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Ophthalmoparesis and unilateral finger flexor muscle weakness in seronegative myasthenia gravis
CASE REPORT Ophthalmoparesis and unilateral finger flexor muscle weakness in seronegative myasthenia gravis A 57-year-old Caucasian man was referred for evaluation of an isolated and self-limited episode of binocular diplopia. Six weeks later, the patient presented with persistent diplopia, ptosis, and distal left upper limb weakness, predominantly in finger flexors. Right eye ptosis was fatigable, but not left-hand weakness. Ancillary tests excluded ischemic, inflammatory, or infectious causes, and neurophysiologic studies confirmed the diagnosis of myasthenia gravis (MG). The patient was started on pyridostigmine and oral prednisolone, with marked clinical improvement. This case illustrates the need of a high level of suspicion regarding MG, even with an atypical muscle involvement and absence of obvious fatigability on muscle strength testing. Myasthenia gravis (MG) is a paradigmatic disorder of the neuromuscular junction, most frequently associated with pathogenic autoantibodies directed toward the skeletal muscle acetylcholine receptor (AChR).1,2 Late-onset MG is commonly defined as first presenting in people older than 40 years. Because of improved diagnosis methods and increased population longevity, its prevalence seems to be increasing, with a small bias toward men.3,4 It is clinically characterized by fluctuating muscle weakness that predominantly affects ocular, bulbar, axial, and limb muscles, generally proximal and symmetrical.5 Ocular weakness, presenting as fluctuating ptosis and/or diplopia (with medial rectus involvement being the most frequent), is the most frequent initial presentation of MG, occurring in about 85% of patients.6 Distal limb muscles are less predominantly affected, and weakness is more apparent in wrist and finger extensors.7,8 We hereby describe a case of an atypical presentation of generalized MG to highlight the importance of considering this potential diagnosis.
CASE REPORT A 57-year-old Caucasian man was referred to an ophthalmology consultation because of progressive impairment of visual acuity in the right eye for approximately 10 years. He also reported an isolated and self-limited episode of binocular diplopia the week before, which lasted less than 10 minutes. He denied any other symptoms, such as headache or pain and trauma or previous infections. Regarding his medical history, he mentioned past smoking habits (30 pack-years) and sporadic episodes of hypertension and insomnia, for which he took lisinopril p.r.n. and zolpidem, respectively. On ophthalmologic examination, best-corrected visual acuity was 20/25 in the right eye and 20/20 in the left eye. Pupillary responses, extraocular movements, and cover testing were normal. Anterior segment examination and
intraocular pressure were also unremarkable. Fundoscopy revealed unspecific pigmented changes in the right eye and a normal fundus in the left eye. Ancillary studies, including optical coherence tomography and fluorescein angiography, confirmed pigmented inactive lesions at the level of the retinal pigmented epithelium (RPE), not related with the present episode. Considering the possible self-limited diplopia episode, a follow-up consultation was scheduled and blood workup and head computed tomography (CT) scan were requested. On the 6-week follow-up appointment, patient’s symptoms had worsened significantly, including persistent diplopia, asymmetric ptosis (more marked on the right eye), and weakness of the left distal upper limb. When questioned, he volunteered a history of hypophonia. There was no fluctuation of symptoms. On examination, an almost complete ptosis was present in the right eye and extraocular movements revealed absent adduction movements and partially limited supraduction, infraduction, and abduction. Also, mild hypophonia was remarked along with Medical Research Council (MRC) grade 4 paresis of the triceps, finger flexors (more prominent in the fifth digit), grade 4þ in finger extensors, and interosseous and abductors of the second and fifth digits on the left, with no identifiable weakness on the right upper limb. Hypophonia and left upper limb weakness did not show any exacerbation with prolonged effort testing. However, the ice-pack test caused a significant improvement of the right eye ptosis (Fig. 1). Moreover, there was significant fatigability as the right eye ptosis worsened after 1 minute of upgaze (Fig. 2). Pupillary reflexes, intraocular pressure, and anterior segment remained normal. Left eye examination was unremarkable. Blood work-up revealed a normal blood cell count and negative inflammatory/infectious markers. Neurophysiologic studies revealed normal conduction velocities and compound muscle action potential (CMAP) amplitudes. However, there was a significant decrement of CMAP amplitude and area after 2 Hz repetitive nerve stimulation. Decrement in amplitude was 27%, 10%, 18%, and 16% in right median, left median, spinal accessory, and facial nerves, respectively. Decrement in area was 27%, 16%, 23%, and 22% in the same nerves. AChR, muscle-specific kinase (MuSK), and low-density lipoprotein receptor–related protein (LRP4) were negative. Head CT scan, brain magnetic resonance imaging, and chest CT scan revealed no abnormal findings. The patient was treated with pyridostigmine 60 mg tid and prednisolone 20 mg every other day, with significant symptom improvement in the subsequent days. During follow-up and because of symptom persistence, pyridostigmine daily dose was increased up to 360 mg, prednisolone up to 80 mg every other day, and azathioprine 50 mg bid was introduced as a steroid-sparing agent. CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
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Case Report
Fig. 1 — Prolonged effort testing. Right eye ptosis at baseline (A) and after 1 minute of upgaze (B).
