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Occurrence of myasthenia gravis in a patient with congenital myotonia
Journal of the Neurological Sciences, 1982, 57:83-88
83
Elsevier Biomedical Press
OCCURRENCE OF MYASTHENIA GRAVIS IN A PATIENT WITH CONGENITAL MYOTONIA
HIROYUKI MATSUMOTO*, TOSHIRO SUG1YAMA, MASAHARU ITO and AKIRA YACHI
The First Department of lnternal Medicine, Sapporo Medical College, Sapporo (Japan) (Received 5 April, 1982) (Accepted 6 May, 1982)
SUMMARY
Myasthenia gravis developed acutely in a 32-year-old woman, who incidentally was found to have myotonia congenita of the autosomal dominant mode of inheritance. The simultaneous occurrence of myasthenia gravis and myotonia congenita was established clinically, pharmacologically and electromyographically. There was no immunologic abnormality, whereas the thymus was detected by pneumomediastinographic tomograms. About 2 months after the onset of myasthenia gravis, thymectomy was performed resulting in progressive improvement of myasthenia without apparent change in the myotonia.
INTRODUCTION
Myasthenia gravis is a disease characterized by variable weakness and fatigability due to reduced contraction of voluntary muscles, whereas myotonia congenita is a congenital disease manifested by a failure of voluntary muscles to relax immediately following contraction. Thus the clinical features and, therefore, the respective treatments are quite opposite. The combination of myasthenia gravis and myotonic disorders is extremely rare, and only one well-documented case with myasthenia gravis and myotonic dystrophy has been found in the literature (Schon 1977). The patient reported here, treated with transthoracic thymectomy, had typical myasthenia gravis and myotonia congenita.
* Address correspondence and reprint requests to: Dr. Hiroyuki Matsumoto, The First Department of Internal Medicine, Sapporo Medical College, South 1 West 16, Sapporo 060, Japan. 0022-510X/82/0000-0000/$02.75 © 1982 Elsevier Biomedical Press
84 CASE REPORT A 32-year-old Japanese housewife developed diplopia without a preceding history of infection or trauma. Over the next 2 weeks this progressed with accompanying ptosis of the right eyelid. She soon noticed diurnal fluctuation of diplopia and ptosis, which were absent or minimal early in the morning and worse toward evening. She was seen on April 6, 1981 about 1 month after the onset. The patient was well-nourished and the general physical examination was unremarkable. She complained of diplopia in all directions except downward, and also had slight bilateral ptosis with greater involvement on the right. During examination she showed a peculiar eyelid spasm elicited by brief blinking, suggestive of myotonia, although she had not complained of myotonic phenomena. Although there was no grip myotonia, percussion myotonia of the lingual and thenar muscles was clearly demonstrated (Fig. IA,B). The patient admitted that she had been aware of the eyelid spasm and of mild difficulty in initiating running since at least age 6. Slight weakness of the neck flexors and hip girdles was found. There was, however, no palatal dysarthria, hollowing of the temporal muscles or pseudohypertrophy of the calves. Reflexes and sensation were normal, and there was no evidence of mental deterioration. An intravenous injection of 2 mg edrophonium chloride brought about a prompt disappearance of ptosis and diplopia together with some eyelid spasm suggesting hypersensitivity to the anticholinesterase agent (Fig. 2A,B). Consequently, the concomitant presence of myasthenia gravis and myotonia was confirmed. She was admitted for further examination. Available family members were seen and myotonia of autosomal dominant mode of inheritance was detected (Fig. 3). None of her other family members, however, were found to have myasthenia gravis. Complete blood count, GOT, GPT, CPK, aldolase and electrolytes were all within normal limits. The oral glucose tolerance test, serum thyroxine, triiodothyronine levels and the TRH test were normal. No abnormality was found in T-,B-cell population, serum protein electrophoresis, immunoglobulin classes or complement levels. The rheumatoid factor, antinuclear factor, anti-DNA antibody, thyroglobulin antibody, microsome antibody, and antismooth and antistriated muscle antibodies were not detected in serum. An EKG was normal. Computed tomograms of the orbit showed no abnormality, whereas tomograms of pneumomediastinography showed a moderate-sized thymus. Needle electromyography of the thenar muscles demonstrated characteristic dive bomber sounds together with rare sharp waves suggesting muscle fiber irritability (Fig. 4A). Percussion myotonia of the thenar muscles was recorded as rhythmical polyphasic neuromotor units of long duration (Fig. 4B). A muscle biopsy specimen from the right rectus femoris revealed no characteristic finding by hematoxylin-eosin, PAS, ATP (pH 4.3 and 9.4) and Gomori trichrome stain, nor by electron microscopic examination. The patient was discharged on 15 mg distigmine bromide a day and awaited thymectomy. During this period myasthenia gravis appeared to be advancing. On May 19, 1981 she had a sudden hematemesis, for which 1200 ml of blood was transfused. Diffuse hemorrhagic gastritis was found by gastrofibroscopy, and was appropriately treated. It was noteworthy, however, that after blood transfusion the
Fig. 1. A : Percussion myotonia of the tongue, and B: of the thenar muscles.
