Robert L. Segal, MD, FRCS(C)
Arthur L. Burnett, II, MD, MBA, FACS
BASICS
DESCRIPTION
• Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by weakness and early fatigability of the skelet al muscles due to antibody-mediated loss of nicotinic acetylcholine (Ach) receptors (1,2)
• Involvement of the external striated urethral sphincter is rare but may be vulnerable to dysfunction after transurethral resection of the prostate (TURP), explaining the relatively high incidence of post-TURP incontinence in this group (3)
• Although smooth muscle is generally not affected, there are rare reports of detrusor areflexia (4)
• Urologic complaints are uncommon but may include incontinence, urgency, retention, or erectile dysfunction
EPIDEMIOLOGY
Incidence
Published estimates of 2–21 cases per million people per year (1,2)
Prevalence
• In patients <40 yr:
– Female > Male (7:3)
• In the 5th decade, new cases of MG are evenly split between the genders
• After the 5th decade:
– Male > Female (3:2) (1,2)
RISK FACTORS
• Thymic hyperplasia is observed in 65–75% of patients (1,2)
• MG has been described as a paraneoplastic syndrome related to renal cell carcinoma (RCC) (5), as well as other malignancies (thymoma, lymphoma, lung cancer, Kaposi’s sarcoma) (6)
Genetics
• Congenital myasthenia syndromes, a subset of MG, stem from genetic mutations resulting in abnormal neuromuscular transmission (1,2)
• HLA types B8 and DR3 are associated with MG
PATHOPHYSIOLOGY
• Autoantibodies develop against Ach nicotinic postsynaptic receptors (1,2).
• The autoantibodies mechanically block the neuromuscular junction binding site and eventually destroy them.
• Cholinergic nerve conduction to striated skelet al muscle is thus impaired.
• Clinical symptoms begin to develop when the number of Ach receptors is reduced to ∼30% of the normal level.
• Smooth and cardiac muscle are not affected.
• The role of the thymus in MG is unclear, but it is suspected to be a site of autoantibody formation.
• A majority of patients with MG have thymic hyperplasia or thymoma.
• Many patients improve clinically following thymectomy.
ASSOCIATED CONDITIONS
• Neonatal MG is a transitory disorder resulting from passive maternal antibody transfer to the fetus.
• Congenital myasthenic syndromes result from genetic mutations that lead to abnormal neuromuscular transmission.
• Ocular MG refers to weakness limited to the extraocular muscles and eyelids.
GENERAL PREVENTION
None
DIAGNOSIS
HISTORY
• Reduced exercise tolerance that improves with rest and worsens with warm temperature (eg, after a hot bath)
• The natural history of MG usually follows a characteristic pattern that initially involves weakness of eyelids and extraocular muscles.
• Difficulty climbing stairs is typical of generalized weakness in MG.
• Weakness is variable and fluctuating, but tends to be worse later in the day.
PHYSICAL EXAM
• Muscle fatigability can be tested for many muscles by repeated action: Ptosis, diplopia, dysphagia, and peripheral muscle weakness
• “Dropped head syndrome”
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Serology tests demonstrate anti-ACh receptor antibodies in ∼90% of patients
• ∼50% of patients who test negative for anti-ACh receptor antibodies have antibodies against the MuSK protein.
Imaging
• Chest computed tomography (CT) to rule out thymoma
• If level of suspicion is high, CT abdomen to rule out RCC (5)
Diagnostic Procedures/Surgery
• Edrophonium chloride test: Positive for MG if IV administration unequivocally yields improved strength
• Repetitive nerve stimulation
• Single-fiber electromyography
• Complete urodynamic evaluation if urologic symptoms are present (4)
• Urodynamics:
– If bladder dysfunction present, resembles lower motor neuron pattern with variable areflexia or atonia
– In one UDS series 63% failing to empty completely due to hypocontractile bladders and 6% had complete areflexia
Pathologic Findings
N/A
DIFFERENTIAL DIAGNOSIS
• Acute inflammatory demyelinating polyradiculoneuropathy
• Botulism
• Lambert–Eaton syndrome
TREATMENT
GENERAL MEASURES
• Intermittent catheterization for rare cases of refractory detrusor areflexia (4)
• Adjust mealtimes to take advantage of daily periods of relative strength
• Install railing in household places where it will be needed for support in rising, such as adjacent to the bathtub and toilet
• Use electric toothbrushes and can openers to conserve strength
• Generalized muscle weakness in the acute setting should prompt careful attention to the possibility of respiratory failure
• Patients with MG have symptoms worsened with high core or ambient temperature; therefore, muscle strength will likely improve when a fever is treated with antipyretics
• Urinary tract symptoms, if present, may respond favorably to therapy for MG
MEDICATION
First Line
• Cholinesterase inhibitors (neostigmine, pyridostigmine) provide temporary strength improvement in patients with MG.
