Download Diagnostic and Therapeutic Pitfalls in Myasthenia Gravis

Myasthenia Gravis
Shahriar Nafissi, MD
Associate Professor of Neurology
Tehran University of Medical Sciences
Diagnosis
• “Delaying the diagnosis of ocular MG is inconsequential but
making an erroneous diagnosis has serious implications”
Daroff RB. The office tensilon test for ocular MG. Arch Neurol 1986;33:843–844
Clinical Features
When to question the clinical diagnosis
• Acute course, spontaneously improving
• Clustering of cases
• Autonomic symptoms
–
–
–
–
Orthostatic hypotension
Sluggish pupils
Constipation, dry mouth
Reduced sweating
• Decreased tendon reflexes
• Familial
• Minor symptoms since infancy/childhood
Clinical Features
• No objective finding
• Diagnosis based solely on subjective
response to Mestinon
• Lack of clues pointing to the immunemediated nature
–
–
–
–
Antibodies
Thymus
Response to IS, IVIG, PE
Associated autoimmune diseases
• Does myasthenic crisis only happen in MG?
Therapeutic trial
Diagnosis should not be based on
subjective improvement of symptoms
especially with Mestinon
Tensilon Test
• Pitfalls
– Acute decompensation
• Oropharyngeal Weakness
• Cholinergic Weakness
– Subjective vs. objective improvement
• Some believe that it should be performed only in patients with
ptosis/ophthamoplegia
– Technical:
• Subcutaneous injection
• Not adequately flushed
• Expired drug
• Complications
– from 23,111 edrophonium tests, 37 (0.16%) were
associated with a serious complication, most often
bradyarrhythmias and syncope. Respiratory failure,
seizures, vomiting, and TIA were also reported
– Sensitivity
• Generalized MG: 72-95%
• Ocular 60-86%
– Specificity 97%
– False positive results:
•
•
•
•
Ocular> Generalized
Other NMJ disorders: LEMS, Botulism, CMS
LMN syndromes e.g., MND
Others: brainstem glioma, MS, pituitary tumor,
compressive aneurysm, GBS, Diabetic 6th palsy
and inflammatory myopathy
Anti-Acetylcholine Receptor Antibody
• High Affinity AChR-Ab
– Find a reliable laboratory
– Sensitivity :
• Ocular 39-71% (44%)
• Generalized 87-98% (our data 82%)
• Sometimes negative first, become positive later
– Specificity 95-99%
– Seronegative MG (~15%)
• 30-70% MuSK-Positive
• 66% of AChR- , MuSK- cases have low affinity AChR Ab
• Low affinity MuSK Ab
– False positive
• SLE, RA, inflammatory neuropathy, motor neuron disease
• Thymoma without MG, D-penicillamine
• Relatives of patients with MG
– Not useful in monitoring response to therapy
Repetitive Nerve Stimulation
• Sensitivity
– Depends on the number of muscles
tested
– Ocular 11-39%
– Generalized 53-98%
• Specificity 95-98%
Common pitfalls
– Technical
• Artifacts
• Submaximal stimulation
• Temperature < 35º C
– Testing 1-2 muscles, mainly distal
– Relying on borderline results
– Missing other NMJ disorders
• LEMS, Botulism, CMS
Technical factors
Ampl (mV) over Study
10
5
0
1
R AB D D IG MIN (U L)
SHARIATI HOSPITAL
Department of Neurology, Electromyography Unit
Repetitive CMAP
After Single
Stimuli
Patient ID:
1350
Name:
mohammadi, nahid
Date of birth: 01/01/1985
NCV / myasthenia test
02/25/2007
01:39:3
A1
N. ulnaris / M. abd. dig. m.
5.0 ms/Div, 3000.0 uV/Div, 1/0, 12mA
Area
A1
Lat
A2
A2
A3
A4
A5
A6
A7
A8
A9
TOENNIES
20
10
0
Change of Ampl. - > M1
N. ulnaris right
[%]
Change of Area - > M1
N. ulnaris right
[%]
-10
-20
-30
-40
-50
-60
0
1
Stim. Site
N. ulnaris right
12/18/2007
2
3
4
5
6
7
8
9
10 M resp.
Decrem. Ampl.
