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Double trouble: Spinal muscular atrophy type II and seropositive myasthenia gravis in the same patient
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Neuromuscular Disorders 22 (2012) 129–130 www.elsevier.com/locate/nmd
Case report
Double trouble: Spinal muscular atrophy type II and seropositive myasthenia gravis in the same patient Manu Jokela a,⇑, Bjarne Udd b,c, Markku Pa¨iva¨rinta a a b
Department of Neurology, Turku University Central Hospital, Turku, Finland Neuromuscular Center, Tampere University Central Hospital, Tampere, Finland c Vasa Central Hospital, Vasa, Finland
Received 8 May 2011; received in revised form 6 July 2011; accepted 28 July 2011
Abstract Autosomal recessive proximal spinal muscular atrophy is caused by deletions in the survival of motor neuron (SMN1) gene, while autoimmune myasthenia gravis is an acquired disorder. An association between these two diseases has not been reported. Our patient with intermediate spinal muscular atrophy (SMA type II) did not need alimentary or respiratory aid until age 51 when he suddenly developed bulbar weakness and respiratory insufficiency. Seropositive myasthenia gravis was confirmed and the corresponding symptoms resolved on treatment. Ó 2011 Elsevier B.V. All rights reserved. Keywords: Spinal muscular atrophy; SMN1; Myasthenia gravis; Acetylcholine receptor antibodies
1. Introduction SMN1 gene defect spinal muscular atrophy (SMA) is a common autosomal recessive disorder caused by progressive loss of lower motor neurons leading to proximal muscle weakness, wasting and respiratory failure. We describe the clinical features of an SMA II patient who developed AChR-Ab-positive myasthenia gravis (MG), a previously unreported association of these two disorders. Estimating a prevalence of 1:83 000 [1] for SMA and 10:100 000 for MG in the general population we would expect one in a billion patients to have both diseases simultaneously if these two disorders are unrelated. 2. Case report The patient, born of non-consanguineous parents, has had spinal muscular atrophy for 51 years. He could sit ⇑ Corresponding author. Address: Turku University Central Hospital, Department of Neurology, P.O. Box 51, 20521 Turku, Finland. E-mail address: mejoke@utu.fi (M. Jokela).
0960-8966/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2011.07.011
unsupported but was never able to walk. MRC grade 2–3 strength in his distal upper limbs enabled him to use an electric wheelchair with a mini-joystick. He had severe scoliosis and his lower extremity muscle strength was MRC 1–2. Facial and bulbar muscles, speech and intellect were normal. The diagnosis of SMA was confirmed by typical EMG findings of severely reduced motor unit numbers with large, high-amplitude MUPs and normal sensory findings and was later corroborated by genetic testing showing homozygous deletion of SMN1. The patient’s neurologic function remained relatively stable over the previous decades without progressive disability. At age 51, worsening dysphagia and masticatory weakness developed over a few weeks. A superimposed mild respiratory infection led to rapid deterioration in ventilatory function requiring emergency tracheostomy and permanent night-time ventilatory support. Communication was possible through lip reading. Tube feeding was initiated via gastrostomy. The onset of bulbar weakness was thought to be compatible with the previous diagnosis of SMA. Four months later the patient was referred to the neurology department because of ptosis and ophtalmoparesis in his
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M. Jokela et al. / Neuromuscular Disorders 22 (2012) 129–130
left eye. A pseudo-internuclear ophthalmoplegia-pattern weakness and ptosis was noted in the left eye together with severe dysarthria, a myopathic face and very little voluntary movement in the patient’s left hand. He recalled having right eye ptosis of a few weeks duration prior the hospitalization. Because ocular findings are highly atypical in SMA, further investigations were performed. MRI of the brain was normal. Repetitive nerve stimulation displayed a 42% decrement in the left musculus nasalis. Serum acethylcholine receptor antibodies were markedly elevated at 44 nmol/l (reference range 0.25–0.40 nmol/l). Edrophonium testing was unequivocally positive with rapid objective improvement in facial muscle strength and resolution of ptosis and ophthalmoplegia. Computed tomography of the chest showed remnants of thymic tissue without hyperplasia or thymoma. The patient received a 5 day course of intravenous immunoglobulin and oral prednisone was started together with pyridostigmine bromide. After six months of follow-up, the patient’s speech and facial function have normalized and he is able to consume soft foods. Azathioprine was started as a steroid-sparing agent while prednisone is gradually being reduced.
respiratory muscles. The possibility of MG could have been overlooked in this setting because most of the patient’s muscles were already nonfunctional and respiratory failure is the commonest form of death in SMA. The almost pathognomonic finding of variable ptosis and weakness of extraocular muscles raised the possibility of myasthenia gravis, which was later confirmed. It is probable that this combination of two rare diseases is a by chance association; this is supported by the lack of similar cases in the literature. Two patients with spinobulbar muscular atrophy (Kennedy’s disease) and with myasthenic syndromes responding to anticholinesterase inhibitor treatment have been reported in the literature [3,4]. We have also seen one patient with the combination of Kennedy’s disease and seropositive, treatment responsive myasthenia gravis (Udd B, unpublished observation). Acetylcholine receptor antibodies have been reported in a percentage of ALS patients, even without previous bungarotoxin therapy [5–8]. It would be interesting to know which percentage of patients with longstanding motor neuropathy and functional decline after a long stable phase have developed autoantibodies against their neuromuscular junction proteins.