85 myasthenia considerably improved for a period of 1 week. On June 8, 1981 she had the thymus removed. Histological examination failed to show lymphoid follicle hyperplasia. Four months after the operation she began to show progressive improvement of the myasthenia without apparent changes in myotonia congenita, although she had been on the same dose of distigrnine bromide.
Fig. 2. A : Complete ptosis of the right eyelid and mild ptosis of the left eyelid. B: An intravenous injection of 2 mg edrophonium chloride brought about a prompt improvement of ptosis.
-?
Fig. 3. Pedigree of family showing members affected by myotonia. The arrow indicates the present case. The dotted members are in unknown condition in relation to myotonia.
86
Fig. 4. A: Positive sharp waves, and B: Percussion myotonia obtained from the thenar muscles. The calibration indicates 1 mV and 10 ms.
DISCUSSION
There is a definite link between myasthenia gravis and a number of diseases that are believed to be related to immunological disturbances, and thymoma is a well-known association with myasthenia gravis. In contrast there has been no close association reported in myotonia congenita. Since some authors have suggested that myotonia congenita is part of a continuous spectrum of diseases including myotonic dystrophies and paramyotonia (Maas and Paterson 1950), from that standpoint one can refer to various associations of myotonic dystrophy. Namely, cataracts, frontal baldness, cardiac abnormalities and less frequently hypogammaglobulinemia have been well-recognized in myotonic dystrophy. There is 1 case report available dealing with the definite combination of myasthenia gravis and myotonic dystrophy in a 13-year-old girl (Schon 1977). The combination of these 2 diseases is said to occur in approximately 1 person in 700 million, assuming that the combination of the 2 diseases is detected by chance alone (Schon 1977). Myotonia congenita is less frequently seen than myotonic dystrophy. The prevalence rate of myotonia congenita has been reported to be between 0.3 and 0.6/100000 persons (Rowland and Layzer 1981a), while that of myotonic dystrophy has been reported to be 2.4 and 4.9/100 000 persons (Rowland and Layzer 1981b). Therelbre, a chance combination of myasthenia gravis and myotonia congenita in the same individual is thought to be astronomically rare, even allowing for some geographical differences in the prevalence rates. The electrical refractoriness associated with repetitive myotonic bursts can elicit pseudomyasthenia in patients with myotonia characterized by decrease in the voltage of successive responses with repetitive stimulation (Borenstein and Desmedt 1973). Therefore, an amplitude decrement alone may not be enough to prove the presence of myasthenia in the present case. Our patient, however, showed diurnal fluctuation of diplopia and ptosis which responded to the anticholinesterase agent and also, retrospectively, to thymectomy. The above clinical feature cannot be expected in myotonia, and consequently the concomitant occurrence of myotonia and myasthenia gravis is reliably supported.
