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My, What Asthenia You Have
SURVEY OF OPHTHALMOLOGY
VOLUME 53 NUMBER 5 SEPTEMBER–OCTOBER 2008
CLINICAL CHALLENGES PETER SAVINO AND HELEN DANESH-MEYER, EDITORS
My, What Asthenia You Have Michael S. Lee, MD,1 Gregory S. Kosmorsky, DO,2 James R. Cook, MD, PhD,3 Jason J.S. Barton, MD, PhD, FRCPC,4,5,6 and Hannah R. Briemberg, MD, FRCPC4 1
Departments of Ophthalmology and Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA; Departments of Ophthalmology; 3Clinical Pathology, Cleveland Clinic Foundation, Ceveland, Ohio, USA; 4 Departments of Medicine (Neurology); 5Ophthalmology and Visual Sciences; and 6Psychology, University of British Columbia, Vancouver, Canada 2
(In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article.)
Case Report. A 59-year-old woman complained of ptosis and diplopia that began 2--3 years earlier. She stated that the symptoms were much better in the morning and worse at the end of the day, often persisting until she went to sleep. For the past 5 years, she also complained of difficulty ascending stairs and noted the need to take smaller bites in order to swallow food. She denied other medical problems and took no medications. She stated that her brother (of five siblings), mother, and maternal grandmother had myasthenia gravis. Her acuities were 20/30 in each eye. Pupillary, slitlamp, and fundus examination were unremarkable. External examination and ocular motility revealed bilateral ptosis, mild ophthalmoplegia, and weakness of the facial muscles (Fig. 1). She had poor levator function and Bell phenomenon. There was no Cogan lid twitch, but fatigable ptosis was present. Neurologic examination demonstrated moderate weakness of lower extremities (proximal greater than distal) and mild weakness of the upper extremities and neck flexors/extensors.
How would you proceed?
Comments Comments by Jason J.S. Barton, MD, PhD, FRCPC, and Hannah R. Briemberg, MD, FRCPC First, let us review what we have learned. In a patient like this it is important to consider exactly what we know and do not know at each step. She has several years of ptosis, diplopia, dysphagia, and probable proximal leg weakness when climbing stairs. The examination comments only about some limitation in eye movements, without specific explanation of the diplopia. It adds weakness of the arms, face, and neck to what we have already learned from history. The limb and ocular deficits (Fig. 1) appear more or less symmetric. This constellation of findings—in particular, the combination of facial weakness and ptosis—points to either a myopathy or a disorder of the neuromuscular junction. 506
Ó 2008 by Elsevier Inc. All rights reserved.
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Fig. 1. External examination shows ptosis of both upper eyelids. Extraocular movements show incomplete, omnidirectional ophthalmoplegia.
From the family history we learn that the patient believes that three other family members suffer from myasthenia gravis. The pattern of transmission is consistent with autosomal dominant inheritance, or possibly the maternal inheritance pattern of mitochondrial genetic defects. What we do not know is the data upon which the diagnosis of myasthenia gravis in these three family members rest. As a very first step it would be helpful to clarify what symptoms they had, the age of onset, what tests were performed, what the results were, how they were treated and how they responded to treatment. Better yet, obtaining their medical records would be a good idea. It would be good to pause to consider the issue of familial myasthenia. There are congenital myasthenic deficits, which are due to inherited abnormalities of the various pre- or post-synaptic proteins involved in neuromuscular transmission, but these generally show symptoms in early life.14,18 These congenital syndromes are not to be confused with neonatal myasthenia, in which the child of a woman with myasthenia gravis suffers transient symptoms due to placental transfer of maternal auto-antibody.9 Familial transmission of autoimmune myasthenia8,27 is a different entity to both of these: such patients inherit some as-yet unidentified susceptibility to developing autoimmunity—sometimes including other autoimmune disorders besides myasthenia,12 or thymoma.21 Familial cases constitute a very small proportion of autoimmune myasthenia.8 How about the patient? Is her own story diagnostic of myasthenia? She reports diurnal worsening toward the end of the day and her examination shows fatigability of ptosis (but no lid
twitch). Variability is characteristic of myasthenia but not necessarily pathognomonic. Fatigue is a quantitative variability, in that deficits get worse with use (the diurnal pattern presumable represents decline in function with activity during the day and improvement after rest with sleep), but other disorders can show fatigue too.13,22 Studies of eye movements have shown that neuropathic and myopathic disorders also show fatigue of saccadic velocities, and the distinction between these and myasthenic ocular motor pareses is not great.1 Worsening with use may be more prominent and more severe in myasthenia that in other disorders of nerve or muscle, but patients with these other disorders can complain of fatigability, too. On the other hand, a qualitative variability, in which the pattern of paresis changes dramatically from one examination to another (e.g., a patient with a superior oblique paresis on one clinic visit who comes in with a lateral rectus paresis in the other eye on the next visit), may be hard to attribute to anything but myasthenia. In this patient we have at most quantitative fatigability of the lids, and presumably none of the limb muscles, although it is not stated if those were tested for fatigue. Also, myasthenia is notorious for its asymmetry, particularly in its ocular motor manifestations. The symmetry in this case, as well as the family history, leaves one uneasy about a diagnosis of myasthenia and makes an autosomal dominant or maternally inherited myopathy a more likely diagnosis. Further investigations are required; fortunately, with generalized limb symptoms, the sensitivity of tests for myasthenia is very high, so these should be very informative.