3. Discussion
References
The morbidity and mortality of SMA II–III patients with prolonged life span is poorly detailed in the literature. SMA type I used to carry a very poor prognosis with only rare patients surviving more than two years. During the last decades, however, improvements in respiratory management have resulted in up to 30% of patients surviving past age 20 [2]. In a Chinese study, 88% of “intermediateSMA” or SMA II patients were alive at age 40 and the cause of death in all deceased patients was cardiorespiratory failure [2]. Since life expectancy is not greatly reduced in the relatively benign SMA III, most of these patients presumably die of SMA-unrelated causes. The clinical course of SMA II is known to include phases of arrested or imperceptible progression, but the cause of progressive symptoms at a later stage is unknown. In our patient, a lengthy progression-free phase was followed by a rapidly evolving weakness involving the facial, extraocular and
[1] Rudnik-Scho¨neborn S, de Visser M, Zerres K. Spinal muscular atrophies. In: Engel A, Franzini-Armstrong C, editors. Myology. McGraw-Hill; 2004. p. 1845–64. [2] Chung BH, Wong VC, Ip P. Spinal muscular atrophy: survival pattern and functional status. Pediatrics 2004;114:e548–5544. [3] Yamada M, Inaba A, Shiojiri J. X-linked spinal and bulbar muscular atrophy with myasthenic symptoms. J Neurol Sci 1997;146:183–5. [4] Boz C, Kalay E, Sahin N. Ocular myasthenia gravis associated with xlinked recessive spinal and bulbar muscular atrophy. J Clin Neuromuscul Dis 2004 Mar;5(3):115–8. [5] Okuyama Y, Mizuno T, Inoue H, Kimoto K. Amyotrophic lateral sclerosis with anti-acetylcholine receptor antibody. Intern Med 1997;36:312–5. [6] Abbott RJ, Holden D, Currie S. False positive antiacetylcholine receptor antibodies in motor neurone disease. Lancet 1986;1:906–7. [7] Ashizawa T. False positive anti-acetylcholine receptor antibodies in motor neurone disease. Lancet 1986;1:1272. [8] Mittag TW, Caroscio J. False-positive immunoassay for acetylcholine receptor antibody in amyotrophic lateral sclerosis. N Engl J Med 1980;302:868.
Neuromuscular Disorders 22 (2012) 129–130 www.elsevier.com/locate/nmd
Case report
Double trouble: Spinal muscular atrophy type II and seropositive myasthenia gravis in the same patient Manu Jokela a,⇑, Bjarne Udd b,c, Markku Pa¨iva¨rinta a a b
Department of Neurology, Turku University Central Hospital, Turku, Finland Neuromuscular Center, Tampere University Central Hospital, Tampere, Finland c Vasa Central Hospital, Vasa, Finland
Received 8 May 2011; received in revised form 6 July 2011; accepted 28 July 2011
Abstract Autosomal recessive proximal spinal muscular atrophy is caused by deletions in the survival of motor neuron (SMN1) gene, while autoimmune myasthenia gravis is an acquired disorder. An association between these two diseases has not been reported. Our patient with intermediate spinal muscular atrophy (SMA type II) did not need alimentary or respiratory aid until age 51 when he suddenly developed bulbar weakness and respiratory insufficiency. Seropositive myasthenia gravis was confirmed and the corresponding symptoms resolved on treatment. Ó 2011 Elsevier B.V. All rights reserved. Keywords: Spinal muscular atrophy; SMN1; Myasthenia gravis; Acetylcholine receptor antibodies
1. Introduction SMN1 gene defect spinal muscular atrophy (SMA) is a common autosomal recessive disorder caused by progressive loss of lower motor neurons leading to proximal muscle weakness, wasting and respiratory failure. We describe the clinical features of an SMA II patient who developed AChR-Ab-positive myasthenia gravis (MG), a previously unreported association of these two disorders. Estimating a prevalence of 1:83 000 [1] for SMA and 10:100 000 for MG in the general population we would expect one in a billion patients to have both diseases simultaneously if these two disorders are unrelated. 2. Case report The patient, born of non-consanguineous parents, has had spinal muscular atrophy for 51 years. He could sit ⇑ Corresponding author. Address: Turku University Central Hospital, Department of Neurology, P.O. Box 51, 20521 Turku, Finland. E-mail address: mejoke@utu.fi (M. Jokela).
