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MYASTHENIC SYNDROMES: VARIANTS

MYASTHENIC SYNDROMES: DRUG-INDUCED

• 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

• 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:
  • General
    • 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
  • Antibiotics
    • Neomycin
    • Streptomycin
    • Gentamicin
    • Colisitins
    • Telithromycin: Exacerbation within 2 hours of administration
    • ? 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
    • Statins ⁸
    • Checkpoint Inhibitors
• 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

• Definition: New immune-mediated myasthenia gravis induced by drug treatment
• Clinical
  • Onset time: Weeks to months after drug treatment
  • Slow & possibly incomplete recovery after drug cessation
• Laboratory
  • 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
    • Tandutinib
    • Anti-programmed cell death 1 (PD-1) antibodies
      • Ipilimumab
      • Nivolumab
      • Pembrolizumab

OCULAR MYASTHENIA GRAVIS ³

General definition MG with any pattern of: Pupil sparing Ophthalmoplegia, ± Ptosis Epidemiology US & Europe: Adult onset Asia: Childhood onset; HLA-Bw46 African MG: Severe EOM dysfunction Association Decay-accelerating factor (DAF; CD55) (c.-198C>G) 9 Frequency in MG Ocular onset of MG in 30% to 50% No relation to age or sex May occur in patients with, or without, anti-AChR antibodies Clinical Onset Diplopia & Ptosis Painless Ptosis as only sign: 10% of Ocular MG Weakness EOM paresis Symptomatic diplopia Distribution: Usually asymmetric & bilateral Fluctuates Worse: In evening; With sustained gaxe Differs from thyroid eye disease: Worse in morning EOM often dysconjugate Saccades: Slower at end of eye movement Selective patterns of weakness Typical: Bilateral; Multiple muscles MLF-like (Bilateral medial rectus): Often symmmetric Elevator muscles Superior rectus & Inferior oblique Often symmetric Superior rectus weakness Most common involvement (65%) More common with longstanding symptoms Single muscles: Rare (12%) IV nerve-like (Superior oblique) VI nerve-like (Lateral rectus) Medial rectus Inferior rectus Levator palpebrae Ptosis Unilateral or Bilateral Worse side may vary from day to day Worse with sustained up gaze Improved with cold Pseudoretraction: Excessive contraction of normal lid Association With attempts to compensate for ptosis of opposite eye Cause: Bilateral equal innervation (Hering’s law) Orbicularis oculi Orbicularis weakness: > 95% of ocular MG "Peek" sign: Partial opening of palpebral fissure Ectropion Pupils: Normal Fatigue Levator palpebrae Ptosis: More with sustained up-gaze Lid twitch (Cogan's lid twitch sign) Movement: With down-gaze to up-gaze Twitch: Lid elevates excessively & then droops again External link: mrcophth Extraocular muscles Saccadic slowing with increased length 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 generalized MG Evolves into generalized weakness in 25% to 60% Time to generalized weakness Mean 9 to 12 months Range 5 to 27 months Can remain localized to extraocular muscles: 40% to 75% MG that remains selectively ocular for 2 years Rarely becomes generalized thereafter Immunomodulating treatment Greatly reduces likelihood of generalization Generalized MG may present with selective ocular changes Frequency: 50% of generalized MG patients 94% progress to develop generalized signs over 1st 2 to 3 years Treatment Corticosteroids: Best improvement 7 Immunosuppression: May be useful Anti-AChE medications: Little long term benefit in most patients Laboratory Thymic hyperplasia Less common (4%) than in generalized MG (12%) Repetitive nerve stimulation Facial nerve most sensitive General sensitivity: 18% toi 35% Specificity: High Single fiber EMG Sensitivity: Abnormal in 80% to 99% of MG when facial muscles also studied False positives: Other neuromuscular disorders; Poor technique Anti-AChR antibodies General ocular MG: Present in 50% to 70% African-Americans: Present in 25% Properties vs generalized MG Lower titers ? Low-affinity Bind better to adult AChRs with e subunit Anti-MuSK antibodies: Rare Anti-AChE antibodies: Common Acetylcholinesterase inhibitors Outcome assessment: Quantitative measurement of eye movements False positives: LEMS; Botulism; Guillain-Barré; ALS; Intracranial neoplasms AChRs at NMJs: Reduced in both ocular & systemic muscles in most patients Ice pack test Cooling may reduce degree of ophthalmoplegia & ptosis Specificity: High Sensitivity: 50% to 60%: Less with severe ptosis Work-up: Other Rule out Intracranial lesion: Head MRI Thyroid ophthalmopathy: Orbit MRI Rule out thymic pathology: Chest CT Thyroid function testing Ptosis differential diagnosis Horner's syndrome 3rd nerve palsy Marcus-Gunn jaw winking ptosis Congenital ptosis Levator dehiscence Blepharophimosis Plexiform neuroma Myasthenia gravis External link: mrcophth 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