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Case Report (Continued) Acetylcholine receptor antibodies (modulating, binding, blocking, MuSK) were negative, but computed tomography of the chest revealed a well circumscribed 2.3 2.0 1.6 cm mass in the anterior mediastinum (Fig. 2). Electromyography (EMG) showed widespread evidence of electrically severe, longstanding generalized myopathy. There was no definitive neuromuscular junction deficit. The EMG was interpreted as consistent with inflammatory myopathy, inclusion body myositis, advanced myasthenia gravis, and muscular dystrophy. How would you like to proceed?
Comments (Continued) Comments by Dr. Barton and Dr. Briemberg The diagnostic tests for myasthenia fall in three categories, two of which are mentioned here. First, there is serologic testing for antibodies. These include those against the acetylcholine receptor, and more recently, against muscle-specific kinase (MuSK).11,23 In generalized myasthenia, the antiacetylcholine receptor antibody assay is 90% sensitive.30 The negative assay is therefore somewhat worrisome. Second, there is electrophysiology. There are two tests. One is the observation on nerve conduction studies that the amplitude of the compound muscle action potential declines with low frequency (3 Hz) repetitive stimulation of the nerve. This indicates that there is reduced probability of transmitter-receptor interaction at the neuromuscular junction, so that the normal decline in amount of acetylcholine released with recurrent firing now leads to insufficient interactions to trigger an action poten-
Fig. 2. Axial chest computed tomography demonstrates a well-circumscribed mass in the anterior mediastinum (arrow).
LEE ET AL
tial in the muscle. Assuming a technically proficient study, a decrement of greater than 10% is considered very specific for a neuromuscular junction disorder. However, although specific, this test is not sensitive. The second test is single-fiber recording on EMG.24 As a nerve fiber discharges, it activates several muscle fibers, and the potentials generated in each of these fibers are usually tightly time-locked to each other. With variable transmission, this relationship loses that consistency, and the temporal variation is called jitter. A finding of increased jitter on single fiber EMG is very sensitive (though not specific) for a neuromuscular junction disorder. In fact, the finding of normal jitter in a weak muscle essentially excludes generalized myasthenia gravis. When providing electrophysiological reports, it is standard to list each study performed with a description of the specific findings of that study, prior to providing an interpretation of the entire test. The only electrophysiological information provided in this case is the interpretation of the results. Thus, although we are told ‘‘there was no definitive neuromuscular junction deficit’’ we are not told the tests that were done on which this interpretation was based (i.e., low frequency repetitive stimulation and/or single fiber EMG). The interpretation of myopathic motor units presumably refers to small, polyphasic motor units. As remarked in the interpretation, this finding is not specific to myopathies and can occasionally be seen in myasthenia gravis and even in rapidly progressive neuropathies. The interpretation depends on the other clinical and electrophysiological findings. In this case, presuming that repetitive stimulation or single fiber EMG was performed and was normal, the finding of myopathic motor units is unlikely to represent myasthenia gravis as most cases of myasthenia severe enough to result in myopathic motor units would also result in abnormal studies of electrophysiological transmission. Furthermore, the clinical picture is not one of severe weakness from advanced myasthenia. Thus, the electrophysiological findings point to an underlying myopathy rather than myasthenia gravis as the explanation for this patient’s symptoms. The presence of a thymic mass—either hyperplasia or a thymoma—raises the likelihood that this patient might have an autoimmune disorder like myasthenia gravis, but does not prove it. Regardless of the neuromuscular diagnosis, though, the thymic mass is going to have to be treated. Another useful test that can help discriminate between myasthenia gravis and primary muscle disease that was not done in this case is the serum creatine kinase (CPK). Although this can be normal in many myopathies, an elevated serum CPK is not
CLINICAL CHALLENGES
a feature of myasthenia gravis and, if present, would add further support to the clinical and electrophysiological findings that suggest her weakness is due to an underlying myopathy.
Case Report (Continued) Thymectomy revealed a micronodular spindle cell thymoma (Fig. 3) with focal invasion into mediastinal soft tissue (Masaoka stage II). The patient received a diagnosis of myasthenia gravis based on the family history and the presence of thymoma. She was treated with intravenous gamma globulin, corticosteroids, and pyridostigmine without improvement. How would you like to proceed?
