Download Neuromuscular Junction Disorders

Neuromuscular Junction
Disorders
David A. Simpson, D.O., F.A.C.N., M.S.
Fellow, American Association of Neuromuscular and Electrodiagnostic Medicine
Michigan Institute for Neurological Disorders
Director MDA Clinic, Farmington Hills, Michigan
Director MDA/ALS Center, Farmington Hills, Michigan
Anatomy and Physiology of
Neuromuscular Junction
Fusion of acetycholine vesicles with the post-synaptic membrane. www.78stepshealth.us/plasma-membrane/neurons-synapases and
communication,html (with permission).
Three types of Ach receptors at the NMJ (pre-junctional, post-junctional, and extrajunctional.
www.anesthesiauk.com/article.aspx?articleid=228 (with permission).
www.neuromuscular.wust.edu/mudist/dag2.htm (with permission).
Acetylcholine receptor. www.163.178.103.176/TemalG/Grupos1/GermanT1/GATP17/a8.htm (with permission)
LRP4, agrin, MuSK and the formation of acetylcholine receptor.
www.elifesciences.org/content/elite/2/e00220/F11.large.jpg (with permission)
LRPs regulate signaling at the cell surface. (A) Formation of the neuromuscular junction is regulated by
LRP4, which self-associates to form a binding site for agrin at the surface of myotubes. The binding of agrin
to LRP4 then promotes interaction of LRP4 with muscle-specific kinase (MusK), resulting in activation of the
kinase. MuSK then triggers events required to form the postsynaptic apparatus on muscle cells, including the
clustering of acetylcholine receptors (AChRs).
Intracellular pathways activated by agrin for AChR clustering. From: Development 2010;137;7:1017-1033 (with permission).
Classification of Neuromuscular
Disorders
Congenital Neuromuscular Syndromes
Adult Neuromuscular Junction Defects
•
Presynaptic
•
•
Lambert Eaton Myasthenic Syndrome
Toxins/Venoms
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•
•
•
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Tick paralysis
Black Widow Spider
Scorpion
Cation-Induced
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•
•
Tetanus
Magnesium
Calcium
Primary Nerve/Muscle Disorder
•
•
•
•
Peripheral neuropathies
Motor Neuron Disorders
Multiple Sclerosis
Primary Myopathies
Adult Neuromuscular Junction Defects
• Post-synaptic
•
•
Myasthenia gravis
Medication Related
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•
•
•
•
Tetracycline
Oxytetracycline
D-penicillamine
Anticholinesterase
d-Tubocurare (curare-like compounds)
Adult Neuromuscular Junction Defects
•
Pre- and post-synaptic
•
•
Anticonvulsants
Antibiotics
•
•
•
•
•
•
•
Polymyxins
Aminoglycosides
•
•
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Streptomycin
Neomycin
Kanamycin
Amino Acid Derivative
•
•
Lincomycin
Clindamycin
Procainamide
Quinidine
Lithium
Beta-adrenergic Blockers
Myasthenia Gravis
Symptoms/signs of myasthenia gravis.
Unilateral lid ptosis. http://www.genelsaglikbilgileri.com/myasthenia-gravis/ (with
permission)
Extraocular muscle impairment in myasthenia gravis.
Normal neuromuscular junction and myasthenia gravis with simplification of post-synaptic membrane and acetylcholine receptor,
binding and blocking antibodies. http://www.listdisase.wordpress.com/2011/10/03/myasthenia-gravis/
Damage to neuromuscular junction occurs through complement-mediated lysis of endplate region, accelerated
degradation of AChR (cross-linking), and blockade of AChR. http://flipper.diff.org/app/items/info/4314 (with
permission)
Damage to neuromuscular junction occurs through complement-mediated lysis of endplate region, accelerated
degradation of AChR (cross-linking), and blockade of AChR. http://www.californialaserspine.com/ourservices/myasthenia-gravis (with permission)
The immunopathogenesis of myasthenia gravis involves the production of high-affinity anti-acetylcholine receptor (AChR) antibodies
whose synthesis is modulated by and dependent on AChR-specific T-cells that are activated after presentation of AChR peptides by antigenpresenting cells (APC). Autoantibodies reduce the number of functional AChRs mainly by complement-mediated lysis of postsynaptic
membrane and by cross-linking of AChRs, causing enhanced endocytosis and degradation. Direct blockade of the acetylcholine-binding site
on the AChR is a less frequent mechanism. From: Continuum Lifelong Learning 2009;15(1):37 (with permission).
This electron micrograph shows part of a motor end plate in untreated human autoimmune myasthenia gravis. Reprinted with
permission from Engel AG, Tsujihata M, Lindstrom JM et al. The motor end plate in myasthenia gravis and experimental autoimmune
myasthenia gravis. A quantitative ultrastructural study [1976] Ann NY Acad Sci, 274:60-79.
Repetitive nerve stimulation at 3 Hz revealing a significant electrodecremental response between responses one and 4. Immediate
post-exercise reveals facilitation and repair. 2 minute and 6 minutes revealed more significant electrodecremental response (posttetanic exhaustion). http://emedicine.medscape.com/article/1140870-overview (with permission)
Single fiber EMG revealing normal jitter.