87 To the best of our knowledge, the present case is the first case in which myasthenia gravis and myotonia congenita exist concomitantly, and is the second case if she is a sufferer of myotonic dystrophy rather than of myotonia congenita. We believe, however, that she has myotonia congenita of the autosomal dominant mode of inheritance, since she did not have cataracts, endocrine abnormalities, hypogammaglobulinemia or any features of muscular dystrophy. Neither were her family members found to have these complications. Muscle fiber membrane hyperirritability appears to be responsible for myotonia (McComas and Mrozek 1968; Lipicky et al. 1971; Gruener 1977), and no neuromuscular transmission abnormality has been demonstrated (Hofmann et al. 1966). On the other hand, neostigmine, an anticholinesterase agent, has been reported to aggravate myotonic dystrophy and myotonia congenita (Russel and Stedman 1936; Kennedy and Wolf 1938). In fact, we found that the patient was sensitive to edrophonium chloride injections, and therefore, we selected thymectomy as the first choice of therapy, since thymectomy can have a beneficial effect on the course of myasthenia gravis (Genkins et al. 1975). Serum anti-acetylcholine-receptor antibodies are detectable in 85-90~ of patients with myasthenia gravis (Lindstrom et al. 1976; Engel et al. 1977). The titer of anti-acetylcholine-receptor antibody of our patient, obtained 6 months after thymectomy, was within normal limits. The significance of this is unknown, however, since the preoperative titer could not be measured due to technical problems. In reviewing the clinical course, the following points are of interest. Firstly, a transient improvement of myasthenia gravis was observed when the patient received blood transfusion for hematemesis, which may imply the usefulness of incidental blood exchange as well as plasmapheresis. Secondly, she began to show some progressive improvement from 4 months after thymectomy despite the absence of follicular hyperplasia of the thymus. This fact supports the importance of early thymectomy for myasthenia gravis even in cases with no detectable autoantibodies in serum. ACKNOWLEDGEMENT
The authors thank Dr. Nobutada Tachi, Department of Pediatrics, for performing enzyme histochemical and electron-microscopic studies of the muscle. REFERENCES Borenstein, S. and J.E. Desmedt (1973) New diagnostic procedures in myasthenia gravis. In: J.E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 1, Karger, Basel, pp. 350-374. Engel, A.G., E.H. Lambert and F.M. Howard, Jr. (1977) Immune complexes (IgG and C3) at the motor end-plate in myasthenia gravis - - Ultrastructural and light microscopic localization and electrophysiologic correlations, Proc. Mayo Clin., 52: 267-280. Genkins, G., A.E. Papatestas, S.H. Horwitz and P. Kornfeld (1975) Studies in myasthenia gravis Early thymectomy Electrophysiologic and pathologic correlations, Amer. J. Med., 58: 517-524. Gruener, R. (1977) In vitro membrane excitability of diseased human muscle. In: L. P. Rowland (Ed.), Pathogenesis of Human Muscular Dystrophies, Excerpta Medica, New York, NY, pp. 242-258.
88 Hoffmann, W.W., W. Alston and G. Rowe (1966) A study of individual neuromuscular junctions in myotonia, Electroenceph. clin. Neurophysiol., 21: 521-537. Kennedy, F. and A. Wolf (1938) Quinine in myotonia and prostigmine in myasthenia, J. Amer. med. Ass., 110:198 201. Lindstrom, J. M., M.E. Seybold, V.A. Lennon, S.D. Whittingham and D.D. Duane (1976) Antibody to acetylcholine receptor in myasthenia gravis Prevalence, clinical correlates and diagnostic value, Neurology (Minneap.), 26: 1054-1059. Lipicky, R.J., S.H. Bryant and J. H. Salomon (1971) Cable parameters, sodium, potassium, chloride and water content, and potassium efflux in isolated external intercostal muscle of normal volunteers and patients with myotonia congenita, J. clin. Invest., 50:2091 2103. Maas, O. and A.S. Paterson (1950) The identity of myotonia congenita, dystrophia myotonica and paramyotonica, Brain, 73:318 336. McComas, A. J. and K. Mrozek (1%8) The electrical properties of muscle fibre membrane in dystrophia myotonica and myotonia congenita, J. Neurol. Neurosurg. Psychiat, 31 : 441-452. Rowland, L.P. and R.B. Layzer (1981a) Muscular dystrophies, atrophies, and related diseases. In: A.B. Baker and L.H. Baker (Eds.), Clinical Neurology, Vol. 3, Harper and Row, Hagerstown, MD, Ch. 37, p. 47. Rowland, L.P. and R.B. Layzer (1981b) ibid., p. 27. Russel, W. R. and E. Stedman (1936) Observation on myotonia, Lancet, ii: 742--743. Schon, R.T. (1977) Myasthenia gravis and myotonic dystrophy in a 13-year-old girl, Neurology (Minneap.), 27 : 546-549.