Comments (Continued) Comments by Dr. Barton and Dr. Briemberg The diagnosis, currently resting on circumstantial evidence, is now put to the test with a trial of treatment. The third diagnostic test would have been an edrophonium challenge,19 looking for improvement after inhibiting the acetylcholinesterase that degrades the transmitter at the neuromuscular junction, thereby increasing the probability of a transmitter--receptor interaction. A therapeutic trial of pyridostigmine accomplishes much the same thing, and the patient fails to improve. This again is surprising given the high sensitivity (about 95%) of generalized myasthenia to acetylcholinesterase inhibitors.19 Prednisone, intended to suppress the autoimmune response that is generating the pathologic antibodies, also fails—although one must keep in mind that sometimes myasthenia can worsen in the first few weeks of prednisone therapy,
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before it begins to improve.25 Treatment with intravenous gamma globulin at this stage is unconventional, as this and plasma exchange are usually reserved for myasthenic crisis. At this stage, there is no myasthenic crisis, but there is a crisis of confidence in the diagnosis. We have a report of familial myasthenia without any information to confirm that these family members really do have myasthenia. We have fatigability of the lids but relatively symmetric deficits of the lids, eye muscles, face, swallowing and limbs. Despite this generalized presentation, we have negative antibody results, no response to acetylcholinesterase inhibition and no electrophysiological evidence of a neuromuscular junction disorder: while false negative results are all too common in ocular myasthenia,10 these are distinctly unusual in generalized myasthenia. Thymoma or no thymoma, we need to go back to consider a differential diagnosis of maternally inherited or autosomal dominant adult-onset myopathy involving the eyes, swallowing, and limbs. The two primary possibilities are 1) oculopharyngeal muscular dystrophy (OPMD) or 2) a mitochondrial myopathy. OPMD is an autosomal dominant muscular dystrophy that, as with this patient, generally presents in the fifth or sixth decades of life. Mitochondrial myopathies can also present later in life and are frequently associated with ptosis, progressive ophthalmoplegia, dysphagia and mild limb girdle weakness. They may occur sporadically, be inherited through the maternal line or demonstrate a Mendelian pattern of inheritance. Mitochondrial myopathy requires muscle biopsy for diagnosis while OPMD can be diagnosed genetically with a blood test. Therefore, it makes the most sense to proceed with genetic testing for OPMD at this point. If this is negative, consideration should be given to proceeding with a biopsy of a moderately
Fig. 3. Light microscopy of the anterior mediastinal mass from Fig. 2 shows features characteristic of micronodular spindle cell thymoma. (A) Nodules of spindle shaped epithelial cells (arrow; hematoxylin and eosin, original magnification 40) and (B) admixed lymphoid hyperplasia (*; hematoxylin and eosin, original magnification 20).
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weak muscle to investigate the possibility of a mitochondrial myopathy.
Case Report (Continued) Genetic testing showed 9 GCG repeats (allele 1) and 6 GCG repeats (allele 2) in the PABP2 gene, and she was diagnosed with OPMD.
Discussion OPMD, an autosomal dominant condition, generally presents with ptosis and dysphagia in the 5th or 6th decade. Familial cases have been identified in over 30 countries, but certain people groups have a much higher prevalence. The prevalence is approximately 1 in 1,000 among French Canadians in Quebec7 and 1 in 600 among Bukhara Jews.3 The patient herein described herself as part Spanish and French. Generalized muscle weakness is uncommon but may occur later in the disease. Typically this involves proximal muscles of the upper extremities and pelvic girdle. In rare cases distal muscle may be affected.4 From 1980 to 1998, clinicians primarily made the diagnosis of OPMD by histopathological and electron microscopic appearance of muscle biopsy. Light microscopy showed somewhat nonspecific rimmed vacuoles. These vacuoles occur in several other disorders most notably in inclusion body myositis.5 Electron microscopy demonstrates unique, diagnostic intranuclear tubular filaments measuring 8.5 nm in diameter and 0.25 microns in length.29 In 1998 the genetic defect was discovered on chromosome 14q11 in the PABPN1 (or PABP2) gene, a gene that produces a ubiquitous nuclear protein. Normally, this gene contains 6 trinucleotide GCG repeats, but in OPMD there are an extra 2--7 repeats. Patients with higher numbers of repeats or with both alleles affected have more severe symptoms. These repeats prevent the normal breakdown of the nuclear protein and eventually disrupt muscle function.6 The patient described herein admitted to a family history of myasthenia gravis. Familial myasthenia gravis (MG) may present from the first to eighth decade. The clinical courses is often indistinguishable from sporadic MG and between 0.8% and 4% of patients with MG note a family history. In support of a genetic cause, Murphy and Murphy reported that both members of 5/14 monozygotic twins were affected by MG compared with 0/5 dizygotic sets.16 Five of 10 siblings in one family2 and nine members from two generations of another family have also
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been reported.17 However, the exact genetic defect remains unclear. The symptomatic family members of the patient herein likely had OPMD rather than MG. The mean age of diagnosis for thymoma is between 45 and 50 years of age. Between 30% and 40% have an associated paraneoplastic syndrome, most commonly myasthenia gravis.15 Micronodular spindle-cell thymomas, a recently described uncommon subset of thymomas, are composed of small nodules of spindle shaped cells surrounded by lymphoid follicles. 26 To date, we found 58 reported cases of micronodular thymoma and only 5 (8.6%) patients suffered from myasthenia gravis.28 These tumors follow a benign course and the general consensus is that they are not associated with myasthenia gravis.20 The patient in this case presented a diagnostic dilemma. She had variable ptosis and diplopia, a thymoma, and possible family history of myasthenia gravis. However, acetylcholine receptor antibodies were absent and the EMG did not show evidence of a neuromuscular junction deficit. When no improvement occurred with treatment of myasthenia, genetic testing for oculopharyngeal muscular dystrophy was performed.