Fig. 2 — Ice-pack test. Right eye ptosis at baseline (A) and after applying ice over the right eye (B). Notice increased frontalis muscle contraction with increasing ptosis in both figures.
DISCUSSION The clinical hallmark of MG is fatigable weakness, usually involving specific susceptible muscle groups. Patients usually report a daily or even hourly change in symptoms, worsening with activity and improving after rest.5 Several degrees of ptosis, diplopia, dysarthria, dysphagia, dyspnea, and facial weakness may be present. Ocular weakness, presenting as fluctuating ptosis and/or diplopia, is the most common initial presentation of MG, occurring in approximately 85% of patients.6 As in this case, ptosis is most commonly asymmetric and medial rectus muscle involvement is the most frequent. Disease progression to generalized weakness usually occurs within 2 years of disease onset.2,5 Although most commonly involving symmetrically the proximal limb muscle groups, there are rare cases of predominantly distal MG, reported as 3%–7% of the cases in 2 retrospective series.7,9 These can be fixed, asymmetric or even unilateral, and most commonly involve finger extensor and abductor muscles.8,10 Our case, however, presented with predominant weakness in finger flexors, which is extremely unusual and, to the best of our knowledge, has not been previously described in detail. Simple maneuvers are available to help us reach the diagnosis: the ice-pack test (Fig. 1) and the characteristic
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fatigability of ptosis after 1 minute of upgaze (Fig. 2). These cost-effective tests should be always performed in case of MG suspicion. In addition, neurophysiologic studies such as repetitive nerve stimulation and singlefibre electromyography,10,11 and testing for the presence of pathogenic autoantibodies such as AChR (85% of generalized MG, 50% of ocular MG), anti-MuSK, or antiLRP4 are useful confirmatory ancillary studies.12,13 Seronegative MG patients, such as our case, represent up to 5% of all myasthenic syndromes and do not have a welldefined muscle pattern distribution.14 Up to 15% of MG patients may have an associated thymic epithelial tumour. Peak age of onset is 50 years, but it may be present in any age group, and is equally prevalent in both sexes. Although seronegative MG patients (especially without anti-AChR and titin antibodies) rarely present with thymoma (as in our case), a thoracic CT scan should be routinely obtained.5,15 Symptomatic treatment with a cholinergic drug such as pyridostigmine and long-term corticosteroid therapy are recommended, along with its adverse effects’ monitoring.1 This case highlights the importance of always bearing in mind this entity, thus avoiding unnecessary delay and costly diagnostic procedures. As the prevalence of lateonset MG is increasing,3,4 one should keep a high index of suspicion.
Case Report Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article. Acknowledgements: The authors would like to acknowledge Isabel Conceição, MD, for the neurophysiological studies performed in the patient, and also Luisa Albuquerque, MD, Filipa Falcão, MD, and Patricia Antunes, MD, for the clinical evaluation and discussion of the patient during admission in the Neurology Department.
David Cordeiro Sousa, MD,*,† Pedro Viana, MD,‡ Inês Leal, MD,*,† Sara Parreira, MD,‡ João Ferreira, MD,‡,§ Fátima Campos, MD, MSc*,† *Department of Ophthalmology, Hospital de Santa Maria, 1649-035, Lisbon, Portugal; †Centro de Estudos Cieˆncias da Visa˜o, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal; ‡Department of Neurosciences and Mental Health, Neurology Service, Hospital de Santa Maria, 1649-035, Lisbon, Portugal; §Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal. Correspondence to: David Cordeiro Sousa, MD: [email protected]. REFERENCES 1. Drachman DB. Myasthenia gravis. N Engl J Med. 1994;330:1797-810. 2. Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis. Lancet. 2001;357:2122-8. 3. Phillips LH. The epidemiology of myasthenia gravis. Semin Neurol. 2004;24:17-20.