[%]
Decrem. Area
[%]
35.8
45.4
TOENNIES NeuroScreen® Plus
1.70c
Page - 1
R ABD POLL BR EVIS
Ampl (mV) over Study
5.0
2.5
0.0
1
R EXT D IG BR EVIS
Ampl (mV) over Study
10
5
0
1
2
R ULNAR - ADM
1
2
3 4
R COMM PERONEAL - EDB
5
1
2
3 4
5
Ankle 1
Wrist 1
30ms 5mV 46mA
2
1
2
1
3 4
30ms 5mV 63mA
1 2
5
B.Elbow 2
4
5
after 10s exercise
30ms 5mV 46mA
30ms 5mV 63mA
2
1
3
5
FibHead 2
30ms 5mV 46mA
3
3 4
3
4
5
after 10s exercise
30ms 5mV 63mA
3
R ABD D IG MIN (U L)
Ampl (mV) over Study
10
5
0
1
False positives
– Denervating diseases (MND)
– Myopathies
• Channelopathies
• Myotonic dystrophy
• Metabolic (McArdle)
Myotonic Dystrophy
R ABD D IG MIN (U L)
Amyotrophic Lateral Scleros
R ABD POLL BREVIS
R ABD POLL BREVIS
Ampl (mV) over Study
5.0
2.5
0.0
1
2
3
Single-Fiber EMG
• Sensitivity:
– Ocular 86-97%
– Generalized 98-100%
• Specificity 94-98%
• Normal jitter in a clinically weak muscle virtually
excludes MG
• False Positive Results
–
–
–
–
Other NMJ disorders
BTX injection
Neurogenic Processes, e.g., MND
Myopathies: PEO, Myositis
• In a patient with clinical features of NMJ, specificity
is high
• Helpful in differentiating central and psychogenic
causes of fatigue from MG
R FRONTALIS
20
10
0
0
100
200
Jitter (µs)
10m s 100 µV
Ri s in g E d ge/ Ris i ng E dge
10m s 100 µV
5m s 200µ V
Ri s in g E d ge/Ris i ng E dge
15m s 200 µV
Ri s in g E d ge/Ris i ng E dge
MuSK-Positive MG
•
•
•
•
•
•
More severe disease, pure ocular cases rare
30-70% AChR-Ab negative cases
80-100% cases female
Severe involvement of facial and bulbar muscles
RNS and SFEMG negative in limb muscles
Thymus pathology rare; not responsive to
thymectomy
• Many cases non-responsive or non-tolerant to
Mestinon
• Usually requires Immunosuppressive therapy
• Complete remission<10%, IS withdrawn<20%
MuSK-positive patients
strong inverse correlation with latitude north
of the equator
Treatment
Mestinon
• Symptomatic therapy; doesn’t affect
underlying mechanism
• No fixed dose schedule
– With any dose, some muscles get
stronger, some don’t change and others
get weaker
– Need more drug with menstruation,
emotional stress, hot weather, infection
• If needs too much or if response
suboptimal, consider other
medications
Mestinon
• Cholinergic Weakness
• Don’t forget irreversible damage to
NMJ
• MuSK-Positive Patients
• When used in combination to IS, try
to discontinue Mestinon as soon as
the patient becomes symptom-free
Thymectomy
• Before deciding about thymectomy,
make sure that the patient has
autoimmune MG
• R/O:
–
–
–
–
–
LEMS
Congenital myasthenic syndrome
Botulism
Neurasthenia
Mitochondrial disease
Thymectomy in MG
• Indicated
– Thymoma
– Seropositive MG onset 15-50 years with
moderate or severe disease
“For patients with non-thymomatous autoimmune MG,
thymectomy is recommended as an option to increase the
probability of remission or improvement (class II evidence)”
Thymectomy in MG
• Not indicated
–
–
–
–
Ocular MG
MuSK-Positive MG
Mild generalized non-thymomatous MG
Late-onset non-thymomatous MG (> 50 or 60)
• No effect of thymectomy
• Titin and Ryanodine Ab positive cases even deteriorated
• Controversial
– Seronegative generalized MG
– Generalized MG with good response to other
treatment modalities
• Wait a while before deciding for
thymectomy but not too long
• Before thymectomy, the patient has to
be in a stable condition
• If the patient is not thymectomized, F/U
CT scan every 2 years
• Any MG patient undergoing thoracotomy
for other causes (e.g., CABG), should
have thymus removed.
