Myasthenia gravis: Difference between revisions
 
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==Background==
==Background==
===Pathophys===
*Autoantibody degradation, dysfunction, and blockade of acetylcholine receptor at the NMJ
thymus abnl in most - thymoma, thymitis, B cells sensitized to Ach receptors here.
*Thymus is abnormal in 75% of patients
**Thymectomy resolves or improves symptoms in most patients, especially those with a thymoma
*No sensory, reflex, pupillary, or cerebellar deficits


===Epi===
===Drugs Associated with Exacerbations===
# mostly women in 20s
====May Unmask or Worsen<ref>https://neurology.uams.edu/wp-content/uploads/sites/49/2018/03/Drugs-that-may-worsen-Myasthenia-Gravis.pdf</ref>====
# peak incid in men is 60-70s
*Antimicrobials ([[Aminoglycosides]], [[clindamycin]], [[erythromycin]], [[tetracycline]], [[doxycycline]], [[azithromycin]], [[fluoroquinolones]], [[vancomycin]], [[chloroquine]], [[hydroxychloroquine]], )<ref> UpToDate Clinical manifestations of myasthenia gravis may 2016</ref>
*Cardiovascular drugs ([[beta blockers]], [[procainamide]], [[quinidine]])
*Neuro/psych meds ([[chlorpromazine]], [[lithium]], [[prochlorperazine]], [[phenytoin]], [[risperidone]],
*Other (Botox, [[quinine]]s, [[magnesium]])
====Usually Well-tolerated, but Occasionally Associated====
*Local anesthetics
*Antibiotics ([[Tetracycline]]/[[doxycycline]], [[macrolides]], [[metronidazole]], [[nitrofurantoin]])
*Anticonvulsants ([[carbamazepine]], [[ethosuximide]], [[gabapentin]], [[phenobarbital]], [[phenytoin]])
*Butyrophenones ([[haloperidol]])
*Phenothiazines ([[chlorpromazine]]/[[prochlorperazine]])
*[[Calcium channel blockers]]
*[[Steroids]]
*Ophthalmic drugs (betaxolol/timolol/proparacaine)
*Other (Iodinated contrast agent)


==DDX==
==Clinical Features==
# Toxin Induced
[[File:DiplopiaMG1.jpg|thumb|Cranial nerve palsy and ptosis in a patient with myasthenia gravis]]
## Botulism
*Muscle [[weakness]]
## Tick Paralysis
**Proximal extremities
## Envenomation (coral snake, black widow spider), paralytic shellfish
**Neck extensors
# Autoimmune - Eaton Lambert
**Facial/bulbar muscles ([[dysphagia]], [[dysarthria]], [[dysphonia]])
# Drug-Induced - aminogly, dilantin, procainamide, chloroquine
*Ocular weakness
# Poisoning - Organophosphates, Carbamates
**Ptosis
# Miller Fisher Variant Guillen Barre
**[[Diplopia]]
# Causes of oculomotor palsy - DM, MS, aneurysm
**[[cranial nerve palsies|CN III, IV, or VI weakness]]
*Symptoms worsen with repetitive use / as the day progresses<ref>Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 7e (2010), Chapter 167. Chronic Neurologic Disorders</ref>


===Botulism===
==Differential Diagnosis==
# toxin binds to presyn prevents AcH release. Wound may be benign in appearance
{{Weakness DDX}}
#GI source - neuro sxs w/in 72 hrs of ingestion usually. Aticholinergic effects include dry mouth, mydriasis, ileus, urine retention then fluctuating but rapidly progressive weakness
#send cx blood, food, stool or wound
# only 33% of food borne source have positive blood cx
# may actually see pos Tensilon test in botulism.
#Wound Botulism - high dose PCN & debridement.


===Eaton Lambert===
==Evaluation==
#rare, defect in release of AcH from presynapse
[[File:Myasthenia gravis ptosis reversal.jpg|thumb|Right partial ptosis (left picture) with left lid showing compensatory pseudo lid retraction because of equal innervation of the levator palpabrae superioris (Hering's law of equal innervation): Right picture: after an edrophonium test, note the improvement in ptosis.]]
#Usually paraneoplastic (part. small cell Ca of lung)
[[File:Tumor Thymoma1.jpg|thumb|A chest CT-scan showing a thymoma (red circle).]]
# Clinically proximal weakness of limb muscles, hyporeflexia, dry mouth, impotence.
===Workup===
# Extraocular & facial muscles usually spared.
====ED Workup====
Always evaluate:<ref>Emergency Medicine Practice -- Weakness: A systemic approach to acute non-traumatic neurologic and neuromuscular causes Dec 2002</ref>
*Tidal volume
*Forced Vital capacity (normal is >25cc/kg in MG)
*FEV
*Negative inspiratory force (NIF) (normal is -80 to -100; respiratory support is indicated for -20 to 0)
*Ability to handle secretions


