IN BRIEF
Distal Myasthenia Gravis Michael G. Fitzgerald, MD, Adam B. Shafritz, MD
M
(MG) is an autoimmune disorder that targets the acetylcholine (Ach) receptors at the neuromuscular junction of skeletal muscle causing progressive weakness and fatigue. The ocular, bulbar, trunk, and proximal extremity musculature are the groups most commonly affected. Clinical examination is suggestive of the diagnosis1e3; however, some presentations are atypical. Therefore, subspecialists other than neurologists may make the diagnosis in these cases. A documented but rare form of MG, called distal myasthenia gravis,1,2,4,5 can occur with isolated involvement of the distal extremities and can even present only in the hands. YASTHENIA GRAVIS
PREVALENCE, DIAGNOSIS, AND PATHOPHYSIOLOGY The prevalence of MG approximates 20.4 per 100,000 people. In the year 2000, it was estimated that 26,000 people in the United States were affected. The incidence seems to be increasing, possibly owing to better detection methods.6 There is a bimodal distribution of the disease, with one peak primarily affecting women in their teens and 20s, and the second peak affecting men in their 50s and 60s.7 MG presents with weakness, which tends to increase with repetitive movement. Classically, facial and bulbar muscles are affected, leading to ptosis and diplopia in the majority of patients. This weakness usually progresses to generalized weakness in the proximal limb and trunk muscles. In severe forms, patients may require mechanical ventilation owing to diaphragm involvement.7 The differential diagnosis includes hyperthyroidism, Graves’ From the Department of Orthopaedic Surgery, University of Vermont College of Medicine Burlington, Vermont. Received for publication September 23, 2013; accepted in revised form December 22, 2013. No benefits in any form have been received or will be received related directly or indirectly to the subject of this article. Corresponding author: Adam B. Shafritz, MD, Department of Orthopaedic Surgery, University of Vermont College of Medicine, 428 Stafford Hall, 95 Carrigan Dr., Burlington, VT 05405; e-mail: [email protected]. 0363-5023/14/---0001$36.00/0 http://dx.doi.org/10.1016/j.jhsa.2013.12.036
disease, motor cortex lesions, distal myopathies, Lambert-Eaton myasthenia syndrome, and botulism.7,8 The pathophysiology involves production of immunoglobulin G (IgG) autoantibodies that irreversibly bind to Ach receptors at the motor end plate, thus preventing contraction of skeletal muscle. However, Ach receptors undergo continual turnover, and therefore, complete recovery with appropriate treatment is possible.7 Thymus dysfunction is associated with MG and 60% of patients have been found to have a hypertrophic thymus.9 Diagnostic tests include the anticholinesterase test, repetitive nerve stimulation, receptor antibody assay, and electrodiagnostics, if necessary. The most specific test is the receptor antibody assay. However, only 85% of patients are positive for antibodies.4 Electrodiagnostic testing shows a typical, yet not pathognomonic, progressive decrement in the compound muscle action potential (CMAP) when using repetitive nerve stimulation (RNS). Single-fiber electromyography (EMG) will show an increase in the magnitude of neuromuscular jitter (the variation in latency between the nerve activation and the muscle action potential) as well as intermittent impulse blockage.10 DISTAL MG Although rare, the disease can present as solely distal upper extremity weakness11,12 or these symptoms may develop years after the initial typical findings.6 Case reports describing the presentation of distal MG usually demonstrate extensor and abductor weakness of one or both hands.5,11,12 Karacostas et al11 described a case of a 30-year-old woman who developed right-hand weakness and 4 months later developed left hand weakness with no other neurological deficit. An extensive work-up was normal except for markedly elevated IgG autoantibodies to Ach receptors and an amplitude decrement of greater than 20% in 4 different muscles of the right hand with RNS. She went on to develop more classic symptoms (ie, diplopia) more than a year after her hand weakness started.11 De Carvalho and Geraldes12 described a case of unilateral distal MG in a 35-year-old woman who experienced 5 years of right hand weakness with
Ó 2014 ASSH
r
Published by Elsevier, Inc. All rights reserved.
