Drug-induced MG

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MYASTHENIC SYNDROMES: VARIANTS

MYASTHENIC SYNDROMES: DRUG-INDUCED

CLINICAL PATTERNS

Rapid Onset

Development of prominent myasthenic signs within days
Anti-AChR antibodies absent
Rapid disappearance after drug withdrawal
Probably related to unmasking of pre-existing disorder of neuromuscular transmission

Exacerbation of Myasthenia Gravis

Develops after days to weeks
Clinical patterns
- Subclinical myasthenia gravis becomes manifest after drug treatment
  - Post-operative respiratory depression
  - Myasthenia gravis becomes chronically present
- Known myasthenia becomes more severe
Anti-AChR antibodies often present
Drugs with clear effects on myasthenia:
- Antibiotics
  - Neomycin
  - Streptomycin
  - Gentamicin
  - Colisitins
  - Telithromycin: Exacerbation within 2 hours of administration⁶
  - ? Kanamycin
- Anti-rheumatic
  - Prednisone (High dose): Onset days after administration
  - Chloroquine
- NMJ blockers
  - Curare
  - Non-depolarizing (Vecuronium)
  - Botulinum toxin
- Other:
  - Quinidine
  - Procainamide
  - Procaine
  - Magnesium
  - β-blockers
  - ? Phenytoin
None of these drugs is absolutely contra-indicated in myasthenia
- If important to treat a serious disorder
  - Monitor myasthenia carefully: Especially respiration & swallowing
  - If new or more severe myasthenic signs develop:
    - Treat & consider stopping the medication if necessary
Other drugs with anecdotal reports of MG exacerbation
- Antibiotics: Tobramycin; Amikacin; Polymyxin B; Tetracyclines; Lincomycin;
  Clindamycin; Erythromycin; Ampicillin;
  ? Fluoroquinolones (Norfloxacin, Ofloxacin, Pefloxacin ® Reduced MEPP amplitude)
- Other: Verapamil; Trimethaphan; Trimethadione; Lithium; Chlorpromazine; Trihexyphenidyl;
  D,L-carnitine; Bretylium; Emetine; Lactate; Methoxyflurane;
  Contrast agents; Citrate anticoagulant; Trasylol; Gabapentin

Drug-induced MG: Slow Onset

New immune-mediated myasthenia gravis induced by drug treatment
Onset: weeks to months after drug treatment
Slow & possibly incomplete recovery after drug cessation
Anti-AChR antibodies may be present
Specific drugs
- Penicillamine
  - Associated with HLA-DR1
  - Clinical: Similar to other autimmune MG
  - Remits on withdrawal of drug
  - May also produce myositis & neuromyotonia
- Other drugs: Diphenylhydantoin; Chloroquine; Quinidine; Trimethadone; Procainamide

OCULAR MYASTHENIA GRAVIS³

MG: Limitation of adduction

MG: Ptosis

Clinical
- Onset: Diplopia & Ptosis
- Weakness
  - EOM paresis
    - Symptomatic diplopia
    - Distribution: Usually asymmetric & bilateral
    - Fluctuates
      - Worse in evening
      - Differs from thyroid eye disease: Worse in morning
    - EOM often dysconjugate
    - Saccades: Slower at end of eye movement
  - Ptosis
    - Unilateral or Bilateral
    - Worse side may vary from day to day
  - Orbicularis oculi
- Pupils: Normal
- Fatigue
  - Levator palpebrae
  - Extraocular muscles
    - Saccadic slowing
    - Rapid small saccades
    - Gaze evoked nystagmus after sustained gaze
    - Quiver eye movements
  - Orbicularis oculi: Afternoon ectropion
- Prognosis of ocular MG
  - Disease course: Variable
    - May represent initial stage of MG that evolves into generalized weakness (40% to 60%), or
    - Can remain localized to extraocular muscles
    - MG that remains selectively ocular for 2 years rarely becomes generalized thereafter
  - Generalized MG may present with selective ocular changes
  - Treatment
    - Immunosuppression or Corticosteroids: Best improvement
    - Anti-AChE medications: Little long term benefit in most patients
Thymic hyperplasia: Occurs but less common than in generalized MG
Laboratory
- Repetitive nerve stimulation: Facial nerve most sensitive
- Single fiber EMG: May be abnormal in up to 95% of MG if facial muscles are included in studies
- Anti-AChR antibodies
  - Present in 50% to 70%
  - Lower titers than with generalized MG
  - Antibodies bind best to adult AChRs with e subunit
- Acetylcholinesterase inhibitors
  - Outcome assessment: Quantitative measurement or eye movements
  - False positives: LEMS; Botulism; Guillain-Barré; ALS; Intracranial neoplasms
- AChRs at NMJs: Reduced in both ocular & systemic muscles in most patients
Work-up: Other