Single fiber EMG revealing significantly abnormal jitter in a patient
with myasthenia gravis.
Acetycholine receptor antibody levels/million people in various ages. http://www.mgacharity.org/archive/mganews/0103-01.htm (with permission)
Acetylcholine receptor antibodies binding to the acetylcholine receptor.
http://www.abcam.com/Nicotinic-Acetylcholine-Receptor-beta-3-antibodyCarboxyterminal-end-ab41175.html
Treatment of Myasthenia Gravis
Introduction
Introduction
• Evolved substantially since the mid-twentieth century when
acetylcholinesterase inhibitors represented the mainstay of
treatment
• The adoption of chronic immune suppression (IS) treatment has
significantly improved the prognosis for many MG patients
Introduction
• Along with the observation that mortality in MG has declined
significantly in parallel with adoption of long-term IS
therapies, a recent review of over 1000 patients treated with
IS for at least 1 year showed that all of forms of MG benefited
from IS, with remission rates ranging from 85% in ocular MG
to 47% in thymomatous MG
Introduction
• However, as a rare and rather heterogeneous disorder with
spontaneous relapses and remissions, prospective,
randomized, controlled clinical trials are difficult to perform in
MG, and few therapies have undergone rigorous trials
Introduction
• With an expanding armamentarium of treatment options and
newly-recognized immunological subtypes, the adage that
therapy in MG must be individualized has never been more
relevant
• The overall treatment objective is to restore normal function with an
absolute minimum of treatment side effects
Introduction
• Formulation of an appropriate management strategy requires
consideration of clinical and immunological characteristics of MG and
the risks for treatment complications
• Relevant clinical characteristics include the distribution (ocular, bulbar,
generalized) and severity (mild, moderate, severe, crisis) of myasthenic
weakness and the impact on function
Introduction
• Immunological issues that influence treatment include the presence of
acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK)
antibodies and the presence of thymoma
• Risks for treatment complications relate to age, gender, medical comorbidities, the ability of the patient to obtain the medication and to
comply with drug dosing schedules, and toxicity monitoring
Acetylcholinesterase Inhibitors
Acetylcholinesterase Inhibitors
• Acetylcholinesterase inhibitors (AChEis) impair hydrolysis of
acetylcholine at the neuromuscular junction and increase the
probability for successful neuromuscular transmission
• As symptomatic treatment for MG, AChEis may elicit temporary
improvement in strength, but do not retard the autoimmune attack on
the neuromuscular endplate
Acetylcholinesterase Inhibitors
• Clinical responses to AChEis are often incomplete and variable over time
and in different muscle groups
• No controlled trials using long-acting AChEis have been performed in
MG despite the frequent clinical use of these agents in MG for nearly
seven decades
Acetylcholinesterase Inhibitors
• AChEis are useful as initial therapy for ocular or mild, generalized
MG, and as an adjunct for patients receiving immunotherapy
who have residual symptoms
• The main advantage of AChEis is a lack of long-term side effects
• Disadvantages include the transient and often incomplete improvement
in myasthenic symptoms, frequent dosing schedule, and muscarinic side
effects
Acetylcholinesterase Inhibitors
• Pyridostigmine bromide (Mestinon) is more widely used than
neostigmine bromide (Prostigmin) due to fewer gastrointestinal
side effects
• A long-acting form of pyridostigmine bromide (Mestinon Timespan 180
mg) is absorbed irregularly and therefore tends to be overdosed
• It may be useful in rare patients for bedtime dosing to reduce early
morning weakness, though severe weakness on awakening is very rare
in MG
Acetylcholinesterase Inhibitors
• AChEis are started at a low dosage and gradually titrated upward
to avoid dose-dependent, though transient, muscarinic side
effects including nausea, vomiting, abdominal cramping,
diarrhea, sweating increased bronchial secretions, lacrimation,
diaphoresis, muscle fasciculations, miosis, and occasionally
bradycardia
Acetylcholinesterase Inhibitors
• The gastrointestinal symptoms may be managed with glycopyrollate
(Robinul), diphenoxylate hydrochloride with atropine (Lomotil), and
loperamide hydrochloride (Imodium)
• The initial oral dose or oral pyridostigmine is 30mg 3-4 times per day (i.e.