r
1
2
DISTAL MYASTHENIA GRAVIS
6 months of acute worsening with no other symptoms. She was found to have positive Ach receptor autoantibodies and a thymoma that was resected. She later went on to develop classic signs of MG but improved with increased prednisolone therapy and intravenous immunoglobulin (IVIG).12 These cases demonstrate that distal MG can be the first or only signs of the disease and can be subtle, unilateral, and in some cases, quite long-standing. Two groups have retrospectively reviewed distal myasthenia gravis in the past 15 years. Nations et al5 found that 3% of 236 patients with a confirmed diagnosis of MG had distal extremity weakness exceeding proximal weakness. More recently, Werner et al1 found that 6 of 84 (7%) patients with MG had a predominance of distal limb muscle weakness and fatigability; 5 of the 6 patients were primarily affected in the intrinsic and extensor hand muscles. This weakness was seen either at presentation or in a later stage of the illness.
given to decrease the effects of the autoantibodies. There is some evidence to show that it can have significant effect in severe cases of MG. There is conflicting evidence with regard to its overall efficacy, but some studies have shown that it is similar to plasma exchange and may have fewer side effects.9 In conclusion, MG is a debilitating neuromuscular disorder that normally affects the proximal, trunk, and facial musculature, but it can also be seen in isolation in the distal extremities, including the hands. The symptoms can have insidious onset, and distal MG may be the only presenting feature for years. It is important for hand surgeons to be able to identify this condition and to understand the possible etiology of the presenting symptoms so that the appropriate treatment and referrals can be initiated promptly. REFERENCES 1. Werner P, Kiechl S, Loscher W, Poewe W, Willeit J. Distal myasthenia gravis—frequency and clinical course in a large prospective series. Acta Neurol Scand. 2003;108(3):209e211. 2. Renard D, Castelnovo G, Labauge P. Distal myasthenia gravis. Acta Neurol Belg. 2008;108(3):107e108. 3. Öztürk A, Deymeer F, Serdaroglu P, Parman Y, Özdemir C. Distribution of extremity weakness in myasthenia gravis: sparing of tibialis anterior muscle. Acta Myol. 2003;22(2):58e60. 4. Uncini A, Di Guglielmo G, Di Muzio A, et al. Distal myasthenia gravis and sensory neuronopathy with anti-50 kDa antibody mimicking sensory-motor neuropathy. J Neurol Neurosurg Psychiatry. 1997;63(3): 414e415. 5. Nations SP, Wolfe GI, Amato AA, Jackson CE, Bryan WW, Barohn RJ. Distal myasthenia gravis. Neurology. 1999;52(3): 632e634. 6. Phillips LH. The epidemiology of myasthenia gravis. Ann N Y Acad Sci. 2003;998:407e412. 7. Drachman DB. Myasthenia gravis. N Engl J Med. 1994;330(25): 1797e1810. 8. Janssen JC, Larner AJ, Harris J, Sheean GL, Rossor MN. Myasthenic hand. Neurology. 1998;51(3):913e914. 9. Skeie GO, Apostolski S, Evoli A, et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol. 2010;17(7):893e902. 10. Meriggioli MN, Sanders DB. Myasthenia gravis: diagnosis. Semin Neurol. 2004;24(1):31e39. 11. Karacostas D, Mavromatis I, Georgakoudas G, Artemis N, Milonas I. Isolated distal hand weakness as the only presenting symptom of myasthenia gravis. Eur J Neurol. 2002;9(4):429e430. 12. De Carvalho M, Geraldes R. Longstanding right hand weakness in a patient with myasthenia gravis. Muscle Nerve. 2006;34(5):670e671.
TREATMENT There are many different options for treatment of MG. The first line of treatment is with Ach esterase inhibitors. Pyridostigmine is most commonly used and allows for increased Ach availability at the neuromuscular junction. Other treatment options focus on immune modulation therapy, which includes corticosteroids, methotrexate, azathioprine, and cyclosporin. These usually need to be continued indefinitely and may have adverse side effects. Thymectomy is recommended for those with a thymoma, but it can also be used for patients without thymus pathology to potentially decrease the immunological response. This usually takes months to have any effect, but remission can be seen in almost 35% of patients.7,9 Other treatments include plasma exchange and IVIG. Plasma exchange works well for short-term relief of MG and is frequently used to transition between other treatment modalities. This consists of removing the specific antibodies from the patient’s blood by membrane filtration. It has a much quicker efficacy than thymectomy, and usually symptomatic relief is seen within 1 week.9 IVIG is a treatment
J Hand Surg Am.