References 1. Barton JJ, Huaman AG, Sharpe JA: Effects of edrophonium on saccadic velocity in normal subjects and myasthenic and nonmyasthenic ocular palsies. Ann Neurol 36:585--94, 1994 2. Bergoffen J, Zmijewski CM, Fischbeck KH: Familial autoimmune myasthenia gravis. Neurology 44:551--4, 1994 3. Blumen SC, Korczyn AD, Lavoie H, et al: Oculopharyngeal MD among Bukhara Jews is due to a founder (GCG)9 mutation in the PABP2 gene. Neurology 55:1267--70, 2000 4. Bouchard JP, Brais B, Brunet D, et al: Recent studies on oculopharyngeal muscular dystrophy in Que´bec. Neuromuscul Disord 7(Suppl 1):S22--9, 1997 5. Brais B: Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease. Cytogenet Genome Res 100:252--60, 2003 6. Brais B, Bouchard JP, Xie YG, et al: Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet 18:164--7, 1998 7. Brais B, Rouleau GA, Bouchard JP, et al: Oculopharyngeal muscular dystrophy. Semin Neurol 19:59--66, 1999 8. Bu B, Yang M, Xu J, et al: The clinical study and HLA genotyping of 112 familial myasthenia gravis patients. J Tongji Med Univ 19:46--9, 1999 9. Djelmis J, Sostarko M, Mayer D, et al: Myasthenia gravis in pregnancy: report on 69 cases. Eur J Obstet Gynecol Reprod Biol 104:21--5, 2002 10. Evoli A, Tonali P, Bartoccioni E, et al: Ocular myasthenia: diagnostic and therapeutic problems. Acta Neurol Scand 77: 31--5, 1988 11. Hoch W, McConville J, Helms S, et al: Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 7: 365--8, 2001 12. Huh WK, Tada J, Fujimoto W, et al: Thyroid gland tumour, pemphigus foliaceus and myasthenia gravis in the daughter
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13. 14. 15. 16. 17. 18. 19. 20.
21. 22. 23.
of a woman with myasthenia gravis. Clin Exp Dermatol 26: 504--6, 2001 Moorthy G, Behrens MM, Drachman DB, et al: Ocular pseudomyasthenia or ocular myasthenia ’plus’: a warning to clinicians. Neurology 39:1150--4, 1989 Mu¨ller JS, Mihaylova V, Abicht A, et al: Congenital myasthenic syndromes: spotlight on genetic defects of neuromuscular transmission. Expert Rev Mol Med 9:1--20, 2007 Mu¨ller-Hermelink HK, Marx A: Thymoma. Curr Opin Oncol 12:426--33, 2000 Murphy J, Murphy SF: Myasthenia gravis in identical twins. Neurology 36:78--80, 1986 Namba T, Brunner N, Brown SB, et al: Familial myasthenia gravis. Report of 27 patients in 12 families and review of 164 patients in 73 families. Arch Neurol 25:49--60, 1971 Newsom-Davis J: The emerging diversity of neuromuscular junction disorders. Acta Myol 26:5--10, 2007 Osserman K, Teng P: Studies in myasthenia gravis—a rapid diagnostic test. JAMA 160:153--5, 1956 Pan CC, Chen WY, Chiang H: Spindle cell and mixed spindle/lymphocytic thymomas: an integrated clinicopathologic and immunohistochemical study of 81 cases. Am J Surg Pathol 25:111--20, 2001 Pascuzzi RM, Sermas A, Phillips LH, et al: Familial autoimmune myasthenia gravis and thymoma: occurrence in two brothers. Neurology 36:423--7, 1986 Ragge NK, Hoyt WF: Midbrain myasthenia: fatigable ptosis, ’lid twitch’ sign, and ophthalmoparesis from a dorsal midbrain glioma. Neurology 42:917--9, 1992 Sanders DB, El-Salem K, Massey JM, et al: Clinical aspects of MuSK antibody positive seronegative MG. Neurology 60: 1978--80, 2003
24. Sanders DB, Howard JF, Johns TR: Single-fiber electromyography in myasthenia gravis. Neurology 29:68--76, 1979 25. Seybold ME, Drachman DB: Gradually increasing doses of prednisone in myasthenia gravis. Reducing the hazards of treatment. N Engl J Med 290:81--4, 1974 26. Suster S, Moran CA: Micronodular thymoma with lymphoid B-cell hyperplasia: clinicopathologic and immunohistochemical study of eighteen cases of a distinctive morphologic variant of thymic epithelial neoplasm. Am J Surg Pathol 23:955--62, 1999 27. Szobor A: Myasthenia gravis: familial occurrence. A study of 1100 myasthenia gravis patients. Acta Med Hung 46:13--21, 1989 28. Tateyama H, Saito Y, Fujii Y, et al: The spectrum of micronodular thymic epithelial tumours with lymphoid Bcell hyperplasia. Histopathology 38:519--27, 2001 29. Tome´ FM, Fardeau M: Nuclear inclusions in oculopharyngeal dystrophy. Acta Neuropathol 49:85--7, 1980 30. Vincent A, Newsom-Davis J: Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry 48:1246--52, 1985 The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. This article was supported by unrestricted Grant from Research to Prevent Blindness (New York, NY) and the Lions Club of Minnesota. Reprint address: Michael S. Lee, MD, Department of Ophthalmology, 420 Delaware Street S.E., MMC 493, Minneapolis, MN 55455.