MG: Limitation of adduction MG: Ptosis Cogan's lid twitch sign Myasthenia gravis: Eye movements .avi movie from D Zee MD

MYASTHENIA GRAVIS, ACQUIRED: OTHER FOCAL SYNDROMES

• Weakness
  • Onset: Dysarthria; Dysphagia
  • Face: Orbicularis oris & oculi
  • Tongue
    • Weakness with little atrophy
    • Chronic weakness: Triple furrowed
  • Masseter: Jaw closure weaker than opening
  • Pharynx
  • Neck: Anterior or Posterior
• Course: May remain localized or progress to more general weakness over time
• Treatments, initial: To produce rapid improvement
  • Anticholinesterase
  • Plasma exchange
  • IVIg
• Differential diagnosis: Bulbar dysfunction

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

• 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
  • Ultrastructure
    • Simplification of post-synaptic regions
    • No 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
  • Associations: Absent anti-AChR Ab
    • Clinical: More common with
      • Ocular & Childhood MG
      • No thymic pathology
    • Other IgG autoantibody-related MG syndromes
      • MuSK: Also see MuSK ⁴
      • LRP4
      • Cortactin
      • Lambert-Eaton MG
  • Methodological causes: Anti-AChR antibodies detected by other methods
    • AChR modulating assay
      • Not specific: Positive results in disorders other than MG
      • Rarely (3%) only detected by this method
    • 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 ε subunit of AChR (adult AChR)
      • Ocular MG
      • Acquired slow channel syndrome
    • Testing for low affinity anti-AChR antibodies
      • Antibody binding better to clustered AChRs
      • Frequency: 66% of antibody negative myasthenia gravis
    • Antibody type: IgG₁ subclass; Activate complement
  • Seronegative MG
    • Clinical
      • Weakness: Fatigable
      • Treatments
        • AChE inhibitors
        • Often poorly responsive to immunomodulation
    • Laboratory
      • AChR binding antibodies
        • 40% may become positive in 2 years after initial testing
      • Electrodiagnosis: Abnormal RNS or SF-EMG
      • Serum: No known autoantibodies detected
      • NMJ pathology: May have C5b-9 or IgG1 deposition ¹⁷
      • Thymus: Usually normal (70%)
      • Rule out: Congenital/Hereditary MG