===Tick Paralysis===
====Neuro Workup====
#acsending flaccid paralysis caused by neurotoxin block acH release
The following may be considered for neurologic workup, but are not typically indicated in the ED:<ref>Myasthenia gravis: Association of British Neurologists’ management guidelines [https://pn.bmj.com/content/15/3/199]</ref>
# late spring, summer in Rockies & NW
*ACh-R antibody testing: first-line investigation. Indication for thymectomy if < 45 years.
# female wood tick or common dog tick
**MuSK antibody testing: for patients negative for ACh-R antibodies
# paralysis progresses over 1-2 days to involve bulbar, extraocular muscles.
*Thyroid function
# Resp paralysis can follow
*Neurophysiology: Repetitive nerve stimulation is the initial test; if negative, consider single-fibre electromyography.
# Ataxia may be early finding
*MR scan of brain: Patients with negative serology and neurophysiology, and symptoms compatible with ocular myasthenia may have structural brain disease.
# normal sens exam usually
*Thymus scanning: All patients with suspected myasthenia, irrespective of distribution (ocular/generalised) or serology (seropositive/negative), should undergo thymus imaging. The modality (CT or MRI) should be decided locally.
# DTRs decreased markedly as in GB
*Edrophonium/Tensilon test
# fatal in 10% if tick not removed
# CHECK for ticks in someone you think has Guillen Barre


==Diagnosis==
{{Myasthenic vs cholinergic crisis}}
===History===
# pts report worse sxs as day progresses.
# insidious onset, can develop over wks to months.
# precipitated by stress, preg, infec


===Symptoms===
===Diagnosis===
# diplopia, ptosis (later in day)
*Prolonged upward gaze test<ref>Ptosis in myasthenia gravis: Extended fatigue and recovery bedside test. Klaus V. Toyka. Neurology Oct 2006, 67 (8) 1524.</ref>
# weakness in eye closure, swallowing muscles of facial expression, difficulty chewing, dysarthria, dysphagia.
**Have the patient gaze upward at examiner's finger for 30 seconds
**Diplopia or ptosis that develops is suggestive of MG
*Ice Pack Test - should improve symptoms temporarily (usually ptosis; high specificity)
**Place ice-pack on eyes for 2 mins, if ptosis decreases by ≥2mm the test is positive
*Acetylcholine receptor antibodies (AcHR-Ab). Positive in 80-90% of generalized MG and 40-55% in Ocular MG.


===Physical Exam===
==Management==
# Provocative tests - ptosis with prolonged upward gaze, hold arms up, clench tongue blade, dysarthria w/ loud counting
;Avoid medications that can cause/worsen exacerbations (see Background), including [[magnesium]] (which can cause [[respiratory failure]])
# sensation, reflexes usually normal
===Myasthenic Crisis===
# always eval tidal volume, FEV & ability to handle secretions
*Acetylcholinesterase inhibitors are discontinued to avoid excessive bronchial secretions
*[[Intubation]] (if needed)
**If possible avoid depolarizing AND non-depolarizing agents
**If patient requires paralysis use non-depolarizing agent at smaller dose
**If must use depolarizing agents, will need higher doses
*[[IVIG]]
**0.4 g/kg/day for 5 days
**Effect lasts 30-45 days
*[[Plasmapheresis]]
**Effect lasts 15-20 days


===Testing===
===Other Medications===
# Always test FEV, consider ABG, Look for infections (resp) or meds, electrolyte problems that may have induced problem.
''[[Pyridostigmine]] and [[neostigmine]] primarily used for symptomatic relief but does not alter course of crisis<ref>Wendell LC and Levine JM. Myasthenic Crisis. Neurohospitalist. 2011 Jan; 1(1): 16–22.</ref>. Consider avoiding in ICU ventilated patients, as these may increase secretions. Continued use of these meds also prevents assessment of other treatment modalities and can increase muscle weakness if used in excess''
# Edrophonium - use caution in trying to test for crisis vs. cholinergic crisis
*[[Pyridostigmine]]: Titrate up to find the lowest effective dose
# Ach receptor antibodies - found 90%
**Initially 30 mg four times daily for 2–4 days
# CT of thymus, TFTs, search for other immun dz
**Then 60 mg (1 tablet) four times daily for 5 days and experiment with timing
**Then increase to 90 mg four times daily over 1 week if required.
**If patient's usual dose has been missed the next dose is usually doubled
**IV route: 1/30th of the PO dose (2-3mg) by slow IV infusion
*[[Neostigmine]]
**0.5mg IV
*[[Prednisolone]]: If symptomatic despite Pyridostigmine. Monitor diabetes mellitus.
**Ocular myasthenia gravis
***Start 5 mg on alternate days for three doses and increase by 5 mg every three doses until symptoms improve.
***The maximum dose is 50 mg on alternate days or 0.75 mg/kg/alternate day
**Generalized myasthenia gravis
***Start 10 mg on alternate days for three doses and increase by 10 mg every three doses until symptoms improve.
***Maximum dose is 100 mg alternate days or 1.5 mg/kg