Abstract. A 59-year-old woman noted intermittent ptosis, diplopia, dysphagia, and proximal muscle weakness for several years. She had a strong family history of myasthenia gravis. Chest computed tomography and sternotomy revealed a micronodular spindle cell thymoma. Electromyography and antibody testing was negative for myasthenia gravis. Genetic testing confirmed a diagnosis of oculopharyngeal muscular dystrophy. (Surv Ophthalmol 53:506--511, 2008. Ó 2008 Elsevier Inc. All rights reserved.) Key words. thymoma
genetic testing
myasthenia gravis
oculopharyngeal muscular dystrophy
VOLUME 53 NUMBER 5 SEPTEMBER–OCTOBER 2008
CLINICAL CHALLENGES PETER SAVINO AND HELEN DANESH-MEYER, EDITORS
My, What Asthenia You Have Michael S. Lee, MD,1 Gregory S. Kosmorsky, DO,2 James R. Cook, MD, PhD,3 Jason J.S. Barton, MD, PhD, FRCPC,4,5,6 and Hannah R. Briemberg, MD, FRCPC4 1
Departments of Ophthalmology and Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA; Departments of Ophthalmology; 3Clinical Pathology, Cleveland Clinic Foundation, Ceveland, Ohio, USA; 4 Departments of Medicine (Neurology); 5Ophthalmology and Visual Sciences; and 6Psychology, University of British Columbia, Vancouver, Canada 2
(In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article.)
Case Report. A 59-year-old woman complained of ptosis and diplopia that began 2--3 years earlier. She stated that the symptoms were much better in the morning and worse at the end of the day, often persisting until she went to sleep. For the past 5 years, she also complained of difficulty ascending stairs and noted the need to take smaller bites in order to swallow food. She denied other medical problems and took no medications. She stated that her brother (of five siblings), mother, and maternal grandmother had myasthenia gravis. Her acuities were 20/30 in each eye. Pupillary, slitlamp, and fundus examination were unremarkable. External examination and ocular motility revealed bilateral ptosis, mild ophthalmoplegia, and weakness of the facial muscles (Fig. 1). She had poor levator function and Bell phenomenon. There was no Cogan lid twitch, but fatigable ptosis was present. Neurologic examination demonstrated moderate weakness of lower extremities (proximal greater than distal) and mild weakness of the upper extremities and neck flexors/extensors.
How would you proceed?
Comments Comments by Jason J.S. Barton, MD, PhD, FRCPC, and Hannah R. Briemberg, MD, FRCPC First, let us review what we have learned. In a patient like this it is important to consider exactly what we know and do not know at each step. She has several years of ptosis, diplopia, dysphagia, and probable proximal leg weakness when climbing stairs. The examination comments only about some limitation in eye movements, without specific explanation of the diplopia. It adds weakness of the arms, face, and neck to what we have already learned from history. The limb and ocular deficits (Fig. 1) appear more or less symmetric. This constellation of findings—in particular, the combination of facial weakness and ptosis—points to either a myopathy or a disorder of the neuromuscular junction. 506
Ó 2008 by Elsevier Inc. All rights reserved.
0039-6257/08/$--see front matter doi:10.1016/j.survophthal.2008.06.010
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Fig. 1. External examination shows ptosis of both upper eyelids. Extraocular movements show incomplete, omnidirectional ophthalmoplegia.
From the family history we learn that the patient believes that three other family members suffer from myasthenia gravis. The pattern of transmission is consistent with autosomal dominant inheritance, or possibly the maternal inheritance pattern of mitochondrial genetic defects. What we do not know is the data upon which the diagnosis of myasthenia gravis in these three family members rest. As a very first step it would be helpful to clarify what symptoms they had, the age of onset, what tests were performed, what the results were, how they were treated and how they responded to treatment. Better yet, obtaining their medical records would be a good idea. It would be good to pause to consider the issue of familial myasthenia. There are congenital myasthenic deficits, which are due to inherited abnormalities of the various pre- or post-synaptic proteins involved in neuromuscular transmission, but these generally show symptoms in early life.14,18 These congenital syndromes are not to be confused with neonatal myasthenia, in which the child of a woman with myasthenia gravis suffers transient symptoms due to placental transfer of maternal auto-antibody.9 Familial transmission of autoimmune myasthenia8,27 is a different entity to both of these: such patients inherit some as-yet unidentified susceptibility to developing autoimmunity—sometimes including other autoimmune disorders besides myasthenia,12 or thymoma.21 Familial cases constitute a very small proportion of autoimmune myasthenia.8 How about the patient? Is her own story diagnostic of myasthenia? She reports diurnal worsening toward the end of the day and her examination shows fatigability of ptosis (but no lid
twitch). Variability is characteristic of myasthenia but not necessarily pathognomonic. Fatigue is a quantitative variability, in that deficits get worse with use (the diurnal pattern presumable represents decline in function with activity during the day and improvement after rest with sleep), but other disorders can show fatigue too.13,22 Studies of eye movements have shown that neuropathic and myopathic disorders also show fatigue of saccadic velocities, and the distinction between these and myasthenic ocular motor pareses is not great.1 Worsening with use may be more prominent and more severe in myasthenia that in other disorders of nerve or muscle, but patients with these other disorders can complain of fatigability, too. On the other hand, a qualitative variability, in which the pattern of paresis changes dramatically from one examination to another (e.g., a patient with a superior oblique paresis on one clinic visit who comes in with a lateral rectus paresis in the other eye on the next visit), may be hard to attribute to anything but myasthenia. In this patient we have at most quantitative fatigability of the lids, and presumably none of the limb muscles, although it is not stated if those were tested for fatigue. Also, myasthenia is notorious for its asymmetry, particularly in its ocular motor manifestations. The symmetry in this case, as well as the family history, leaves one uneasy about a diagnosis of myasthenia and makes an autosomal dominant or maternally inherited myopathy a more likely diagnosis. Further investigations are required; fortunately, with generalized limb symptoms, the sensitivity of tests for myasthenia is very high, so these should be very informative.