• Corticosteroids can produce rapid improvements in MG but are associated with numerous dose-dependent side effects
Second Line
• Plasmapheresis is reserved for short-term treatment in response to myasthenic exacerbations or crises.
• Intravenous immunoglobulin (IgG) also provides short-term improvements in strength during myasthenic exacerbations or crises as an alternative for patients who are poor plasmapheresis candidates because of vascular access issues.
• Immunosuppressive agents (azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate mofetil, rituximab, tacrolimus) for steroid-sparing protocols, or for refractory disease (6)
SURGERY/OTHER PROCEDURES
• If surgical intervention for bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH) is being considered, some advocate suprapubic prostatectomy to reduce risk of incontinence (3)
• Thymectomy results in complete remission in 35% of cases and clinical improvement in 85% of patients
• If MG presents as paraneoplastic syndrome associated with RCC, effective treatment for RCC may resolve MG symptoms (5)
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
β-Agonist and anticholinergic bronchodilators can reduce bronchospasm and respiratory distress resulting from cholinergic medications.
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Most (96%) of patients have normal lifespan when appropriate medical care involving cholinesterase inhibitors, plasmapheresis, and immunosuppressive agents is given.
• Thymectomy results in complete remission in about 1/3 of patients, but the postsurgical prognosis is otherwise highly variable.
COMPLICATIONS
• Post-TURP incontinence
• Respiratory failure
• Cholinergic crisis from excessive use of cholinesterase inhibitors
• Multiple complicating effects may result from chronic steroid use, including poor wound healing and opportunistic infection
FOLLOW-UP
Patient Monitoring
Patients with MG should be followed by a neurologist with urology referral as needed.
Patient Resources
National Institute of Neurological Disorders and Stroke: Myasthenia Gravis Fact Sheet (http://www.ninds.nih.gov/disorders/myasthenia_gravis/detail_myasthenia_gravis.htm Accessed August 8, 2014)
REFERENCES
1. Phillips LH. The epidemiology of myasthenia gravis. Ann NY Acad Sci. 2003;998:407–412.
2. Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis. Lancet 2001;357:2122–2128.
3. Wise GJ, Gerstenfeld JN, Brunner N, et al. Urinary incontinence following prostatectomy in patients with myasthenia gravis. Br J Urol. 1982;54:369–371.
4. Christmas TJ, et al. Detrusor failure in myasthenia gravis. Br J Urol. 1990;65:422.
5. Torgerson EL, Khalili R, Dobkin BH, et al. Myasthenia gravis as a paraneoplastic syndrome associated with renal cell carcinoma. J Urol. 1999;162(1):154–155.
6. van Sonderen A, Wirtz PW, Verschuuren JJ, et al. Paraneoplastic syndromes of the neuromuscular junction: Therapeutic options in myasthenia gravis, lambert-eaton myasthenic syndrome, and neuromyotonia. Curr Treat Options Neurol. 2013;15(2):224–239.
ADDITIONAL READING
Mayo ME, Chetner MP. Lower urinary tract dysfunction in multiple sclerosis. Urology. 1992;39(1):67–70.
See Also (Topic, Algorithm, Media)
Neurogenic Bladder, General
CODES
ICD9
• 358.00 Myasthenia gravis without (acute) exacerbation
• 788.30 Urinary incontinence, unspecified
• 788.63 Urgency of urination
ICD10
• G70.00 Myasthenia gravis without (acute) exacerbation
• N39.41 Urge incontinence
• R32 Unspecified urinary incontinence
CLINICAL/SURGICAL PEARLS
• Patients with MG may develop voiding dysfunction, most commonly detrusor areflexia resulting in urinary retention.
• Urinary incontinence may develop after TURP.
• Urologic symptoms may be improved by systemic MG therapy, although specific therapy for urologic complications, such as urinary retention or incontinence, may need to be instituted.