0960-8966/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2011.07.011
unsupported but was never able to walk. MRC grade 2–3 strength in his distal upper limbs enabled him to use an electric wheelchair with a mini-joystick. He had severe scoliosis and his lower extremity muscle strength was MRC 1–2. Facial and bulbar muscles, speech and intellect were normal. The diagnosis of SMA was confirmed by typical EMG findings of severely reduced motor unit numbers with large, high-amplitude MUPs and normal sensory findings and was later corroborated by genetic testing showing homozygous deletion of SMN1. The patient’s neurologic function remained relatively stable over the previous decades without progressive disability. At age 51, worsening dysphagia and masticatory weakness developed over a few weeks. A superimposed mild respiratory infection led to rapid deterioration in ventilatory function requiring emergency tracheostomy and permanent night-time ventilatory support. Communication was possible through lip reading. Tube feeding was initiated via gastrostomy. The onset of bulbar weakness was thought to be compatible with the previous diagnosis of SMA. Four months later the patient was referred to the neurology department because of ptosis and ophtalmoparesis in his
130
M. Jokela et al. / Neuromuscular Disorders 22 (2012) 129–130
left eye. A pseudo-internuclear ophthalmoplegia-pattern weakness and ptosis was noted in the left eye together with severe dysarthria, a myopathic face and very little voluntary movement in the patient’s left hand. He recalled having right eye ptosis of a few weeks duration prior the hospitalization. Because ocular findings are highly atypical in SMA, further investigations were performed. MRI of the brain was normal. Repetitive nerve stimulation displayed a 42% decrement in the left musculus nasalis. Serum acethylcholine receptor antibodies were markedly elevated at 44 nmol/l (reference range 0.25–0.40 nmol/l). Edrophonium testing was unequivocally positive with rapid objective improvement in facial muscle strength and resolution of ptosis and ophthalmoplegia. Computed tomography of the chest showed remnants of thymic tissue without hyperplasia or thymoma. The patient received a 5 day course of intravenous immunoglobulin and oral prednisone was started together with pyridostigmine bromide. After six months of follow-up, the patient’s speech and facial function have normalized and he is able to consume soft foods. Azathioprine was started as a steroid-sparing agent while prednisone is gradually being reduced.
respiratory muscles. The possibility of MG could have been overlooked in this setting because most of the patient’s muscles were already nonfunctional and respiratory failure is the commonest form of death in SMA. The almost pathognomonic finding of variable ptosis and weakness of extraocular muscles raised the possibility of myasthenia gravis, which was later confirmed. It is probable that this combination of two rare diseases is a by chance association; this is supported by the lack of similar cases in the literature. Two patients with spinobulbar muscular atrophy (Kennedy’s disease) and with myasthenic syndromes responding to anticholinesterase inhibitor treatment have been reported in the literature [3,4]. We have also seen one patient with the combination of Kennedy’s disease and seropositive, treatment responsive myasthenia gravis (Udd B, unpublished observation). Acetylcholine receptor antibodies have been reported in a percentage of ALS patients, even without previous bungarotoxin therapy [5–8]. It would be interesting to know which percentage of patients with longstanding motor neuropathy and functional decline after a long stable phase have developed autoantibodies against their neuromuscular junction proteins.
3. Discussion
References
The morbidity and mortality of SMA II–III patients with prolonged life span is poorly detailed in the literature. SMA type I used to carry a very poor prognosis with only rare patients surviving more than two years. During the last decades, however, improvements in respiratory management have resulted in up to 30% of patients surviving past age 20 [2]. In a Chinese study, 88% of “intermediateSMA” or SMA II patients were alive at age 40 and the cause of death in all deceased patients was cardiorespiratory failure [2]. Since life expectancy is not greatly reduced in the relatively benign SMA III, most of these patients presumably die of SMA-unrelated causes. The clinical course of SMA II is known to include phases of arrested or imperceptible progression, but the cause of progressive symptoms at a later stage is unknown. In our patient, a lengthy progression-free phase was followed by a rapidly evolving weakness involving the facial, extraocular and
[1] Rudnik-Scho¨neborn S, de Visser M, Zerres K. Spinal muscular atrophies. In: Engel A, Franzini-Armstrong C, editors. Myology. McGraw-Hill; 2004. p. 1845–64. [2] Chung BH, Wong VC, Ip P. Spinal muscular atrophy: survival pattern and functional status. Pediatrics 2004;114:e548–5544. [3] Yamada M, Inaba A, Shiojiri J. X-linked spinal and bulbar muscular atrophy with myasthenic symptoms. J Neurol Sci 1997;146:183–5. [4] Boz C, Kalay E, Sahin N. Ocular myasthenia gravis associated with xlinked recessive spinal and bulbar muscular atrophy. J Clin Neuromuscul Dis 2004 Mar;5(3):115–8. [5] Okuyama Y, Mizuno T, Inoue H, Kimoto K. Amyotrophic lateral sclerosis with anti-acetylcholine receptor antibody. Intern Med 1997;36:312–5. [6] Abbott RJ, Holden D, Currie S. False positive antiacetylcholine receptor antibodies in motor neurone disease. Lancet 1986;1:906–7. [7] Ashizawa T. False positive anti-acetylcholine receptor antibodies in motor neurone disease. Lancet 1986;1:1272. [8] Mittag TW, Caroscio J. False-positive immunoassay for acetylcholine receptor antibody in amyotrophic lateral sclerosis. N Engl J Med 1980;302:868.