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Case Report (Continued) Acetylcholine receptor antibodies (modulating, binding, blocking, MuSK) were negative, but computed tomography of the chest revealed a well circumscribed 2.3 2.0 1.6 cm mass in the anterior mediastinum (Fig. 2). Electromyography (EMG) showed widespread evidence of electrically severe, longstanding generalized myopathy. There was no definitive neuromuscular junction deficit. The EMG was interpreted as consistent with inflammatory myopathy, inclusion body myositis, advanced myasthenia gravis, and muscular dystrophy. How would you like to proceed?
Comments (Continued) Comments by Dr. Barton and Dr. Briemberg The diagnostic tests for myasthenia fall in three categories, two of which are mentioned here. First, there is serologic testing for antibodies. These include those against the acetylcholine receptor, and more recently, against muscle-specific kinase (MuSK).11,23 In generalized myasthenia, the antiacetylcholine receptor antibody assay is 90% sensitive.30 The negative assay is therefore somewhat worrisome. Second, there is electrophysiology. There are two tests. One is the observation on nerve conduction studies that the amplitude of the compound muscle action potential declines with low frequency (3 Hz) repetitive stimulation of the nerve. This indicates that there is reduced probability of transmitter-receptor interaction at the neuromuscular junction, so that the normal decline in amount of acetylcholine released with recurrent firing now leads to insufficient interactions to trigger an action poten-
Fig. 2. Axial chest computed tomography demonstrates a well-circumscribed mass in the anterior mediastinum (arrow).
LEE ET AL
tial in the muscle. Assuming a technically proficient study, a decrement of greater than 10% is considered very specific for a neuromuscular junction disorder. However, although specific, this test is not sensitive. The second test is single-fiber recording on EMG.24 As a nerve fiber discharges, it activates several muscle fibers, and the potentials generated in each of these fibers are usually tightly time-locked to each other. With variable transmission, this relationship loses that consistency, and the temporal variation is called jitter. A finding of increased jitter on single fiber EMG is very sensitive (though not specific) for a neuromuscular junction disorder. In fact, the finding of normal jitter in a weak muscle essentially excludes generalized myasthenia gravis. When providing electrophysiological reports, it is standard to list each study performed with a description of the specific findings of that study, prior to providing an interpretation of the entire test. The only electrophysiological information provided in this case is the interpretation of the results. Thus, although we are told ‘‘there was no definitive neuromuscular junction deficit’’ we are not told the tests that were done on which this interpretation was based (i.e., low frequency repetitive stimulation and/or single fiber EMG). The interpretation of myopathic motor units presumably refers to small, polyphasic motor units. As remarked in the interpretation, this finding is not specific to myopathies and can occasionally be seen in myasthenia gravis and even in rapidly progressive neuropathies. The interpretation depends on the other clinical and electrophysiological findings. In this case, presuming that repetitive stimulation or single fiber EMG was performed and was normal, the finding of myopathic motor units is unlikely to represent myasthenia gravis as most cases of myasthenia severe enough to result in myopathic motor units would also result in abnormal studies of electrophysiological transmission. Furthermore, the clinical picture is not one of severe weakness from advanced myasthenia. Thus, the electrophysiological findings point to an underlying myopathy rather than myasthenia gravis as the explanation for this patient’s symptoms. The presence of a thymic mass—either hyperplasia or a thymoma—raises the likelihood that this patient might have an autoimmune disorder like myasthenia gravis, but does not prove it. Regardless of the neuromuscular diagnosis, though, the thymic mass is going to have to be treated. Another useful test that can help discriminate between myasthenia gravis and primary muscle disease that was not done in this case is the serum creatine kinase (CPK). Although this can be normal in many myopathies, an elevated serum CPK is not
CLINICAL CHALLENGES
a feature of myasthenia gravis and, if present, would add further support to the clinical and electrophysiological findings that suggest her weakness is due to an underlying myopathy.
Case Report (Continued) Thymectomy revealed a micronodular spindle cell thymoma (Fig. 3) with focal invasion into mediastinal soft tissue (Masaoka stage II). The patient received a diagnosis of myasthenia gravis based on the family history and the presence of thymoma. She was treated with intravenous gamma globulin, corticosteroids, and pyridostigmine without improvement. How would you like to proceed?
