatment occur within the first three years
      • If remission lasts >1 yr and recurs disease tend to be progressive.
      • Isolated ocular myasthenia > 1 yr, subsequent generalisation is only 16%
      • The course is altered by thymectomy (even drug free remissions)
  • 17. BASIC PHYSICAL EXAMINATION
      • Sensory examination and DTR’s are normal
      • Muscle strength testing
      • Recognize patients who may develop respiratory failure (i.e. difficult breathing)
  • 18. CLINICAL PRESENTATION
    • MUSCLE STRENGTH
      • Ocular muscle weakness
      • Facial muscle weakness
      • Bulbar muscle weakness
      • Limb muscle weakness
      • Respiratory weakness
    Bulbar Muscles
  • 19. 1. OCULAR MUSCLE WEAKNESS
      • ASYMMETRIC
      • Usually affects more than one extraocular muscle and is not limited to muscles innervated by one cranial nerve
      • Weakness of lateral and medial recti may produce a pseudo internuclear opthalmoplegia
      • Ptosis is caused by Levator palpebrae weakness
      • “ Sustained upward gaze for 30 seconds”
      • Diplopia is very common
      • “ Lid-twitch” sign , Repeated ocular versions
      • Bright sunlight aggravate the ocular signs and COLD improves them
  • 20. 2. FACIAL MUSCLE WEAKNESS
    • Facial muscle weakness is almost always present
      • bilateral facial muscle weakness
      • Sclera below limbus may be exposed due to weak lower lids
      • Muscles of facial expression
  • 21. 3. BULBAR MUSCLE WEAKNESS
    • Bulbar muscle weakness ( more in Anti MuSK Ab positive cases)
      • Palatal muscles
        • “ Nasal voice”, nasal regurgitation
        • Chewing may become difficult
        • Severe jaw weakness may cause jaw to hang open
        • Swallowing may be difficult and aspiration may occur with fluids—coughing and choking while drinking
      • Neck muscles
        • Neck flexors affected more than extensors
  • 22. 4. LIMB MUSCLE WEAKNESS
      • Upper limbs more common than lower limbs
      • Proximal > than distal muscles
      • Usually asymmetric weakness
    Upper Extremities Deltoids Wrist extensors Finger extensors Triceps > Biceps Lower Extremities Hip flexors (most common) Quadriceps Hamstrings Foot dorsiflexors Plantar flexors
  • 23. 5. RESPIRATORY MUSCLE WEAKNESS
      • Weakness of the intercostal muscles and the diaphragm may result in CO2 retention due to hypoventilation
        • May cause a neuromuscular emergency
      • Weakness of pharyngeal muscles may collapse the upper airway
      • Monitor negative inspiratory force, vital capacity and tidal volume
      • Do NOT rely on pulse oximetry
        • Arterial blood oxygenation may be normal while CO2 is retained
  • 24.
    • As the disease progresses it can involve the external sphincters of bowel and bladder.
    • A temporary increase in weakness may follow vaccination, menstruation and exposure to extremes of temperature
    • Weakened muscles “ NEVER GO FOR ATROPHY”
    • Tendon reflexes are retained till late
    • Smooth and cardiac muscles are not involved
    • Tongue may display a central and 2 lateral longitudinal furrows “trident tongue”
    • Symptoms may appear first during pregnancy, puerperium or in response to drugs used during anesthesia.
    • Transient NEONATAL MYASTHENIA
  • 25. CO-EXISTING AUTOIMMUNE DISEASES
      • Hashimoto’s thyroiditis/thyrotoxicosis
        • Occurs in 5-10%% MG patients
        • Weakness may not improve with treatment of MG alone in patients with co-existing hyperthyroidism
      • Rheumatoid arthritis
      • Scleroderma
      • Lupus erythematosus,
      • Sj ӧ gren syndrome,
      • mixed connective tissue disease
      • anticardiolipin antibody
      • polymyositis
  • 26. MYASTHENIC CRISIS
    • A rapid and severe deterioration of myasthenia called “myasthenic crisis” can bring patient to the brink of respiratory failure and quadriparesis in hours
    • A respiratory infection or a sedative medication with NM block may be the reason
    • It can develop at any time after the diagnosis of myasthenia
    • Anticipate if patient is restless, anxious with diaphoresis and develops tremor.
    • Require respiratory support
  • 27. NEUROLOGIC CONDITIONS MIMICKING MYASTHENIA GRAVIS
    • CONDITION SIGNS AND SYMPTOMS
    • ALS Asymmetric muscle weakness and atrophy
    • Botulism Generalized limb weakness
    • Guillain-Barré syndrome Ascending limb weakness
    • Inflamm. muscle disorders Proximal symmetric limb weakness
    • Lambert-Eaton syndrome Proximal symmetric limb weakness
    • Multiple sclerosis Bilateral internuclear ophthalmoplegia
    • Periodic paralysis Intermittent generalized muscle weakness
    • Thyroid disease
    • Congenital myasthenic syndromes
    • Brainstem syndromes/encephalitis
  • 28. LAMBERT-EATON SYNDROME
    • Presynaptic disorder of NMJ
    • Antibodies against P/Q type calcium channels at the motor nerve terminals ( +ve in 85% )
    • Impaired release of Ach from nerve terminals
    • Muscle weakness similar t MG ( proximal>distal, CN involvement >70%)
    • “ Warming up ” phenomenon
        • Depressed/absent reflexes
        • Autonomic changes
        • Incremental response to RNS
    • Associated with Ca Lung(small cell Ca).. “paraneoplastic”
    • Treatment: Immunosuppression; plasmapheresis; 3,4-DAP; pyridostigmine
  • 29. DRUGS PRECIPITATING MYASTHENIA
    • Anti-infective Agents Cardiovascular Agents Other Agents
    • Aminoglycosides Propranolol Chloroquine
    • Ampicillin Verapamil Corticosteroids
    • Ciprofloxacin Quinidine “d-penicillamine”
    • Erythromycin Procainamide Phenytoin  
    • Imipenem Propafenone Mydriatics
    • Kanamycin Acebutolol Trihexyphenidyl
    • Pyrantel Practolol Interferon
    • Timolol Trimethadione
    • Oxyprenolol
  • 30.  
  • 31.  
  • 32.  
  • 33.  
  • 34. Prognosis
    • Long-term outlook better for children than adults
    • Life expectancy slightly reduced
    • Most favorable outcome for bulbar weakness
    • Drug free remissions possible with thymectomy
    • Death rate reduced from 30% to <5% with pharmacotherapy and surgery
  • 35. Differential diagnoses
    • Lambert-Eaton Myasthenic Syndrome
    • Oaculopharyngeal muscular dystrophy
    • Multiple Sclerosis
    • Botulism
    • Brainstem syndromes
    • Brainstem gliomas
    • Thyroid disease
    • Sarcoidosis and Neuropathy
    • Amyotropic Lateral Sclerosis
    • Basilar Artery Thrombosis
    • Cavernous sinus syndromes
    • Dermatomyositis
    • Congenital myasthenic syndromes
    • Drugs/Antibiotics