Corticosteroids
• Corticosteroid-related exacerbations in
the first 2 weeks : 15-30%
– Patients with weakness in bulbar and
respiratory muscles need PE first
• Some don’t tolerate alternate day
regimen
• Suboptimal response to steroid < 20%
• Steroid dependency
Cyclosporine
• Response begins after 1-2 months
• Contraindicated in renal impairment
and uncontrolled hypertension
• Important drug interactions
– NSAIDs
– Statins
– ACE inhibitors
Mycophenolate Mofetil
(Cellcept)
• Relatively safe drug but
Good for MG or not?
Azathioprine
• Particularly used as a steroid-sparing
agent
• Active metabolite 6-mercaptopurine
• Competes with hypoxanthine and
inhibits DNA/RNA synthesis
• Induces B and T-cell lymphopenia
• 10% of population have genetically
reduced activity of enzyme thiopurine
methyltransferase (TPMT)
• AZA metabolism is reduced 
vulnerable to myelosuppression
• 1/300 have undetectable TPMT
activity. AZA contraindicated
• Important interaction with allopurinol
– Increased toxicity and myelosuppression
– Dose reduced to 25%
Contraindications
• Known hypersensitivity to azathioprine.
• Pregnancy, except where benefit outweigh
risk
• Breastfeeding
• Very low or absent TPMT activity
• Dose adjustment needed with allopurinol
• Malignancy.
• Renal or hepatic insufficiency (relative
contraindication
Risks
•
•
•
•
•
•
Cancer
Infection
Hypersensitivity reactions
Megaloblastic changes, leukopenia
Hepatotoxicity
Acute pancreatitis
Cancer
• Risk of malignancy for treatment
duration < 10 yrs is small
• Lymphoma risk increased 4-fold or 1
case/1000 patient years
• AML/ myelodysplasia rare
• Increased risk of skin cancer
– Skin protection with UVA blockers
Infection
• When used in combination with
steroids, increased susceptibility to
viral, bacterial and fungal infection
• Live vaccines contraindicated
• Diminished response to killed vaccines
(e.g., Hepatitis B)
Dosage
• TPMT activity should be measured
• Usual dosage 1-3 mg/kg
• Slow onset of action
– Wait several months, usually 4-6 but up to 18
months for response
– Is a good choice when delayed response is
acceptable
• Start Prednisone + AZT in moderate to
severe cases from the beginning
• Weekly CBC, LFT for 4 weeks
Mycophenolate Mofetil
(Cellcept)
Mycophenolate mofetil
• Active metabolite: mycophenolic acid
• Inhibits inosine monophosphate dehydrogenase
and depletes guanine inhibition of DNA
synthesis
• lymphocyte selective immunosuppressive agent
• Compared to AZA:
– More selective- less adverse effects
– Hepatotoxicity lower
– Risk of lymphoma slightly higher
Dosage
•
•
•
•
•
•
Expensive drug
1-3 gr/day
Usually effect starts in two months
CBC, LFT, blood chemistry monitored
Dose reduction in renal insufficiency
Should not be taken with azathioprine
Side effects
• GI upset 20%
• Hematologic < 5%
– Anemia, leukopenia, thrombocytopenia
– Usually mild, dose-dependent, reversible
• Genitourinary symptoms
– dysuria, urgency, frequency, sterile pyuria,
hematuria
• Hepatotoxicity, respiratory failure rare
• Allergic reactions
Infections
•
•
•
•
In > 2 g/day
CMV and other herpes family viruses
Bacterial, fungal
PML (10 confirmed, 7 possible)
Cancer risk
• Mainly in transplant patients receiving
multiple immunosuppressives
• Lymphoma
• Solid organ tumors
• Skin cancer
• Pregnancy
• FDA pregnancy category D
• only use MMF in pregnant women if the
potential benefit outweighs the potential
risk to the fetus (e.g., transplant patients)
• Fetal malformation in 4/15 live born infants
• Breast feeding contraindicated
Cyclosporine
(Sandimmune, Neoral)
Cyclosporine
• First immunosuppressive drug found to act
selectively on T cells
• The helper T cell is the main target, but
the T suppressor cell may also be affected
• Cyclosporine inhibits calcineurin
phosphorylase, block genes that transcript
IL-2 that is required for T cell activation
• Metabolites mainly excreted in bile
Dosing
• distribution of the drug is limited