Comments (Continued) Comments by Dr. Barton and Dr. Briemberg The diagnosis, currently resting on circumstantial evidence, is now put to the test with a trial of treatment. The third diagnostic test would have been an edrophonium challenge,19 looking for improvement after inhibiting the acetylcholinesterase that degrades the transmitter at the neuromuscular junction, thereby increasing the probability of a transmitter--receptor interaction. A therapeutic trial of pyridostigmine accomplishes much the same thing, and the patient fails to improve. This again is surprising given the high sensitivity (about 95%) of generalized myasthenia to acetylcholinesterase inhibitors.19 Prednisone, intended to suppress the autoimmune response that is generating the pathologic antibodies, also fails—although one must keep in mind that sometimes myasthenia can worsen in the first few weeks of prednisone therapy,
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before it begins to improve.25 Treatment with intravenous gamma globulin at this stage is unconventional, as this and plasma exchange are usually reserved for myasthenic crisis. At this stage, there is no myasthenic crisis, but there is a crisis of confidence in the diagnosis. We have a report of familial myasthenia without any information to confirm that these family members really do have myasthenia. We have fatigability of the lids but relatively symmetric deficits of the lids, eye muscles, face, swallowing and limbs. Despite this generalized presentation, we have negative antibody results, no response to acetylcholinesterase inhibition and no electrophysiological evidence of a neuromuscular junction disorder: while false negative results are all too common in ocular myasthenia,10 these are distinctly unusual in generalized myasthenia. Thymoma or no thymoma, we need to go back to consider a differential diagnosis of maternally inherited or autosomal dominant adult-onset myopathy involving the eyes, swallowing, and limbs. The two primary possibilities are 1) oculopharyngeal muscular dystrophy (OPMD) or 2) a mitochondrial myopathy. OPMD is an autosomal dominant muscular dystrophy that, as with this patient, generally presents in the fifth or sixth decades of life. Mitochondrial myopathies can also present later in life and are frequently associated with ptosis, progressive ophthalmoplegia, dysphagia and mild limb girdle weakness. They may occur sporadically, be inherited through the maternal line or demonstrate a Mendelian pattern of inheritance. Mitochondrial myopathy requires muscle biopsy for diagnosis while OPMD can be diagnosed genetically with a blood test. Therefore, it makes the most sense to proceed with genetic testing for OPMD at this point. If this is negative, consideration should be given to proceeding with a biopsy of a moderately
Fig. 3. Light microscopy of the anterior mediastinal mass from Fig. 2 shows features characteristic of micronodular spindle cell thymoma. (A) Nodules of spindle shaped epithelial cells (arrow; hematoxylin and eosin, original magnification 40) and (B) admixed lymphoid hyperplasia (*; hematoxylin and eosin, original magnification 20).
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weak muscle to investigate the possibility of a mitochondrial myopathy.
Case Report (Continued) Genetic testing showed 9 GCG repeats (allele 1) and 6 GCG repeats (allele 2) in the PABP2 gene, and she was diagnosed with OPMD.
Discussion OPMD, an autosomal dominant condition, generally presents with ptosis and dysphagia in the 5th or 6th decade. Familial cases have been identified in over 30 countries, but certain people groups have a much higher prevalence. The prevalence is approximately 1 in 1,000 among French Canadians in Quebec7 and 1 in 600 among Bukhara Jews.3 The patient herein described herself as part Spanish and French. Generalized muscle weakness is uncommon but may occur later in the disease. Typically this involves proximal muscles of the upper extremities and pelvic girdle. In rare cases distal muscle may be affected.4 From 1980 to 1998, clinicians primarily made the diagnosis of OPMD by histopathological and electron microscopic appearance of muscle biopsy. Light microscopy showed somewhat nonspecific rimmed vacuoles. These vacuoles occur in several other disorders most notably in inclusion body myositis.5 Electron microscopy demonstrates unique, diagnostic intranuclear tubular filaments measuring 8.5 nm in diameter and 0.25 microns in length.29 In 1998 the genetic defect was discovered on chromosome 14q11 in the PABPN1 (or PABP2) gene, a gene that produces a ubiquitous nuclear protein. Normally, this gene contains 6 trinucleotide GCG repeats, but in OPMD there are an extra 2--7 repeats. Patients with higher numbers of repeats or with both alleles affected have more severe symptoms. These repeats prevent the normal breakdown of the nuclear protein and eventually disrupt muscle function.6 The patient described herein admitted to a family history of myasthenia gravis. Familial myasthenia gravis (MG) may present from the first to eighth decade. The clinical courses is often indistinguishable from sporadic MG and between 0.8% and 4% of patients with MG note a family history. In support of a genetic cause, Murphy and Murphy reported that both members of 5/14 monozygotic twins were affected by MG compared with 0/5 dizygotic sets.16 Five of 10 siblings in one family2 and nine members from two generations of another family have also
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been reported.17 However, the exact genetic defect remains unclear. The symptomatic family members of the patient herein likely had OPMD rather than MG. The mean age of diagnosis for thymoma is between 45 and 50 years of age. Between 30% and 40% have an associated paraneoplastic syndrome, most commonly myasthenia gravis.15 Micronodular spindle-cell thymomas, a recently described uncommon subset of thymomas, are composed of small nodules of spindle shaped cells surrounded by lymphoid follicles. 26 To date, we found 58 reported cases of micronodular thymoma and only 5 (8.6%) patients suffered from myasthenia gravis.28 These tumors follow a benign course and the general consensus is that they are not associated with myasthenia gravis.20 The patient in this case presented a diagnostic dilemma. She had variable ptosis and diplopia, a thymoma, and possible family history of myasthenia gravis. However, acetylcholine receptor antibodies were absent and the EMG did not show evidence of a neuromuscular junction deficit. When no improvement occurred with treatment of myasthenia, genetic testing for oculopharyngeal muscular dystrophy was performed.