every 4 hours)
Acetylcholinesterase Inhibitors
• The dosage schedule should be tailored to treat the most symptomatic
muscle weakness and gradually advance to symptom relief or to a
maximum dosage of 90 mg three to four times daily
• A few patients tolerate higher doses (120mg every 4 hours while awake),
but overdosing may elicit increased weakness
Acetylcholinesterase Inhibitors
• If weakness increases despite higher pyridostigmine dosages, no further
increase in the dosage should be made, and IS treatment should be
considered
• Improved muscle strength is usually apparent 20-30 minutes after
dosing with a peak effect around 45 minutes, and the improved strength
may last up to 4 hours
Acetylcholinesterase Inhibitors
• Dose frequency is usually every 4-8 hours or 3-4 times per day
• Contraindications to AChEis include mechanical intestinal or urinary
obstruction, reactive airway disease, and hypersensitivity to
cholinesterase inhibitors
Acetylcholinesterase Inhibitors
• A cholinergic crisis may be precipitated by excessive dosage of
AChEis in the setting of myasthenic exacerbation
• In cholinergic crisis, weakness increases due to depolarization blockade
• Beyond weakness indistinguishable from MG, prominent muscarinic
signs develop
• Excessive oropharyngeal and bronchopulmonary secretions present an
additional risk for aspiration with airway obstruction
Corticosteroids
Corticosteroids
• Corticosteroids (CSa) have wide effects on the immune system
and may ameliorate autoimmune disease by reducing
inflammatory cytokine transcription
• Prednisone elicits rapid and significant improvement or remission in
most MG patients
• In a large retrospective trial, most patients experienced significantly
improved strength after 2-3 weeks of treatment and 80% experienced
marked improvement or remission
Corticosteroids
• The mean time to reach marked improvement or remission was 3.1
months, and the median time to maximum benefit was between 5-6
months
• Prednisone is an appropriate initial treatment for patients with ocular or
generalized myasthenia who fail to achieve a satisfactory response to
AChEis
Corticosteroids
• Although CSs are well known to be rapidly effective in most
patients, the primary disadvantages of CSs are numerous,
predominantly dose- and duration-related side effects
• Risks for side effects include baseline hypertension, glucose intolerance,
diabetes, obesity, glaucoma, osteoporosis, and affective thought
disorders
• An alternative IS therapy may be considered in such patients
Corticosteroids
• With the high-dose treatment strategy, prednisone is dosed at
0.75-1.0 mg/k/day or 60-80 mg/day
• If sustained improvement is documented at a clinical reassessment after
2-4 weeks, the dose is modified to 60mg alternating with 40 mg every
other day x 2 weeks, then 60mg alternating with 20mg every other day x
2 weeks, then 60mg every other day x 1 month, then decrease by 5 mg
weekly (i.e. 55mg qod x 1 week, then 50mg qod x 1 week….)
Corticosteroids
• All dosage reductions should be preceded by clinical assessment of MG
• Some patients do not tolerate alternate day dosing due to variations in
myasthenia, mood swings, or difficulty glycemic control
Corticosteroids
• If symptoms or signs recur at any point, the taper should be stopped
• Myasthenic relapses may be delayed for 2-3 weeks after prednisone
dose reductions
• Although rare patients are successfully tapered off prednisone, most
patients will require indefinite treatment with 10-20 mg on alternate
days unless another IS agent is used
Corticosteroids
• CSs can also be started at a low dosage and slowly increased to
reduce risk for corticosteroid-related exacerbation
• However, the onset of improvement is unpredictable and can be
significantly delayed, and the risk for corticosteroid-related
exacerbation is eliminated
Corticosteroids
• CS side effects are numerous and include glucose intolerance,
hypertension, obesity, osteoporosis, cushingoid features, acne,
skin friability, cataracts, glaucoma, gastric ulceration, juvenile
growth suppression, sodium retention, fluid retention, potassium
loss, mood swings, and personality change
Corticosteroids
• Purified protein derivative (PPD) skin testing should be considered to
screen for tuberculosis prior to beginning treatment with CSs or any
long-term IS therapy
• During CS treatment, blood pressure, weight, serum electrolytes, and
serum glucose are monitored
• Patients are encouraged to maintain a high-protein, low-carbohydrate,
low-fat, low-sodium diet
Corticosteroids
• Calcium supplementation at 1500mg/day and vitamin D is
recommended in order to minimize bone mineral loss
• In postmenopausal women, a baseline bone density is performed and
repeated every 6 months
• If bone density decreases, treatment with a biphosphonate is considered
Corticosteroids
• Corticosteroid-related myasthenic exacerbations may be
precipitated by initial treatment with CSs and result in transient,
but potentially serious increases in weakness in up to 15% of MG
patients
• The increased weakness begins within 7-10 days after beginning CSs and
may last for up to 1 week before strength improves
• Corticosteroids-causes depolarization, which eventually leads to a
reduction in the release of ACh as well as altering MEPPs and
intracellular potassium concentrations
Corticosteroids