primarily to lean body mass in obese
patients
• Dosing should be based on ideal body
weights and divided two times/day
• Significant inter- and intra-individual
variability in bioavailability (1-86%)
• Significant variation in bioavailability
between different brands. The same
brand should be used
• Serum concentration
• Rapid onset of action (1-2 months)
• Microemulsion formulation better
absorbed (Neoral)
• Higher serum concentration with
empty stomach
• Importance of taking cyclosporine
consistently before or after meals
Contraindications
•
•
•
•
uncontrolled hypertension
Significant renal impairment
Serious infections
Previous history of malignancy,
excluding basal cell carcinoma
• Pregnancy, breast feeding
• Hepatic dysfunction
Drug interactions with cyclosporine
Drug interactions with cyclosporine
Adverse effects
• Renal dysfunction
– Acute: usually transient on dose
reduction
– Chronic: Usually irreversible, increases
with duration of treatment
– Better to stop the drug in 1-2 years
– If >30% Cr rise 25% dose 4 w  if
not corrected, 50%  4 w if not: stop
and don’t re-start until normalized
Adverse effects
• Hypertension
Cancer risk
•
•
•
•
•
Skin SCC
Lymphoma
Solid tumors
Paraproteinemia
Reduced risk of breast and colon CA
Adverse effects
• Neurologic:
–
–
–
–
Tremor, paresthesia, headache
Seizure: dose-dependent
RPLS
PML
• Gingival hyperplasia
• Hepatotoxicity
Adverse effects
• Infection: rare, may require dose
• Hyperlipidemia: TG> Chol
– Caution with statins. Risk of rabdomyolysis
•
• Vaccination
• Live vaccines contraindicated
• Response to killed vaccines reduced but still
recommended( Influenza, Pneumococcal)
• Pregnancy
•
•
•
•
Category C drug in pregnancy
No increase in teratogenicity (629 pregnancies)
trends towards low birth weight and prematurity
16% incidence of mental developmental delay
(175 children) attributed to premature birth
• Excreted in breast milk
Cyclophosphamide
(Endoxan)
Cyclophosphamide
• Alkylating chemotherapeutic agent
• Binds to DNA and interferes with mitosis
and cell replication
• Suppresses cell-mediated & humoral
immunity through its actions on T cells and
B cells
• Alters T lymphocytes towards a less
inflammatory phenotype
• Good bioavailability within the CNS
Side effects
•
•
•
•
Alopecia
nausea/vomiting
Transient myelosuppression
Hemorrhagic cystitis 4.5%
• Fluid intake + Mesna
• Pregnancy: contraindicated
• Breast feeding: contraindicated
• Bladder Cancer
– 3-5%
– Mean interval of 5.8 (3-10) years
– Risk of malignancy related to the
cumulative dose > 80 gr
• Gonadotoxicity
– Amenorrhea 33-44%
• IM monthly GnRH resulted in restoration of
normal ovarian cycle in > 93%of women
– Azospermia
• More when cumulative dose > 300mg/kg
Dosage
• Oral cyclophosphamide
• Monthly IV pulse 700mg/m2
• Adjust next monthly dose on Nadir
WBC (at mid-month)
• High dose myeloablation (resetting)
• 50 mg/kg/day for 4 days
• Max lifetime dose < 80-100 gr
Rituximab (RTX)
• Monoclonal Ab that targets the trans
-membrane protein CD20 of B-cells
significant depletion of B-cells
Neurological diseases with
reported use of RTX
•
•
•
•
•
•
•
•
•
IgM mediated neuropathy
Neuromyelitis optica
Dermatomyositis
Multiple sclerosis
Multifocal motor neuropathy
Myasthenia gravis
CIDP
Sjogren associated neuropathy
Lambert- Eaton myasthenic syn.
Protocols
•
•
•
•
375 mg/m2 x 4 (each week)
750 mg/m2 x 2 (2 weeks apart)
Combining RTX with IVIG
Marked B-cell depletion for 6-9
months, sometimes up to 2 years
• Should not be used with other
immunosuppressive especially T-cell
depletors
Safety
• Overall safe
• Infusion related reactions in 84%
– Minor in 97%
– nausea, headache, fatigue, rash, and flulike symptoms, orthostatic hypotension
– Pre-treatment with acetaminophen,
steroid, and antihistamine recommended
– Most severe after the first infusion
• RTX associated infections 30%
– Usually mild
– Only 1-2% severe/ life threatening
• Risk of PML