r
Vol. -, - 2014
Distal Myasthenia Gravis Michael G. Fitzgerald, MD, Adam B. Shafritz, MD
M
(MG) is an autoimmune disorder that targets the acetylcholine (Ach) receptors at the neuromuscular junction of skeletal muscle causing progressive weakness and fatigue. The ocular, bulbar, trunk, and proximal extremity musculature are the groups most commonly affected. Clinical examination is suggestive of the diagnosis1e3; however, some presentations are atypical. Therefore, subspecialists other than neurologists may make the diagnosis in these cases. A documented but rare form of MG, called distal myasthenia gravis,1,2,4,5 can occur with isolated involvement of the distal extremities and can even present only in the hands. YASTHENIA GRAVIS
PREVALENCE, DIAGNOSIS, AND PATHOPHYSIOLOGY The prevalence of MG approximates 20.4 per 100,000 people. In the year 2000, it was estimated that 26,000 people in the United States were affected. The incidence seems to be increasing, possibly owing to better detection methods.6 There is a bimodal distribution of the disease, with one peak primarily affecting women in their teens and 20s, and the second peak affecting men in their 50s and 60s.7 MG presents with weakness, which tends to increase with repetitive movement. Classically, facial and bulbar muscles are affected, leading to ptosis and diplopia in the majority of patients. This weakness usually progresses to generalized weakness in the proximal limb and trunk muscles. In severe forms, patients may require mechanical ventilation owing to diaphragm involvement.7 The differential diagnosis includes hyperthyroidism, Graves’ From the Department of Orthopaedic Surgery, University of Vermont College of Medicine Burlington, Vermont. Received for publication September 23, 2013; accepted in revised form December 22, 2013. No benefits in any form have been received or will be received related directly or indirectly to the subject of this article. Corresponding author: Adam B. Shafritz, MD, Department of Orthopaedic Surgery, University of Vermont College of Medicine, 428 Stafford Hall, 95 Carrigan Dr., Burlington, VT 05405; e-mail: [email protected]. 0363-5023/14/---0001$36.00/0 http://dx.doi.org/10.1016/j.jhsa.2013.12.036
disease, motor cortex lesions, distal myopathies, Lambert-Eaton myasthenia syndrome, and botulism.7,8 The pathophysiology involves production of immunoglobulin G (IgG) autoantibodies that irreversibly bind to Ach receptors at the motor end plate, thus preventing contraction of skeletal muscle. However, Ach receptors undergo continual turnover, and therefore, complete recovery with appropriate treatment is possible.7 Thymus dysfunction is associated with MG and 60% of patients have been found to have a hypertrophic thymus.9 Diagnostic tests include the anticholinesterase test, repetitive nerve stimulation, receptor antibody assay, and electrodiagnostics, if necessary. The most specific test is the receptor antibody assay. However, only 85% of patients are positive for antibodies.4 Electrodiagnostic testing shows a typical, yet not pathognomonic, progressive decrement in the compound muscle action potential (CMAP) when using repetitive nerve stimulation (RNS). Single-fiber electromyography (EMG) will show an increase in the magnitude of neuromuscular jitter (the variation in latency between the nerve activation and the muscle action potential) as well as intermittent impulse blockage.10 DISTAL MG Although rare, the disease can present as solely distal upper extremity weakness11,12 or these symptoms may develop years after the initial typical findings.6 Case reports describing the presentation of distal MG usually demonstrate extensor and abductor weakness of one or both hands.5,11,12 Karacostas et al11 described a case of a 30-year-old woman who developed right-hand weakness and 4 months later developed left hand weakness with no other neurological deficit. An extensive work-up was normal except for markedly elevated IgG autoantibodies to Ach receptors and an amplitude decrement of greater than 20% in 4 different muscles of the right hand with RNS. She went on to develop more classic symptoms (ie, diplopia) more than a year after her hand weakness started.11 De Carvalho and Geraldes12 described a case of unilateral distal MG in a 35-year-old woman who experienced 5 years of right hand weakness with
Ó 2014 ASSH
r
Published by Elsevier, Inc. All rights reserved.