• Once improvement begins, further worsening related to CSs is rare
• Patients at high risk for serious exacerbations have moderate or severe
bulbar and/or generalized MG
• As such patients may lapse into myasthenia crisis, they should be
observed in an inpatient setting for the first 10 days of CS treatment
Corticosteroids
• Therapeutic plasma exchange (TPE) may be performed in
patients at high risk prior to beginning CSs in order to
circumvent an exacerbation and to achieve more rapid clinical
improvement
Azathioprine
Azathioprine
• azathioprine (AZA) is metabolized by the liver to 6mercatopurine, an antimetabolite that interferes with nucleotide
synthesis and blocks T-lymphocyte proliferation
• AZA is most commonly used as a steroid-sparing agent in MG, but it is
also used as initial therapy in patients who are at risk for CS side effects
Azathioprine
• In retrospective studies, AZA was effective in 70-90% of MG patients
• A prospective, randomized, double-blind study comparing prednisolone
monotherapy to prednisolone combined with AZA demonstrated a more
durable benefit, along with reduced treatment failures, side effects, and
CS maintenance doses in the combined AZA treatment group
Azathioprine
• AZA may be more effective and better tolerated when used in
combination with CS, and many MG patients taking azathioprine require
a lower dose of adjunctive CSs to maintain control of MG
Azathioprine
• Although it has a favorable side-effect profile when compared to high
dose CS therapy, a 4-8 month delay to improved strength limits the
usefulness of AZA as an initial treatment in patients with symptomatic
MG
• In addition, there is a very small, but increased risk for lymphoma and
other cancers with long term use
Azathioprine
• AZA is initially dosed at 50 mg/day, and the dose is increased by
50mg/day each week to a target dose of 2-3 mg/kg/day
• Relative contraindications include history of AZA idiosyncratic reactions,
malignancy, anemia, leucopenia, thrombocytopenia, and thiopurine
methyltransferase (TPMT) deficiency
Azathioprine
• dose-dependent side effects include myelosuppression with
leucopenia and macrocytic anemia, toxic hepatitis, and alopecia
• a rare, idiosyncratic, hypersensitivity pancreatitis may occur
• serum lipase and amylase assays should be considered for patients with
persistent abdominal pain
Azathioprine
• a more common idiosyncratic reaction involving fever, nausea, vomiting,
abdominal pain, and sometimes rash may occur in 10-15% of patients
during the first 3 weeks of treatment
• the reaction resolves within 1 day of stopping AZA and recurs with drug
rechallenge
• AZA is a potential teratogen and women of childbearing potential
should use effective contraception
Azathioprine
• Surveillance for AZA toxicity should include blood count and liver
transaminases weekly for the first month, then monthly for the
first year of treatment, then every 3-4 months thereafter if the
dosage remains stable
• Erythocyte macrocytosis is expected and acceptable within the
therapeutic dosage range
Azathioprine
• If the white blood cell (WBC) count falls below 3500/mm3, the dosage
should be reduced, and if the WBC falls below 3000/mm3, AZA should be
discontinued
• Screening with TPMT deficiency is suggested prior to beginning
treatment with AZA and should be considered in patients developing
leucopenia on AZA
• Concurrent use of allopurinol increases 5-mercatopurine levels by
inhibition of xanthine oxidase with increased immunosuppressive and
myelosuppressive effects
Mycophenolate Mofetil
Mycophenolate Mofetil
• Mycophenolate mofetil (MMF) selectively suppresses T and B
lymphocyte proliferation by blocking lymphocyte purine
synthesis
• Although several retrospective case series of MMF suggested efficacy in
MG, two recent randomized, controlled trials failed to demonstrate
additional benefit of MMF beyond prednisone (20mg daily as initial IS
therapy) in MG
Mycophenolate Mofetil
• Since many experts remain convinced of the effectiveness of MMF, the
conflict between the negative-controlled trial findings and the positive
retrospective data may owe to study design issues including an
unexpectedly positive response to prednisone, a relatively short period
of study, and a study population with relatively mild MG
Mycophenolate Mofetil
• In light of a favorable side effect profile, MMF is used as an initial
therapy in patients who are at risk for CS side effects
• The onset of benefit occurs around 2-5 months, which is somewhat
earlier than observed with AZA treatment (approximately 4-8 months)
Mycophenolate Mofetil
• The standard dosage for MMF is 1000-1500 mg twice daily
• Higher doses are associated with myelosupression and blood counts
should be checked periodically as surveillance for myelosupression
• Diarrhea, abdominal pain, and nausea are occasionally observed but
rarely require discontinuing the medication
Mycophenolate Mofetil
• Probenecid, acyclovir, and gancylovir may increase the effective level of
mycophenolate due to reduced renal tubular excretion
• Concurrent use with AZA, another purine antagonist, may result in
untoward IS and myelosupression
• MMF is teratogenic and contraindicated in pregnancy
• Women of childbearing potential on MMF must use two effective forms
of contraception
Cyclosporine
Cyclosporine
• Cyclosporine (CyA) disrupts calcineurin signaling with inhibition