Myasthenia Gravis: Serum IgG binding to MuSK ⁴

• MuSK protein
• MuSK Antibodies
• Epidemiology
  • Frequency
    • 5% to 8% of MG
    • Present in many (40%; 30% to 70%) European anti-AChR antibody negative MG patients
    • Less common in Japan, Norway & Phillipines
    • More common in
      • Patients
        • African-Americans in US
        • Female (80% to 90%) > Male
        • More males at older ages
      • Geography: Warmer latitiudes
    • AChR Ab- patients
      • US & England: Up to 70%
      • Sardinia: High prevalence; May be related to TNFSF13B variant
      • China: 4% to 27%
  • HLA associations
    • DRB1*14; DQB1*05
    • Increased risk: DQ5-DR14, DQ5-DR16
    • Protective: DQ3-DR4, DQ3-DR11
  • Not usually present with
    • Ocular MG: Pure
    • Thymus pathology: Thymoma; Thymic hyperplasia
    • Anti-AChR antibodies
• Clinical associations
  • Clinical syndromes
    • Onset age ¹⁹
      • Range: Neonatal to 68 years
      • Especially 20 to 60 years: Peak 4th decade
      • Younger or Older than Anti-AChR antibody positive females
      • Younger than Anti-AChR antibody positive males
    • Weakness
      • Face (100%)
      • Bulbar (90% to 100%): Dysarthria (Nasal speach)
      • Ocular (75% to 96%) ¹⁵
        • At disease onset: 59%
        • Diplopia: Often intermittent
        • Ptosis: Symmetric
        • Ophthalmoparesis: Symmetric; Conjugate gaze paralysis (35%)
        • Usually progress to generalized disease
      • Respiratory (30%): Crises common
      • Limbs (30% to 50%): Less often at onset
      • More severe when double+ for LRP4 Ab
    • Muscle atrophy: Face & Tongue
    • Other features
      • Spontaneous activity
        • Myokymia
        • Fasciculations
        • Cramps
      • Scoliosis: Children
      • Neoplasm association: Possible ²⁰
        • Frequency: 14%; Concurrent in 3%
        • MuSK protein may be expressed in some neoplasm cell nuclei
    • Course
      • Onset: Often acute or subacute
      • Bulbar onset: Associated with rapidly progressive course
      • Exacerbations: Common
        • Frequency: 40%
        • Weakness: Respiratory
        • Associated with
          • Pregnancy
          • Drugs: Ciprofloxacin, Azithromycin, Magnesium, Hydrocodone, β-blockers
      • Permanent weakness
        • Common
        • Face & Tongue: With atrophy
        • Pharyngeal
    • Variant syndromes
      • Posterior neck, Shoulder & Respiratory weakness with preserved EOM
      • Oculobulbar + Facial
        • Tongue atrophy: May improve with treatment
        • Often resistant to immunotherapy
        • Electrodiagnostic: RNS may be normal; SFEMG abnormal in face
      • Pure ocular MG
      • Onset after thymectomy for Anti-AChR antibody Positive MG
        • AChR antibodies usually absent during new MuSK syndrome
      • Only Cell-based assay MuSK antibody positive ¹⁴
        • Younger disease onset: Mean 25 vs 40 years
        • Disease pattern: Milder; Less frequently generalized (60%)
        • More frequent response to AChE inhibitors
    • Treatment
      • General
        • Often only partial benefit: Residual symptoms common
        • Exacerbations reported during immunosuppression
      • Rapid onset of action: Days to Weeks
        • Plasma exchange: Effective for crises; Benefit in 93%
        • IVIg: Effective in some patients (63%)
      • Corticosteroids: Often produce some improvement
      • Rituximab: May be useful for difficult to treat patients
      • Other
        • Cyclosporine
        • ? Azathioprine
      • Anti-AChE medications (Pyridostigmine)
        • Frequency of benefit
          • Little or none in 50% to 80%
          • More with: Cell-based-Assay-only Ab positive
        • Useful in some patients: More stable course
        • Side effects: Fasciculations; Cramps
      • Thymectomy: No benefit
• Laboratory
  • Electrophysiology
    • RNS: Decrement
      • Frequency of decrement ¹³
        • Any muscle: 57% to 87%
        • Face: 78%
        • Limbs: 22%
      • May be present in some muscles but not others
      • Less frequent in limbs than in Ab- MG patients
    • EMG
      • Myotonic discharges (10%)
      • Motor unit potentials (40%): Myopathic even in mild disease
    • 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
      • Testing: Methodologies
        • Radioimmunoassay: Common method of testing
        • Cell based assays (CBA) ¹⁴
          • May be more sensitive in detecting MuSK antibodies
          • Clinical correlations of CBA only positive results
      • IgG Class
        • Mostly IgG₄
          • IgG₄ antibodies: Other
        • Some IgG_1-3
      • Properties
        • Often directed against amino terminal (extracellular, IgG-like) sequences of MuSK
        • May induce some AChR aggregation on myotubes
        • High affinity binding
        • Interfere with MuSK binding to ColQ
        • IgG₄
          • Monovalent
          • Block binding site for LRP4 on MuSK
      • Titers: May correlate with clinical severity
    • 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
    • Fewer denervation changes than Anti-AChR Ab+ MG
    • Tongue MRI: Atrophy; Increased signal
• Also see: Congenital MG with MuSK deficiency