4. Somnier FE. Increasing incidence of late-onset anti-AChR antibodyseropositive myasthenia gravis. Neurology. 2005;65:928-30. 5. Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 2009;8: 475-90. 6. Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle Nerve. 2008;37:141-9. 7. 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;108:209-11. 8. Nations SP, Wolfe GI, Amato AA, Jackson CE, Bryan WW, Barohn RJ. Distal myasthenia gravis. Neurology. 1999;52:632-4. 9. Fitzgerald MG, Shafritz AB. Distal myasthenia gravis. J Hand Surg Am. 2014;39:1419-20. 10. Oh SJ, Kim DE, Kuruoglu R, Bradley RJ, Dwyer D. Diagnostic sensitivity of the laboratory tests in myasthenia gravis. Muscle Nerve. 1992;15:720-4. 11. Sanders DB, Howard JF, Johns TR. Single-fiber electromyography in myasthenia gravis. Electroencephalogr Clin Neurophysiol. 1977:43. M 014. 12. Meriggioli MN, Sanders DB. Myasthenia gravis: diagnosis. Semin Neurol. 2004;24:31-9. 13. Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD. Antibody to acetylcholine receptor in myasthenia gravis: prevalence, clinical correlates, and diagnostic value. Neurology. 1998;51: 933. 14. Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 2015;14:1023-36. 15. Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375:511-22.
Can J Ophthalmol 2017;]:]]]–]]] 0008-4182/17/$-see front matter & 2017 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2017.04.012
CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
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CASE REPORT A 57-year-old Caucasian man was referred to an ophthalmology consultation because of progressive impairment of visual acuity in the right eye for approximately 10 years. He also reported an isolated and self-limited episode of binocular diplopia the week before, which lasted less than 10 minutes. He denied any other symptoms, such as headache or pain and trauma or previous infections. Regarding his medical history, he mentioned past smoking habits (30 pack-years) and sporadic episodes of hypertension and insomnia, for which he took lisinopril p.r.n. and zolpidem, respectively. On ophthalmologic examination, best-corrected visual acuity was 20/25 in the right eye and 20/20 in the left eye. Pupillary responses, extraocular movements, and cover testing were normal. Anterior segment examination and
intraocular pressure were also unremarkable. Fundoscopy revealed unspecific pigmented changes in the right eye and a normal fundus in the left eye. Ancillary studies, including optical coherence tomography and fluorescein angiography, confirmed pigmented inactive lesions at the level of the retinal pigmented epithelium (RPE), not related with the present episode. Considering the possible self-limited diplopia episode, a follow-up consultation was scheduled and blood workup and head computed tomography (CT) scan were requested. On the 6-week follow-up appointment, patient’s symptoms had worsened significantly, including persistent diplopia, asymmetric ptosis (more marked on the right eye), and weakness of the left distal upper limb. When questioned, he volunteered a history of hypophonia. There was no fluctuation of symptoms. On examination, an almost complete ptosis was present in the right eye and extraocular movements revealed absent adduction movements and partially limited supraduction, infraduction, and abduction. Also, mild hypophonia was remarked along with Medical Research Council (MRC) grade 4 paresis of the triceps, finger flexors (more prominent in the fifth digit), grade 4þ in finger extensors, and interosseous and abductors of the second and fifth digits on the left, with no identifiable weakness on the right upper limb. Hypophonia and left upper limb weakness did not show any exacerbation with prolonged effort testing. However, the ice-pack test caused a significant improvement of the right eye ptosis (Fig. 1). Moreover, there was significant fatigability as the right eye ptosis worsened after 1 minute of upgaze (Fig. 2). Pupillary reflexes, intraocular pressure, and anterior segment remained normal. Left eye examination was unremarkable. Blood work-up revealed a normal blood cell count and negative inflammatory/infectious markers. Neurophysiologic studies revealed normal conduction velocities and compound muscle action potential (CMAP) amplitudes. However, there was a significant decrement of CMAP amplitude and area after 2 Hz repetitive nerve stimulation. Decrement in amplitude was 27%, 10%, 18%, and 16% in right median, left median, spinal accessory, and facial nerves, respectively. Decrement in area was 27%, 16%, 23%, and 22% in the same nerves. AChR, muscle-specific kinase (MuSK), and low-density lipoprotein receptor–related protein (LRP4) were negative. Head CT scan, brain magnetic resonance imaging, and chest CT scan revealed no abnormal findings. The patient was treated with pyridostigmine 60 mg tid and prednisolone 20 mg every other day, with significant symptom improvement in the subsequent days. During follow-up and because of symptom persistence, pyridostigmine daily dose was increased up to 360 mg, prednisolone up to 80 mg every other day, and azathioprine 50 mg bid was introduced as a steroid-sparing agent. CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
1
Case Report
Fig. 1 — Prolonged effort testing. Right eye ptosis at baseline (A) and after 1 minute of upgaze (B).
Fig. 2 — Ice-pack test. Right eye ptosis at baseline (A) and after applying ice over the right eye (B). Notice increased frontalis muscle contraction with increasing ptosis in both figures.