==Treatment==
==Disposition==
# Plasmapherisis or plasma exchenge in acute setting
*Typically MICU or neuro ICU, consideration for thymectomy if not done already
# Anticholinesterase agent such as Pyridostigmine 60 mg tid
*Consideration for [[corticosteroids]] or other immunosuppressants (i.e. corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine)
# Corticosteroids produce good results in >80% but are reserved for those who don't respond to anti-cholinesterases and thymectomy due to adverse effects. Decreases levels of antiAch receptor Ab. Also may initially aggravate muscle weakness so usually begun in hosp & at low doses


#don't treat Myasthenic with meds that may exacerbate weakness
==See Also==
# search for source of infection or electrolyte problem w/ weakness
*[[Weakness]]


===Myasthenic Crisis vs. Cholinergic===
==References==
# Cholinergic - usually present w/ signs of cholinergic overactivity (miosis, sweats, salivation, GI distress-musc) & cramps, fasciculations (nicotinic)
<references/>
# Myasthenic - more common, caused by noncompliance, drug interaction, infection, stress
## aminoglycosides, flouroquinolones, clinda, sulfas, erythro, ampicillin, Dilantin, phenobarb, B blockers, Ca channel Blk, procainamide, steroids, lithium, phenothiazines, MSO4, benzos, antihistamines


VERY DANGEROUS & UNRELIABLE to use Tensilon Test to distinguish between the two.


==Source==
[[Category:Neurology]]
Harwood Nuss p.1002
 
[[Category:Neuro]]

Latest revision as of 17:37, 17 April 2024

Background

  • Autoantibody degradation, dysfunction, and blockade of acetylcholine receptor at the NMJ
  • Thymus is abnormal in 75% of patients
    • Thymectomy resolves or improves symptoms in most patients, especially those with a thymoma
  • No sensory, reflex, pupillary, or cerebellar deficits

Drugs Associated with Exacerbations

May Unmask or Worsen[1]

Usually Well-tolerated, but Occasionally Associated

Clinical Features

Cranial nerve palsy and ptosis in a patient with myasthenia gravis

Differential Diagnosis

Weakness

Evaluation

Right partial ptosis (left picture) with left lid showing compensatory pseudo lid retraction because of equal innervation of the levator palpabrae superioris (Hering's law of equal innervation): Right picture: after an edrophonium test, note the improvement in ptosis.
A chest CT-scan showing a thymoma (red circle).

Workup

ED Workup

Always evaluate:[4]

  • Tidal volume
  • Forced Vital capacity (normal is >25cc/kg in MG)
  • FEV
  • Negative inspiratory force (NIF) (normal is -80 to -100; respiratory support is indicated for -20 to 0)
  • Ability to handle secretions

Neuro Workup

The following may be considered for neurologic workup, but are not typically indicated in the ED:[5]

  • ACh-R antibody testing: first-line investigation. Indication for thymectomy if < 45 years.
    • MuSK antibody testing: for patients negative for ACh-R antibodies
  • Thyroid function
  • Neurophysiology: Repetitive nerve stimulation is the initial test; if negative, consider single-fibre electromyography.
  • MR scan of brain: Patients with negative serology and neurophysiology, and symptoms compatible with ocular myasthenia may have structural brain disease.
  • Thymus scanning: All patients with suspected myasthenia, irrespective of distribution (ocular/generalised) or serology (seropositive/negative), should undergo thymus imaging. The modality (CT or MRI) should be decided locally.
  • Edrophonium/Tensilon test

Myasthenic versus cholinergic crisis

Flaccid paralysis resulting from cholinergic crisis can be distinguished from myasthenia gravis by the use of the drug edrophonium, which worsens the paralysis caused by cholinergic crisis, but strengthens the muscle in the case of myasthenia gravis. (Edrophonium is an cholinesterase inhibitor hence increases the concentration of acetylcholine present).