Myasthenia Gravis: Serum IgG binding to LRP4 ¹⁰

• LRP4 protein
  • Post-synaptic
  • Agrin binding: Induces MuSK activation
• LRP4 antibody
  • Properties
    • Subclass: IgG₁ > IgG₂; No IgG₄
    • Action
      • May inhibit interaction between neural agrin & extracellular portion of Lrp4
      • Inhibit AChR aggregation
  • Clinical MG associations
    • Epidemiology
      • Female/Male ratio: 2.5/1
      • Onset ages
        • Mean: Females 33 years; Males 42 years
        • > 50 years: 16%
    • Clinical
      • Adult onset
      • Weakness
        • Generalized or Ocular
        • Mild to Severe
        • Increased severity
          • Ab to both LRP4 & AChR
          • LRP4 Ab in AChR antibody-negative MG ¹⁸
      • Thymus
        • Thymoma: None
        • Hyperplasia: 32%
      • Treatment response
        • Similar to MG with only AChR Ab+
        • Responsive to: Prednisone; Pyridostigmine
    • Laboratory
      • Electrodiagnostic ¹²
        • RNS decrement: Often absent
        • SFEMG Jitter: Less common than in AChR or MuSK antibody + patients
      • LRP4 antibody: No specificity for MG in AChR Ab negative patients
        • NMJ disorders (Myasthenic syndromes)
          • AChR antibody-negative MG: 0% to 50%
          • AChR antibody-positive MG: 0% to 8%
          • MuSK antibody-positive MG: 10%; Somewhat lower titers than without MuSK antibodies
          • AChR & MuSK antibody-negative MG: Up to 50%; Mean 20%
          • LEMS: 1%
        • Other
          • Multiple sclerosis: 4%
          • Amyotrophic lateral sclerosis
            • Frequency: 23%
            • Male = Female
            • LRP Ab+ in serum: Also commonly in CSF
            • No correlation with LMN, UMN or bulbar ALS
          • Healthy controls: 4%

Myasthenia Gravis: Serum IgG binding to Agrin ¹¹

• Agrin protein: Heparan sulfate proteoglycan
• Agrin antibodies
  • Location: Serum
  • Antibody type: IgG
  • Frequency in
    • Acquired MG: 8% to 15%
      • AChR antibody +: 1% to 15%
      • AChR antibody -: 0% to 50%
    • Controls: 0/80
• Clinical associations
  • Epidemiology: Middle-aged males in China
  • Onset age: 30 to 83 years
  • Weakness: Generalized; Ocular, Bulbar, Limb
  • Treatment: Prednisone
  • RNS decrement: 80% of patients

Myasthenia Gravis: Serum IgG binding to Collagen XIII ¹⁶

• Collagen XIII protein
• Collagen XIII antibodies
  • Location: Serum
  • Type: IgG
• Clinical associations: MG
  • Epidemiology: 5 female patients
  • MG syndrome
    • Generalized > Ocular
    • Onset age: Mean 25 years
  • Thymus: Hyperplasia (80%)
  • AChR Antibodies: Positive in 40%

Myastheniua Gravis: Telithromycin-associated ⁶

• Drug
  • Uses: Ketolide antibiotic
  • Disease mechanism
    • Inhibits postsynaptic nicotinic ACh stimulated current in AChRs
    • Exacerbation of pre-existing MG
• Epidemiology
  • Frequency: 10 patients reported
  • Myasthenia: Previously undiagnosed (20%) to MG for 16 years
• Clinical
  • Onset
    • Time: Often within 2 hours of 1st drug intake
    • Age: 29 to 82 years
  • Weakness
    • Location: Bulbar; Face; Respiratory; Some general
    • Course: Recovery over 1 to 30 days common
  • Other systemic: Bradycardia; Mydriasis
• Laboratory
  • May occur in patients with either AChR or MuSK antibodies

MYASTHENIA GRAVIS: Animals ^{1, 2}

• Epidemiology
  • Relative risk
  • Higher: After 2 to 3 years of age
  • Lower: Sexually intact male dogs
  • 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

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