of interleukin-2 production and T-cell proliferation
• A randomized, placebo-controlled, double-blind trial of CyA in steroiddependent MG demonstrated significant improvement in CyA
treatment group
• In a long-term retrospective study of patients taking CyA, 96% of
patients demonstrated clinical improvement with CyA treatment and
95% were able to taper or discontinue CSs
Cyclosporine
• Although effective, CyA use in MG has been limited by
nephrotoxicity and numerous drug interactions
• CyA is therefore most often used in refractory, generalized myasthenia
gravis and as a steroid-sparing agent in patients who fail treatment with
AZA and MMF
• With serum levels in a therapeutic range, improved strength is generally
observed within the first 2 months of treatment an maximum
improvement occurs after about 6 months
Cyclosporine
• CyA is administered at 5 mg/kg/day in 2 daily dosages given 12
hours apart
• The desired serum trough level is 100-150 g/L
• Higher serum trough levels are associated with nephrotoxicity
• Serum trough CyA levels, creatinine, and blood pressure should be
monitored every other week until a stable dosage is achieved, then
every 4-8 weeks thereafter
• After stable improvement is achieved, many patients can experience
sustained benefit at lower CyA maintenance doses of 3 mg/kg/day or less
Cyclosporine
• The most common side effects include hypertension,
nephrotoxicity, tremor, hirsutism, gingival hypertrophy,
headaches, nausea, and increased risk of malignancy
• Contraindications include uncontrolled hypertension, renal failure,
pregnancy, and malignancy
Cyclosporine
• CyA is associated with numerous drug interactions that may
result in nephrotoxicity, accumulation of drugs in circulation, and
increases or reductions in serum CyA levels
• Concurrent use of nonsteroidal anti-inflammatory drugs in combination
with CyA may elicit azotemia
• Hyperkalemia may occur when CyA is used with angiotensin converting
enzyme inhibitors, and myopathy may occur when CyA is used with
statins
Cyclophosphamide
Cyclophosphamide
• cyclophosphamide is an alkylating agent that has been used in a
limited fashion for MG, most often in selected cases of severe,
refractory generalized disease
• in a small controlled trial, monthly, intravenous, pulsed doses
• cyclophosphamide (500mg/m2) improved strength and reduced the CS
requirement in patients with refractory, generalized MG
Cyclophosphamide
• in a few cases, cyclophosphamide has also been administered at high
doses (50mg/kg) with marrow ablation and rescue with durable
improvement in MG
• cyclophosphamide side effects include myelosuppression, hemorrhagic
cystitis, infection, and increased cancer risk
• owing to its toxicity and risk profile, cyclophosphamide should be
reserved for the rare patient with severe, highly refractory, generalized
myasthenia
Tacrolimus
Tacrolimus
• Like CyA, tacrolimus (FK506) inhibits calcineurin with reduced
interleukin-2 production resulting in T-Cell suppression
• Although thought to be less nephrotoxic than CyA, hyperglycemia due
to transcriptional inhibition of insulin has been problematic in transplant
populations treated with tacrolimus
Tacrolimus
• There are several reports of effectiveness in MG including a randomized,
unblended trial
• At present, tacrolimus may be a consideration for refractory,
generalized MG patients for steroid sparing who fail to respond to AZA,
MMF, and CyA
• The typical dosing range for MG is 3-5 mg/day
Plasma Exchange
Plasma Exchange
• TPE is an effective short-term treatment for myasthenic
exacerbations or crises, to prepare symptomatic patients for
thymectomy or other surgical procedures, and to prevent
steroid-induced exacerbation in patients with moderate to
severe oropharyngeal or generalized MG
• TPE may also be used chronically in the rare patient with MG refractory
to all other treatments
Plasma Exchange
• During TPE, plasma containing AChR antibodies is removed and
replaced by albumin or by fresh frozen plasma
• Most centers perform a series of five to six exchanges of 2-3 liters every
other day
Plasma Exchange
• Significantly improved strength in a majority of patients in myasthenic
crisis with TPE is well documented in several series, and is supported
by a National Institutes of Health Consensus Statement
•
•
Onset of improvement is variable, but generally occurs after two or three
exchanges
Following a TPE series, improvement in strength is temporary and may last
several weeks at best, unless an immune modulator is used
Plasma Exchange
• Many complications of TPE are associated with large-bore,
central venous catheters, such as venous thrombosis, infection,
and pneumothorax, or are associated with the large volume
shifts occurring during the procedure, such as hypotension,
bradycardia, and congestive heart failure
• Wherever feasible, TPE should be performed via peripheral access using
antecubital veins to reduce morbidity
Intravenous Gammaglobulin
Intravenous Gammaglobulin
• Intravenous immunoglobulin (IVIg) is an effective, short-term
immunotherapy for myasthenic exacerbations or crises and for
surgical preparation
• It may also be used as chronic therapy for selected patients with
refractory disease, or as an alternative to TPE for individuals with poor
venous access
Intravenous Gammaglobulin