  • Myasthenic Crisis
    • Respiratory failure is feared complication
    • Much more common
    • Due to medication non-adherence, infection, surgery, tapering of immunosuppressants, meds
  • Cholinergic Crisis
    • Excessive anticholinesterase medication may cause weakness and cholinergic symptoms
    • Rarely if ever seen with dose limitation of pyridostigmine to less than 120mg q3hr
    • If on usual dose of meds assume exacerbation due to MG even with cholinergic side effects
  • Edrophonium (Tensilon) test to distinguish the two is controversial
    • Give 1-2mg IV slow push. If any fasciculations, respiratory depression, or cholinergic symptoms within a few minutes, problem is likely cholinergic crisis (no more edrophonium). If no evidence of cholinergic excess, give total of 10mg and observe improvement in case of myasthenic crisis.
    • Side effects of Edrophonium: Arrhythmias, Hypotension, Bronchospasm
    • Thus, need to be on a monitor, with atropine on hand
    • Treatment: Atropine

Diagnosis

  • Prolonged upward gaze test[6]
    • Have the patient gaze upward at examiner's finger for 30 seconds
    • Diplopia or ptosis that develops is suggestive of MG
  • Ice Pack Test - should improve symptoms temporarily (usually ptosis; high specificity)
    • Place ice-pack on eyes for 2 mins, if ptosis decreases by ≥2mm the test is positive
  • Acetylcholine receptor antibodies (AcHR-Ab). Positive in 80-90% of generalized MG and 40-55% in Ocular MG.

Management

Avoid medications that can cause/worsen exacerbations (see Background), including magnesium (which can cause respiratory failure)

Myasthenic Crisis

  • Acetylcholinesterase inhibitors are discontinued to avoid excessive bronchial secretions
  • Intubation (if needed)
    • If possible avoid depolarizing AND non-depolarizing agents
    • If patient requires paralysis use non-depolarizing agent at smaller dose
    • If must use depolarizing agents, will need higher doses
  • IVIG
    • 0.4 g/kg/day for 5 days
    • Effect lasts 30-45 days
  • Plasmapheresis
    • Effect lasts 15-20 days

Other Medications

Pyridostigmine and neostigmine primarily used for symptomatic relief but does not alter course of crisis[7]. Consider avoiding in ICU ventilated patients, as these may increase secretions. Continued use of these meds also prevents assessment of other treatment modalities and can increase muscle weakness if used in excess

  • Pyridostigmine: Titrate up to find the lowest effective dose
    • Initially 30 mg four times daily for 2–4 days
    • Then 60 mg (1 tablet) four times daily for 5 days and experiment with timing
    • Then increase to 90 mg four times daily over 1 week if required.
    • If patient's usual dose has been missed the next dose is usually doubled
    • IV route: 1/30th of the PO dose (2-3mg) by slow IV infusion
  • Neostigmine
    • 0.5mg IV
  • Prednisolone: If symptomatic despite Pyridostigmine. Monitor diabetes mellitus.
    • Ocular myasthenia gravis
      • Start 5 mg on alternate days for three doses and increase by 5 mg every three doses until symptoms improve.
      • The maximum dose is 50 mg on alternate days or 0.75 mg/kg/alternate day
    • Generalized myasthenia gravis
      • Start 10 mg on alternate days for three doses and increase by 10 mg every three doses until symptoms improve.
      • Maximum dose is 100 mg alternate days or 1.5 mg/kg

Disposition

  • Typically MICU or neuro ICU, consideration for thymectomy if not done already
  • Consideration for corticosteroids or other immunosuppressants (i.e. corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine)

See Also

References

  1. ↑ https://neurology.uams.edu/wp-content/uploads/sites/49/2018/03/Drugs-that-may-worsen-Myasthenia-Gravis.pdf
  2. ↑ UpToDate Clinical manifestations of myasthenia gravis may 2016
  3. ↑ Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 7e (2010), Chapter 167. Chronic Neurologic Disorders
  4. ↑ Emergency Medicine Practice -- Weakness: A systemic approach to acute non-traumatic neurologic and neuromuscular causes Dec 2002
  5. ↑ Myasthenia gravis: Association of British Neurologists’ management guidelines [1]
  6. ↑ Ptosis in myasthenia gravis: Extended fatigue and recovery bedside test. Klaus V. Toyka. Neurology Oct 2006, 67 (8) 1524.
  7. ↑ Wendell LC and Levine JM. Myasthenic Crisis. Neurohospitalist. 2011 Jan; 1(1): 16–22.
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