Myasthenia gravis:
Eye movements
.avi movie from D Zee MD
- Rule out
  - Intracranial lesion: Head MRI
  - Thyroid ophthalmopathy: Orbit MRI
- Rule out thymic pathology: Chest CT
- Thyroid function testing
Treatment
- Prednisone is most effective
  - Start at 5 mg/day
  - Increase daily dose by 5 mg each week
  - Stop increasing: Symptoms begin to improve, or 30 mg q.d.
  - Taper slowly over months when symptoms have resolved
  - Maintenance: Low doses of 10 to 15 mg q.o.d.; Usually few side effects
- Anticholinesterase medications: Often not effectve
- Mechanical: Lid crutches; Taping eyeglasses
External links
- Ophthalmology CPC
- Eye movement disorders

MYASTHENIA GRAVIS, ACQUIRED: OTHER FOCAL SYNDROMES

Bulbar

Onset: Dysarthria; Dysphagia
Weakness
- Orbicularis oris
- Tongue
- Masseter: Jaw opening & closing
- Pharynx
- Other: Neck, anterior or posterior
Differential diagnosis: Bulbar dysfunction
Course: May remain localized or progress to more general weakness over time
Treatments, initial: To produce rapid improvement
- Anticholinesterase
- Plasma exchange
- IVIg

Respiratory failure

Onset: May be only initial symptom or sign of disease
Differential diagnosis: Respiratory failure
Treatments, initial: To produce rapid improvement
- Anticholinesterase
- Plasma exchange
- IVIg

Distal weakness⁵

Epidemiology
- Frequency of predominantly distal weakness: 3% to 7% of acquired MG
- Similar age gender & response to therapy as generized MG
Onset of distal weakness
- Onset of disease: 33%
- Develops later in disease course: 66%
  - May develop years after onset of disease
Weakness
- Hands: Wrist & finger extensors; Intrinsic hand muscles
- Feet: Foot drop; 20%
- More proximal muscles also involved: Biceps; Triceps
- Usually bilateral
- Occasionally asymmetric
Laboratory
- Distal repetitive nerve stimulation at 3 Hz
  - Frequently shows decrement (87%)
  - More commonly positive than with generalized MG (55%)
- Anti-AChR antibodies: Commonly present (80% to 100%)
- Thymoma: Not described

MYASTHENIA GRAVIS: ACQUIRED SLOW CHANNEL SYNDROME

Weakness: Variable
- Ocular: Extraocular muscle (EOM) weakness; Ptosis
- Bulbar: Dysphagia
- Limb: May be focal in legs or arms
- Repetitive contraction: Fatigue after transient increase
Electrophysiology
- Decrement at 1 to 5 HZ
- Increment: Mild (50%) at 10 to 50 Hz
- Repetitive compound muscle action potentials (CMAPs)
- MEPPs: Low amplitude with Longer time constant of decay
- AChR channel properties altered: Reduced Total current; Slow closure
Pathology
- Inflammation: CD3+ T-cells > CD20+ B-cells
- Higher # of NMJs on single muscle fiber
- Normal number of α-bungarotoxin binding sites
- Electron microscopy: Simplification of post-synaptic regions without degeneration of junctional folds
- Thymus: Hyperplastic
Anti-AChR antibodies
- Borderline titers by conventional assay (Mostly fetal AChRs)
- Positive in assay of binding to adult AChRs: ? Recognize epitopes on e-subunit
Treatment
- Response to anticholinesterase agents: Variable; Poor to Good
Also see: Hereditary slow channel syndromes

MYASTHENIA GRAVIS: ANTI-AChR ANTIBODY NEGATIVE

Anti-AChR antibodies normally detected by
- Binding to AChR
- Methodology: Immunoprecipitation assay
Immune MG: Negative anti-AChR antibody testing by routine assay
- Clinical associations
  - Absent anti-AChR Ab more common with ocular & childhood disease
  - MG with IgG binding to MuSK: Also see MuSK ⁴
- Methodological causes: Anti-AChR antibodies detected by other methods
  - Rarely (3%) only detected by AChR modulating assay
    - AChR modulating assay is not specific: Positive results in disorders other than MG
  - Some patients have plasma antibody (?IgM) that alters AChR function
    - Reduced AChR opening frequency
    - Increased AChR phosphorylation
  - Anti-AChR antibodies may become absent after immunosuppression
  - Antibody binding to e subunit of AChR (adult AChR)
    - Ocular MG
    - Acquired slow channel syndrome
Rule out
- Congenital/Hereditary MG
- Lambert-Eaton MG