References 1. Barton JJ, Huaman AG, Sharpe JA: Effects of edrophonium on saccadic velocity in normal subjects and myasthenic and nonmyasthenic ocular palsies. Ann Neurol 36:585--94, 1994 2. Bergoffen J, Zmijewski CM, Fischbeck KH: Familial autoimmune myasthenia gravis. Neurology 44:551--4, 1994 3. Blumen SC, Korczyn AD, Lavoie H, et al: Oculopharyngeal MD among Bukhara Jews is due to a founder (GCG)9 mutation in the PABP2 gene. Neurology 55:1267--70, 2000 4. Bouchard JP, Brais B, Brunet D, et al: Recent studies on oculopharyngeal muscular dystrophy in Que´bec. Neuromuscul Disord 7(Suppl 1):S22--9, 1997 5. Brais B: Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease. Cytogenet Genome Res 100:252--60, 2003 6. Brais B, Bouchard JP, Xie YG, et al: Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet 18:164--7, 1998 7. Brais B, Rouleau GA, Bouchard JP, et al: Oculopharyngeal muscular dystrophy. Semin Neurol 19:59--66, 1999 8. Bu B, Yang M, Xu J, et al: The clinical study and HLA genotyping of 112 familial myasthenia gravis patients. J Tongji Med Univ 19:46--9, 1999 9. Djelmis J, Sostarko M, Mayer D, et al: Myasthenia gravis in pregnancy: report on 69 cases. Eur J Obstet Gynecol Reprod Biol 104:21--5, 2002 10. Evoli A, Tonali P, Bartoccioni E, et al: Ocular myasthenia: diagnostic and therapeutic problems. Acta Neurol Scand 77: 31--5, 1988 11. Hoch W, McConville J, Helms S, et al: Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 7: 365--8, 2001 12. Huh WK, Tada J, Fujimoto W, et al: Thyroid gland tumour, pemphigus foliaceus and myasthenia gravis in the daughter
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of a woman with myasthenia gravis. Clin Exp Dermatol 26: 504--6, 2001 Moorthy G, Behrens MM, Drachman DB, et al: Ocular pseudomyasthenia or ocular myasthenia ’plus’: a warning to clinicians. Neurology 39:1150--4, 1989 Mu¨ller JS, Mihaylova V, Abicht A, et al: Congenital myasthenic syndromes: spotlight on genetic defects of neuromuscular transmission. Expert Rev Mol Med 9:1--20, 2007 Mu¨ller-Hermelink HK, Marx A: Thymoma. Curr Opin Oncol 12:426--33, 2000 Murphy J, Murphy SF: Myasthenia gravis in identical twins. Neurology 36:78--80, 1986 Namba T, Brunner N, Brown SB, et al: Familial myasthenia gravis. Report of 27 patients in 12 families and review of 164 patients in 73 families. Arch Neurol 25:49--60, 1971 Newsom-Davis J: The emerging diversity of neuromuscular junction disorders. Acta Myol 26:5--10, 2007 Osserman K, Teng P: Studies in myasthenia gravis—a rapid diagnostic test. JAMA 160:153--5, 1956 Pan CC, Chen WY, Chiang H: Spindle cell and mixed spindle/lymphocytic thymomas: an integrated clinicopathologic and immunohistochemical study of 81 cases. Am J Surg Pathol 25:111--20, 2001 Pascuzzi RM, Sermas A, Phillips LH, et al: Familial autoimmune myasthenia gravis and thymoma: occurrence in two brothers. Neurology 36:423--7, 1986 Ragge NK, Hoyt WF: Midbrain myasthenia: fatigable ptosis, ’lid twitch’ sign, and ophthalmoparesis from a dorsal midbrain glioma. Neurology 42:917--9, 1992 Sanders DB, El-Salem K, Massey JM, et al: Clinical aspects of MuSK antibody positive seronegative MG. Neurology 60: 1978--80, 2003
24. Sanders DB, Howard JF, Johns TR: Single-fiber electromyography in myasthenia gravis. Neurology 29:68--76, 1979 25. Seybold ME, Drachman DB: Gradually increasing doses of prednisone in myasthenia gravis. Reducing the hazards of treatment. N Engl J Med 290:81--4, 1974 26. Suster S, Moran CA: Micronodular thymoma with lymphoid B-cell hyperplasia: clinicopathologic and immunohistochemical study of eighteen cases of a distinctive morphologic variant of thymic epithelial neoplasm. Am J Surg Pathol 23:955--62, 1999 27. Szobor A: Myasthenia gravis: familial occurrence. A study of 1100 myasthenia gravis patients. Acta Med Hung 46:13--21, 1989 28. Tateyama H, Saito Y, Fujii Y, et al: The spectrum of micronodular thymic epithelial tumours with lymphoid Bcell hyperplasia. Histopathology 38:519--27, 2001 29. Tome´ FM, Fardeau M: Nuclear inclusions in oculopharyngeal dystrophy. Acta Neuropathol 49:85--7, 1980 30. Vincent A, Newsom-Davis J: Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry 48:1246--52, 1985 The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. This article was supported by unrestricted Grant from Research to Prevent Blindness (New York, NY) and the Lions Club of Minnesota. Reprint address: Michael S. Lee, MD, Department of Ophthalmology, 420 Delaware Street S.E., MMC 493, Minneapolis, MN 55455.
Abstract. A 59-year-old woman noted intermittent ptosis, diplopia, dysphagia, and proximal muscle weakness for several years. She had a strong family history of myasthenia gravis. Chest computed tomography and sternotomy revealed a micronodular spindle cell thymoma. Electromyography and antibody testing was negative for myasthenia gravis. Genetic testing confirmed a diagnosis of oculopharyngeal muscular dystrophy. (Surv Ophthalmol 53:506--511, 2008. Ó 2008 Elsevier Inc. All rights reserved.) Key words. thymoma
genetic testing
myasthenia gravis
oculopharyngeal muscular dystrophy