• The mechanism for improved MG likely relates to down regulation of
AChR antibodies and/or induction of anti-idiotypic antibodies
Intravenous Gammaglobulin
• Several controlled trials have demonstrated the effectiveness of
IVIg in MG
• A recent controlled trial comparing TPE (1 liter plasma volume exchange
times five exchanges) with IVIg (1 gm/kg daily on 2 consecutive days)
revealed comparable efficacy in response rates and duration of
improvement in patients with moderate to severe MG
Intravenous Gammaglobulin
• IVIg is administered as a 10% solution, and the standard dosage
is 2 gm/kg over 2-5 days
• Treatment over a greater number of days reduces the risk for volume
overload or for solute-induced renal failure
• A standard infusion protocol should be followed allowing for frequent
monitoring of vital signs by experienced staff
Intravenous Gammaglobulin
• Patients with renal insufficiency or diabetic nephropathy are at
risk for acute tubular necrosis with renal failure due to large
solute load associated with the infusions
• In the setting of cardiomyopathy or valvular heart disease, the large
volume associated with the infusions may precipitate congestive heart
failure
Intravenous Gammaglobulin
• Idiosyncratic side effects are similar to those observed in blood
transfusions such as headache, chills, fever, and malaise and may
be controlled by pre-treatment with acetaminophen and
diphenhydramine
• Patients may develop severe vascular headaches with nausea and
vomiting and sterile meningitis
• Volume overload with congestive heart failure and renal failure may
develop in susceptible patients
• High-infusion rates may be associated with thrombosis and stroke
Thymectomy
Thymectomy
• Since Blalock’s early demonstration of remissions following
thymectomy in non-thymomatous myasthenia gravis,
thymectomy procedures have been widely performed to reduce
remissions in MG
• To date, there have been no prospective, randomized studies to access
the technique or effectiveness of thymectomy in non-thymomatous MG
Thymectomy
• In an evidence-based literature review of thymectomy in nonthymomatous MG, there was no Class I studies documenting disease
remission or improvement
•
•
alth0ugh there are several Class 4 studies documenting remission or
improvement
current evidence based reviews conclude that this association could be due
to either thymectomy or differences in study populations
Thymectomy
• It was therefore recommended that in non-thymomatous MG,
thymectomy be considered an option to increase the probability of
remission or improvement
• A large international multi-center trial is currently being conducted to
assess the effect of thymectomy in non-thymomatous MG
Thymectomy
• The response to thymectomy is not immediate and may be delayed for
several years
• Patients with moderate to severe, generalized or bulbar MG should
undergo pre-operative TPE or IVIg infusions to improve strength
Thymectomy
• Thymectomy is rarely performed after the age of 60 years due to
increased surgical risk
• It is thought that thymectomy is more effective when performed early in
the course of MG, though this may owe to the nonlinear remission rate
in MG with remissions more likely to occur early in the disease
Thymectomy
• Whether patients with non-thymomatous ocular MG should undergo
thymectomy remains controversial
• Clinical series of patients with MuSK-positive myasthenia gravis raise
doubt about the benefits of thymectomy in this patient subpopulation,
and there have been no reports to date of thymoma in MuSK-positive
myasthenia gravis
Thymectomy
• though more invasive, the combined transternal-transcervical
technique is considered by many to be optimal, as it permits the
widest surgical exposure for complete removal of thymic tissue
that may be widely distributed in the mediastinum and neck
• The future role for video-assisted, robotic procedures for thymectomy
remains undefined, though less invasive procedures promise reduced
perioperative morbidity along with the possibility for complete removal
of thymic tissue
Thymectomy
• the only absolute indication for thymectomy is the presence of
thymoma, which is observed in 10% to 20% of patients with MG
• surgical removal should be recommended in all patients with thymoma,
understanding that thymectomy is not an emergent or urgent
procedure, and should be undertaken only after treatment of MG is
optimized
Emerging Therapies
Emerging Therapies
• Although the current chronic IS therapies for MG are effective,
they exert broad and relatively nonspecific effects on the
immune system
• TPE and IVIg also provide effective, though transient, immune
modulation with non-antigen specific effects
• Several novel biological agents with highly focused and specific effects
on the immune system have shown promise in MG
Emerging Therapies
• Rituximab is a chimeric, monoclonal antibody directed against
the CD20 B cell surface marker that depletes circulating B
lymphocytes
• Rituximab has been utilized for treatment of B-cell lymphomas and was
recently approved for use in rheumatoid arthritis
Emerging Therapies
• Findings emerging in case reports and small series suggest that
rituximab is effective in some cases of refractory, generalized AChR
antibody-positive MG
• Rituximab may be particularly effective in refractory MuSK MG and may
induce durable remissions lasting for many months