r
1
2
DISTAL MYASTHENIA GRAVIS
6 months of acute worsening with no other symptoms. She was found to have positive Ach receptor autoantibodies and a thymoma that was resected. She later went on to develop classic signs of MG but improved with increased prednisolone therapy and intravenous immunoglobulin (IVIG).12 These cases demonstrate that distal MG can be the first or only signs of the disease and can be subtle, unilateral, and in some cases, quite long-standing. Two groups have retrospectively reviewed distal myasthenia gravis in the past 15 years. Nations et al5 found that 3% of 236 patients with a confirmed diagnosis of MG had distal extremity weakness exceeding proximal weakness. More recently, Werner et al1 found that 6 of 84 (7%) patients with MG had a predominance of distal limb muscle weakness and fatigability; 5 of the 6 patients were primarily affected in the intrinsic and extensor hand muscles. This weakness was seen either at presentation or in a later stage of the illness.
given to decrease the effects of the autoantibodies. There is some evidence to show that it can have significant effect in severe cases of MG. There is conflicting evidence with regard to its overall efficacy, but some studies have shown that it is similar to plasma exchange and may have fewer side effects.9 In conclusion, MG is a debilitating neuromuscular disorder that normally affects the proximal, trunk, and facial musculature, but it can also be seen in isolation in the distal extremities, including the hands. The symptoms can have insidious onset, and distal MG may be the only presenting feature for years. It is important for hand surgeons to be able to identify this condition and to understand the possible etiology of the presenting symptoms so that the appropriate treatment and referrals can be initiated promptly. REFERENCES 1. Werner P, Kiechl S, Loscher W, Poewe W, Willeit J. Distal myasthenia gravis—frequency and clinical course in a large prospective series. Acta Neurol Scand. 2003;108(3):209e211. 2. Renard D, Castelnovo G, Labauge P. Distal myasthenia gravis. Acta Neurol Belg. 2008;108(3):107e108. 3. Öztürk A, Deymeer F, Serdaroglu P, Parman Y, Özdemir C. Distribution of extremity weakness in myasthenia gravis: sparing of tibialis anterior muscle. Acta Myol. 2003;22(2):58e60. 4. Uncini A, Di Guglielmo G, Di Muzio A, et al. Distal myasthenia gravis and sensory neuronopathy with anti-50 kDa antibody mimicking sensory-motor neuropathy. J Neurol Neurosurg Psychiatry. 1997;63(3): 414e415. 5. Nations SP, Wolfe GI, Amato AA, Jackson CE, Bryan WW, Barohn RJ. Distal myasthenia gravis. Neurology. 1999;52(3): 632e634. 6. Phillips LH. The epidemiology of myasthenia gravis. Ann N Y Acad Sci. 2003;998:407e412. 7. Drachman DB. Myasthenia gravis. N Engl J Med. 1994;330(25): 1797e1810. 8. Janssen JC, Larner AJ, Harris J, Sheean GL, Rossor MN. Myasthenic hand. Neurology. 1998;51(3):913e914. 9. Skeie GO, Apostolski S, Evoli A, et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol. 2010;17(7):893e902. 10. Meriggioli MN, Sanders DB. Myasthenia gravis: diagnosis. Semin Neurol. 2004;24(1):31e39. 11. Karacostas D, Mavromatis I, Georgakoudas G, Artemis N, Milonas I. Isolated distal hand weakness as the only presenting symptom of myasthenia gravis. Eur J Neurol. 2002;9(4):429e430. 12. De Carvalho M, Geraldes R. Longstanding right hand weakness in a patient with myasthenia gravis. Muscle Nerve. 2006;34(5):670e671.
TREATMENT There are many different options for treatment of MG. The first line of treatment is with Ach esterase inhibitors. Pyridostigmine is most commonly used and allows for increased Ach availability at the neuromuscular junction. Other treatment options focus on immune modulation therapy, which includes corticosteroids, methotrexate, azathioprine, and cyclosporin. These usually need to be continued indefinitely and may have adverse side effects. Thymectomy is recommended for those with a thymoma, but it can also be used for patients without thymus pathology to potentially decrease the immunological response. This usually takes months to have any effect, but remission can be seen in almost 35% of patients.7,9 Other treatments include plasma exchange and IVIG. Plasma exchange works well for short-term relief of MG and is frequently used to transition between other treatment modalities. This consists of removing the specific antibodies from the patient’s blood by membrane filtration. It has a much quicker efficacy than thymectomy, and usually symptomatic relief is seen within 1 week.9 IVIG is a treatment
J Hand Surg Am.
r
Vol. -, - 2014
