Diagnostic and Therapeutic Pitfalls in Myasthenia Gravis

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Diagnostic and Therapeutic Pitfalls in Myasthenia Gravis Powered By Docstoc
					   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 immune-
  mediated 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
                            R AB D D IG MIN (U L)
     Ampl (mV) over Study
10



5



0
               1
                                                                               SHARIATI HOSPITAL
                                                                   Department of Neurology, Electromyography Unit

                      P atient ID: 1350                                                                                         NCV / myasthenia test
                      Name:          mohammadi, nahid                                                                                   02/25/2007     01:39:3




Repetitive CMAP
                      Date of birth: 01/01/1985
                                     A1
                                                                                                                        N. ul naris / M. abd. dig. m.
                                                                                                                        5.0 ms/Div, 3000.0 uV/Div, 1/0, 12mA




  After Single
                                          Area

                                                                                                              A1
                              Lat

                                                      A2
                                                                                                              A2


                                                                                                              A3




    Stimuli
                                                                                                              A4


                                                                                                              A5


                                                                                                              A6


                                                                                                              A7



                                                                                                              A8


                                                                                                              A9




                                                                                                   TOENNIES
                        20
                                                                                              C h a n ge o f A m p l . -> M 1    [% ]
                        10                                                                    N. ulnaris right

                         0                                                                    C h a n ge o f A re a   -> M 1     [% ]
                                                                                              N. ulnaris right
                        -10

                        -20

                        -30

                        -40

                        -50

                        -60


                              0       1      2    3        4   5   6   7   8     9    10 M resp.




                   S ti m . S i te               D e cre m . A m p l . D e cre m . A re a
                                                        [%]                  [%]

                  N. ul naris ri ght                       35.8                45.4




                      12/18/2007                                                  T OENNIES NeuroScreen® Pl us                                       Page - 1
                                                                                           1.70c
                             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                          R COMM PERONEAL - EDB

    2                                                      2
1           3 4                          5             1       3 4                           5
                                             Wrist 1                                         Ankle 1
                               30ms 5mV 46mA                                       30ms 5mV 63mA
                2
        1            3 4                      5                        1 2   3 4       5
                                       B.Elbow 2                                           FibHead 2
    2                          30ms 5mV 46mA                                       30ms 5mV 63mA
                                                           2
1           3                             5            1       3                           5
                             after 10s exercise   3                4           after 10s exercise   3
                4
                               30ms 5mV 46mA                                       30ms 5mV 63mA
                            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
                                          20
R FRONTALIS

                                          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 flu-
    like 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

				
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