DISCUSSION The clinical hallmark of MG is fatigable weakness, usually involving specific susceptible muscle groups. Patients usually report a daily or even hourly change in symptoms, worsening with activity and improving after rest.5 Several degrees of ptosis, diplopia, dysarthria, dysphagia, dyspnea, and facial weakness may be present. Ocular weakness, presenting as fluctuating ptosis and/or diplopia, is the most common initial presentation of MG, occurring in approximately 85% of patients.6 As in this case, ptosis is most commonly asymmetric and medial rectus muscle involvement is the most frequent. Disease progression to generalized weakness usually occurs within 2 years of disease onset.2,5 Although most commonly involving symmetrically the proximal limb muscle groups, there are rare cases of predominantly distal MG, reported as 3%–7% of the cases in 2 retrospective series.7,9 These can be fixed, asymmetric or even unilateral, and most commonly involve finger extensor and abductor muscles.8,10 Our case, however, presented with predominant weakness in finger flexors, which is extremely unusual and, to the best of our knowledge, has not been previously described in detail. Simple maneuvers are available to help us reach the diagnosis: the ice-pack test (Fig. 1) and the characteristic
2
CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
fatigability of ptosis after 1 minute of upgaze (Fig. 2). These cost-effective tests should be always performed in case of MG suspicion. In addition, neurophysiologic studies such as repetitive nerve stimulation and singlefibre electromyography,10,11 and testing for the presence of pathogenic autoantibodies such as AChR (85% of generalized MG, 50% of ocular MG), anti-MuSK, or antiLRP4 are useful confirmatory ancillary studies.12,13 Seronegative MG patients, such as our case, represent up to 5% of all myasthenic syndromes and do not have a welldefined muscle pattern distribution.14 Up to 15% of MG patients may have an associated thymic epithelial tumour. Peak age of onset is 50 years, but it may be present in any age group, and is equally prevalent in both sexes. Although seronegative MG patients (especially without anti-AChR and titin antibodies) rarely present with thymoma (as in our case), a thoracic CT scan should be routinely obtained.5,15 Symptomatic treatment with a cholinergic drug such as pyridostigmine and long-term corticosteroid therapy are recommended, along with its adverse effects’ monitoring.1 This case highlights the importance of always bearing in mind this entity, thus avoiding unnecessary delay and costly diagnostic procedures. As the prevalence of lateonset MG is increasing,3,4 one should keep a high index of suspicion.
Case Report Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article. Acknowledgements: The authors would like to acknowledge Isabel Conceição, MD, for the neurophysiological studies performed in the patient, and also Luisa Albuquerque, MD, Filipa Falcão, MD, and Patricia Antunes, MD, for the clinical evaluation and discussion of the patient during admission in the Neurology Department.
David Cordeiro Sousa, MD,*,† Pedro Viana, MD,‡ Inês Leal, MD,*,† Sara Parreira, MD,‡ João Ferreira, MD,‡,§ Fátima Campos, MD, MSc*,† *Department of Ophthalmology, Hospital de Santa Maria, 1649-035, Lisbon, Portugal; †Centro de Estudos Cieˆncias da Visa˜o, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal; ‡Department of Neurosciences and Mental Health, Neurology Service, Hospital de Santa Maria, 1649-035, Lisbon, Portugal; §Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal. Correspondence to: David Cordeiro Sousa, MD: [email protected]. REFERENCES 1. Drachman DB. Myasthenia gravis. N Engl J Med. 1994;330:1797-810. 2. Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis. Lancet. 2001;357:2122-8. 3. Phillips LH. The epidemiology of myasthenia gravis. Semin Neurol. 2004;24:17-20.
4. Somnier FE. Increasing incidence of late-onset anti-AChR antibodyseropositive myasthenia gravis. Neurology. 2005;65:928-30. 5. Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 2009;8: 475-90. 6. Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle Nerve. 2008;37:141-9. 7. 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;108:209-11. 8. Nations SP, Wolfe GI, Amato AA, Jackson CE, Bryan WW, Barohn RJ. Distal myasthenia gravis. Neurology. 1999;52:632-4. 9. Fitzgerald MG, Shafritz AB. Distal myasthenia gravis. J Hand Surg Am. 2014;39:1419-20. 10. Oh SJ, Kim DE, Kuruoglu R, Bradley RJ, Dwyer D. Diagnostic sensitivity of the laboratory tests in myasthenia gravis. Muscle Nerve. 1992;15:720-4. 11. Sanders DB, Howard JF, Johns TR. Single-fiber electromyography in myasthenia gravis. Electroencephalogr Clin Neurophysiol. 1977:43. M 014. 12. Meriggioli MN, Sanders DB. Myasthenia gravis: diagnosis. Semin Neurol. 2004;24:31-9. 13. Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD. Antibody to acetylcholine receptor in myasthenia gravis: prevalence, clinical correlates, and diagnostic value. Neurology. 1998;51: 933. 14. Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 2015;14:1023-36. 15. Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375:511-22.
Can J Ophthalmol 2017;]:]]]–]]] 0008-4182/17/$-see front matter & 2017 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2017.04.012
CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
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