Emerging Therapies
• The dosing strategies for rituximab treatment of lymphoma and
rheumatoid arthritis differ, and the optimal dosing strategy for MG
remains undefined
• Infusions may be associated with fever, chills, nausea, and hypotension
• Though very rare, progressive multifocal leukoencephalopathy
represents the most serious potential complication of rituximab therapy
Emerging Therapies
• Eculizumab is a humanized, monoclonal antibody that blocks
formation of terminal complement membrane attack complex by
inhibiting cleavage of C5
• It is currently approved for use in paroxysmal nocturnal hemoglobinuria
• In a recent small, controlled phase 2 trial, 86% of patients exhibited
significant improvement and over 50% exhibited a marked improvement
in refractory generalized MG
Emerging Therapies
• Belimumab, a human monoclonal antibody against B
lymphocyte stimulator was recently approved for use in systemic
lupus erythematosus, and is currently undergoing clinical trials in
refractory generalized MG
Therapeutic Strategy for Treatment of
Generalized Myasthenia
Therapeutic Strategy for Treatment of
Generalized Myasthenia
• First line-pyridostigmine, prednisone, thymectomy
• Second line-azathioprine, mycophenolate mofetil
• Third line-cyclosporine, tacrolimus
• Fourth line-plasma exchanges (serial), IVIg (serial), rituximab,
cyclophosphamide
• Fifth line-total lymphoid irradiation, stem cell transplant
• 30mg to 90 mg every 4-5 hours
• 40 mg/d to 80 mg/d
Pyrdiostigmine
Prednisone
Thymectomy
Azathioprine
Mycophenolate mofetil
IVIg
Cyclosporine
Tacrolimus
Plasma exchange
Rituximab
Cyclophosphamide
Total lymphoid
irradiation
Stem cell replacement
• 2mg/kg/d to 3 mg/kg/d
• 2 gm/d to 3 gm/d
• 2 gm/kg over 4-5 days
• 4 mg/kg/d-5 mg/kg/d in two divided doses
• 2 mg/d to 3 mg/d
• 1 to 3 exchanges every 2 to 4 weeks
• 375 mg/m2 weekly x 4
• 500mg/m2 IV monthly
Treatment of Other Forms of Myasthenia
• Ocular myasthenia-acetylcholinesterase inhibitor, prednisone
• MuSK antibody syndrome-prednisone, mycophenolate mofetil, plasma
exchange, rituximab
• Myasthenia gravis in pregnancy-corticosteroids, plasma exchange, and IVIg
Evidenced-Based Guideline: Intravenous
Immunoglobulin in the
Treatment of Neuromuscular Disorders [Report
of the Therapeutics and Technology Assessment
Subcommittee of the American Academy of
Neurology]
Evidenced-based guideline: Intravenous immunoglobulin in the
treatment of neuromuscular disorders [Report of the Therapeutics and Technology
Assessment Subcommittee of the American Academy of Neurology]
• Conclusions
•
•
Based on one Class 1 study, IVIg is probably effective in treating patients with MG
Evidence is insufficient to compare the efficacy of IVIg and plasmapharesis in treating
MG
• Recommendations
•
IVIg should be considered in the treatment of MG (Level B)
Evidenced-Based Guideline: Intravenous Immunoglobulin in the
Treatment of Neuromuscular Disorders [Report of the Therapeutics and
Technology Assessment Subcommittee of the American Academy of Neurology
• Clinical context
• This recommendation was based on studies involving primarily
moderately or severely affected patients
• The benefits and risks of this medication should be weighed carefully in
patients with mild MG
• Further studies of IVIg efficacy in MG are warranted due to the few
randomized trials and small study size to date
Consensus statement: The Use of
Intravenous Immunoglobulin in the
Treatment of Neuromuscular Conditions
[Report of the AANEM AD HOC Committee]
Consensus statement: The Use of Intravenous
Immunoglobulin in the Treatment of Neuromuscular
Conditions [Report of the AANEM AD HOC Committee]
• Class I evidence supports the prescription of IVIg to treat patients
with Guillain-Barre syndrome (GBS), CIDP, multifocal motor
neuropathy, refractory exacerbations of myasthenia gravis,
Lambert-Eaton syndrome, dermatomyositis, and stiff person
syndrome
Retrospective Review MDA/MIND (1991-2013):
224 patients with MG
Incidence
Incidence
• Generalized myasthenia: 197 patients (88%)
• Ocular myasthenia: 18 patients (8%)
• Ocular-bulbar-Anti-MuSK antibody positive: 9 patients (4%)
• Myasthenic crisis: 38 patients (17%)
Treatment of Generalized Myasthenia
Treatment of Generalized Myasthenia
• First line
• Pyridostigmine: 197 patients (100%)
• IVIg: 167 patients (84.7%), primary treatment alone-87 patients (52.1
%)
• Prednisone-30 patients (15.3%)-0% as primary treatment alone
• Thymectomy-thymoma-25 patients (13%)
Treatment of Generalized Myasthenia
• Second line
• Mycophenolate mofetil (MM)added to IVIg + AChI: 80 patients (47.9%)
• Azathoprine added to prednisone + AChI-25 patients (85.0%)
• MM added to prednisone + AChI-5 patients (15%)
Treatment of Generalized Myasthenia
• Third line
• Of the 80 patients treated with IVIg and MM, 6 patients (7%) had MM
discontinued, and cyclosporine instituted
• Of the 25 patients treated with prednisone and azathioprine, 2 patients
(6%) treated with cyclosporine
• Of the 6 patients treated with IVIg and cyclosporine, 2 patients placed
on tacrolimus
• Of the 2 patients treated with prednisone and cyclosporine, one patient
had cyclosporine stopped and switched to tacrolimus
Treatment of Generalized Myasthenia
• Fourth line
• Of the 2 patients treated with IVIg and tacrolimus, IVIg and tacrolimus
discontinued, two patients treated with recurrent plasma exchanges