Myasthenia Gravis with serum IgG binding to MuSK⁴

MuSK protein
Epidemiology
- Female predominant (80%)
- Onset age
  - Range: 6 to 68 years
  - Especially 20 to 60 years
  - Younger than anti-AChR antibody positive patients
- Frequency
  - Present in many (30% to 70%) European anti-AChR antibody negative MG patients
  - Less common in Japan, Norway & Phillipines
  - More common in Afro-Americans
  - Female > Male
Clinical associations
- Clinical syndrome
  - General: Similar to generalized MG with anti-AChR antibodies
  - Onset: Often acute or subacute
  - Prominent signs
    - Face weakness (100%)
    - Bulbar: Dysarthria (Nasal speach) 100%
    - Ocular (90%)
    - Respiratory: Crises common
    - Limb weakness: 30%; Less often at onset
  - Associated MG may be more difficult to treat: Anti-AChE drugs not effective
  - Variant syndromes
    - Posterior neck & Respiratory weakness with preserved EOM
    - Oculobulbar + Facial
      - Tongue atrophy
      - Often resistant to immunotherapy
      - Electrodiagnostic: RNS may be normal; SFEMG abnormal in face
  - Permanent weakness
    - Common
    - Face & Tongue: With atrophy
    - Pharyngeal
- Not present with
  - Ocular MG: Pure
  - Thymus pathology: Thymoma; Thymic hyperplasia
  - Anti-AChR antibodies
- Course: Episodic exacerbations common
Electrophysiology
- RNS: Decrement
  - In some patients (57%)
  - May be present in some muscles but not others
  - Less frequent than in other Ab- MG patients
- SFEMG
  - Abnormal in selective muscles with weakness
  - More severe than degree of myopathic changes
  - More severe involvement in facial muscles
- EMG: Irritable myopathy in some patients
Serum factors
- IgG vs MuSK properties
  - Class
    - Mostly IgG4
    - Some IgG1
  - Properties
    - Often directed against amino terminal (extracellular, IgG-like) sequences of MuSK
    - May induce some AChR aggregation on myotubes
    - High affinity binding
- Other serum factors
  - Non-IgG: Reduces AChR function
Muscle pathology
- NMJ pathology
  - Less post-synaptic damage
  - Less widening of synaptic cleft
  - Number of AChRs at NMJs: May be normal
- Varied fiber size
- Scattered necrosis
- Tongue MRI: Atrophy; Increased signal
Treatment
- Often only partial benefit: Residual symptoms common
- Exacerbations reported during immunosuppression
- Plasma exchange: Effective for crises
- IVIg: Effective in some patients
- Corticosteroids
- Cyclosporine
- ? Azathioprine
- Anti-AChE medications (Pyridostigmine)
  - Little or no benefit in majority
  - Useful in some patients
- Thymectomy: No benefit
Also see: Congenital MG with MuSK deficiency

MYASTHENIA GRAVIS: Animals^1,2

Acquired MG

Epidemiology
- Relative risk
- Breeds with predisposition
  - Cats: Abyssinians (and related Somalis)
  - Dogs: Akitas; German shorthaired pointers; Chihuahuas
    Rottweilers; Doberman Pinschers; Dalmations; Newfoundland
Clinical features
- Weakness
  - Generalized (~ 50% to 60%)
  - Focal: Face; Posterior neck; Eyes; Trunk
  - Fatigue: Ptosis of eyelids, ears, head
  - Shortened stride
  - Refusal to move
- Dysphagia & Regurgitation: Megaesophagus
- Extraocular muscle weakness
- Course
  - Dogs: Often monophasic with remission within 1 to 2 years
  - Cats: More frequent chronic course
Laboratory
- Mediastinal mass (3% to 5%)
  - Thymoma
    - Common in cats with MG (80%)
    - Uncommon in dogs (2%): More in older dogs
  - Megaesophagus
- Serum: Anti-AChR antibodies
Treatment
- Megaesophagus
  - Small feedings while erect: Elevate food & water
  - Gastrostomy
- Thymoma: Thymectomy
- Weakness
  - Pyridostigmine bromide (Syrup): Start with low dose; May be poorly tolerated
    - Dogs: 0.5 to 3.0 mg/kg po bid or tid
    - Cats: 0.5 mg/kg q 12 h po
  - Neostigmine: Dogs: 0.5 mg/kg po bid or tid; 0.04 mg/kg q6h IM
  - Prednisone
    - Dogs: 0.5 mg/kg/day increasing in 0.5 mg/kg/day increments every 4 days to 2.0 mg/kg/day
    - Cats: 1.5 to 2 mg/kg q12h po

Congenital MG

Breeds
- Jack Russel terriers
- Smooth haired fox terriers
- Springer spaniels
- Gammel Dansk honsehunds
- Samoyeds

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References
1. J Am Vet Med Assoc 2000;216:55-57
2. J Am Vet Med Assoc 1997;211:1428-1431
3. Semin Neurol 2000;20:7-20
4. Nature Medicine 2001;7:365-368, Lab Invest 2002;82:1139�1146, Neurology 2002;59:1672�1673
Brain 2003;126: Online June, Neurology 2003;60:1978�1980
5. Acta Neurol Scand 2003;108:209�210, Neurology 1999;52:632-634
6. Neurology 2006;67:2256�2258

12/27/2006