followed by rituxin
• Of the patient treated with prednisone + tacrolimus, patient failed to
respond, prednisone weaned, tacrolimus discontinued, and PE + rituxin
tried
Treatment of Generalized Myasthenia
• Fifth line
• Of 3 patients on PE + rituxin, 1 patient had lymphoid radiation and stem
cell replacement (Northwestern University)
Tiers of treatment for myasthenia gravis-DAS (1991-2013)
Pyridostigmine
IVIg
Prednisone
Thymectomy
Mycophenolate mofetil
Azathioprine
Cyclosporine
•30mg -120 mg every 4 hours while awake; 180mg SR if patient awakens with weakness
•0.5 gm/kg IBW daily x 4,then 1.0 gm/kg IBW every 2 weeks x 3, then 1.0gm/kg IBW every 3 weeks x 2, then 1.0 gm/kg IBW every 4 weeks and maintain
•60mg oral daily x 1 month, then 60mg alternating with 40mg every other day x 2 weeks, then 60mg alternating with 20mg every other day x 2 weeks, then 60 mg every other day x 1
month, then 55mg every other day x 1 week, then 50mg every other day x 1 week, then 45......(decreasing by 5 mg per week to a dose that maintains cliinical symptoms
• 2 gm/d to 3 gm/d
• 50mg daily x 1 week, then 50mg bid x 1 week, then 50mg tid
• 4 mg/kg/d to 5mg/kg/d divided in two doses
• 2mg/d to 3mg/d
Tacrolimus
Plasma exchange (serial
treatments)
Rituximab
Cyclophosphamide
Total lymphoid irradiation
Stem cell transplant
• 2-3 liter exchanges every 2-4 weeks
• 325 mg/m2 weekly x 4, repeat if needed in 6 months
• 500 mg/m2 IV montly
Tiers of treatment for myasthenia gravis-Current Recommendations (2014)
Treatment of Ocular Myasthenia
Treatment of Ocular Myasthenia
• Pyridostigmine-27 patients treated, 3/27 (11.1%) able to be
maintained alone
• Prednisone + pyridostigmine
• 10mg-24/27 patients treated, 18 (75%) improved and controlled
• 20mg-of 6 patients not improved on Pred 10mg and AChI, 5/6 controlled
on Pred 20mg + AChI
• 30mg-patient which was not controlled on Pred 20mg + AChI was
controlled
Treatment of Ocular Myasthenia-DAS protocol
Anti-MuSK Antibody Syndrome
Anti-MuSK Antibody Syndrome
•
pyridostigmine alone-0/38 patients controlled
• non-crisis (34/38 patients): Prednisone + MM-29/34 patients
controlled (85.2%)
• of the 5 patients not in crisis and not controlled on Pred + MM, 3
responded to addition of 1-2 PE
Anti-MuSK Antibody Syndrome
• crisis (4/38 patients)
• PE 1-2 exchanges + Pred + MM (3/4 patients controlled) (96%)
• Of the 2 patients, not presenting in crisis,that did not respond to
Pred + MM + PE, addition of rituxin controlled symptoms
• Of the 1 patient, presenting in crisis, and no response to PE (up to 5
exchanges), and on Pred (60mg) + MM (2000mg), rituxin of benefit
Treatment of anti-MuSK MG-DAS protocol
Rituximab 325 mg/m2 weekly x 4 weeks, can repeat in 6
months
Plasma exchange 2-3 liters 1-2 exchanges
Mycophenolate 1000mg bid, can increase if needed to
2500mg x 1 week, then if needed 3000mg daily
Prednisone 60mg daily x 1 month, then 60mg
alternating with 40mg qod, then 60 mg alternating with
20mg qod, then 60mg qod x 1 month, then decrease by
5 mg weekly (i.e. 55mg qod x 1 week, then 50mg qod x 1
week...to lowest dose along with mycophenolate .
Anti-MuSK MG usually non-responsive to anti-cholinesterase medication, IVIg,
azathioprine.
Treatment of Mysathenic Crisis
Treatment of Myasthenic Crisis (DAS protocol)
ER
• ABC (ABG, Chest xray, FVC)
• Intubate if evidence of respiratory muscle fatigue with increasing tachypna and declining tital volumes, hypoxemia, hypercapnea, and difficulty with
secretions
• If not intubated, FVC and negative inspiratory force (NIF) every 4 hours; intubate if FVC below 1 liter and NIF 20 cm H2O or less
• Discontinue cholinesterase medication
ICU
ICU
•
•
•
•
•
Treat infections if present (i.e. pneumonia, UTI, bacteremia/septicemia)
Plasma exchanges 2-3 liters qod x 5; replace volume/volume with albumin; start PE ASAP
IVIg of similar efficacy to PE, but prefer PE in MG crisis
Swittch as many of the other medications that patient was taking prior to admission to IV route if possible
Insert NG tube for enteral feedings and for other medicaations that cannot be administered IV (i.e.mycophenolate, imuran)
• Do not rush to get patient off mechanical ventilation
• Allow at least 2 plasma exchanges , which will result in more successful attempts at extubation
ICU
ICU
ICU
• Weaning trials should begin after pateints demonstrate a clear trend of improved respiratory muscle strength (usually at a vital capacity greater than
15 ml/kg)
• The trial should be terminated if the patient exhibits any sign of respiratory fatigue (tachypnea, tachycardia, diaphoriesis, or agitation
•
•
•
•
•
Once determined to be ready for weaning , restart cholinesterase inhibitors at 30mg every 4 hours
Extubate
Continue to monitor FVC and NIF
Once respiratory status determined to be stable and no difficulty with secretions, titer up the cholinesterase medication (i.e. 60 mg every 4 hours )
Discontinue NG tube if no dysphagia and secretions controlled
• After 3rd plasma exchange, start IV Solumedrol 125mg q 6 hours (if still on ventilator); 60mg oral prednisone if off the ventilator
ICU/Step downtelemetry
Step
down/telemetry
• Continue prednisone 60mg daily and anti-cholinesterase medication 60mg every 4 hours
• Finish plasma exchanges for a total of 5
• PT/OT
• Discharge to home if fullly stable
• Discharge to subacute rehab if needed
Regular floor