83
Elsevier Biomedical Press
OCCURRENCE OF MYASTHENIA GRAVIS IN A PATIENT WITH CONGENITAL MYOTONIA
HIROYUKI MATSUMOTO*, TOSHIRO SUG1YAMA, MASAHARU ITO and AKIRA YACHI
The First Department of lnternal Medicine, Sapporo Medical College, Sapporo (Japan) (Received 5 April, 1982) (Accepted 6 May, 1982)
SUMMARY
Myasthenia gravis developed acutely in a 32-year-old woman, who incidentally was found to have myotonia congenita of the autosomal dominant mode of inheritance. The simultaneous occurrence of myasthenia gravis and myotonia congenita was established clinically, pharmacologically and electromyographically. There was no immunologic abnormality, whereas the thymus was detected by pneumomediastinographic tomograms. About 2 months after the onset of myasthenia gravis, thymectomy was performed resulting in progressive improvement of myasthenia without apparent change in the myotonia.
INTRODUCTION
Myasthenia gravis is a disease characterized by variable weakness and fatigability due to reduced contraction of voluntary muscles, whereas myotonia congenita is a congenital disease manifested by a failure of voluntary muscles to relax immediately following contraction. Thus the clinical features and, therefore, the respective treatments are quite opposite. The combination of myasthenia gravis and myotonic disorders is extremely rare, and only one well-documented case with myasthenia gravis and myotonic dystrophy has been found in the literature (Schon 1977). The patient reported here, treated with transthoracic thymectomy, had typical myasthenia gravis and myotonia congenita.
* Address correspondence and reprint requests to: Dr. Hiroyuki Matsumoto, The First Department of Internal Medicine, Sapporo Medical College, South 1 West 16, Sapporo 060, Japan. 0022-510X/82/0000-0000/$02.75 © 1982 Elsevier Biomedical Press
84 CASE REPORT A 32-year-old Japanese housewife developed diplopia without a preceding history of infection or trauma. Over the next 2 weeks this progressed with accompanying ptosis of the right eyelid. She soon noticed diurnal fluctuation of diplopia and ptosis, which were absent or minimal early in the morning and worse toward evening. She was seen on April 6, 1981 about 1 month after the onset. The patient was well-nourished and the general physical examination was unremarkable. She complained of diplopia in all directions except downward, and also had slight bilateral ptosis with greater involvement on the right. During examination she showed a peculiar eyelid spasm elicited by brief blinking, suggestive of myotonia, although she had not complained of myotonic phenomena. Although there was no grip myotonia, percussion myotonia of the lingual and thenar muscles was clearly demonstrated (Fig. IA,B). The patient admitted that she had been aware of the eyelid spasm and of mild difficulty in initiating running since at least age 6. Slight weakness of the neck flexors and hip girdles was found. There was, however, no palatal dysarthria, hollowing of the temporal muscles or pseudohypertrophy of the calves. Reflexes and sensation were normal, and there was no evidence of mental deterioration. An intravenous injection of 2 mg edrophonium chloride brought about a prompt disappearance of ptosis and diplopia together with some eyelid spasm suggesting hypersensitivity to the anticholinesterase agent (Fig. 2A,B). Consequently, the concomitant presence of myasthenia gravis and myotonia was confirmed. She was admitted for further examination. Available family members were seen and myotonia of autosomal dominant mode of inheritance was detected (Fig. 3). None of her other family members, however, were found to have myasthenia gravis. Complete blood count, GOT, GPT, CPK, aldolase and electrolytes were all within normal limits. The oral glucose tolerance test, serum thyroxine, triiodothyronine levels and the TRH test were normal. No abnormality was found in T-,B-cell population, serum protein electrophoresis, immunoglobulin classes or complement levels. The rheumatoid factor, antinuclear factor, anti-DNA antibody, thyroglobulin antibody, microsome antibody, and antismooth and antistriated muscle antibodies were not detected in serum. An EKG was normal. Computed tomograms of the orbit showed no abnormality, whereas tomograms of pneumomediastinography showed a moderate-sized thymus. Needle electromyography of the thenar muscles demonstrated characteristic dive bomber sounds together with rare sharp waves suggesting muscle fiber irritability (Fig. 4A). Percussion myotonia of the thenar muscles was recorded as rhythmical polyphasic neuromotor units of long duration (Fig. 4B). A muscle biopsy specimen from the right rectus femoris revealed no characteristic finding by hematoxylin-eosin, PAS, ATP (pH 4.3 and 9.4) and Gomori trichrome stain, nor by electron microscopic examination. The patient was discharged on 15 mg distigmine bromide a day and awaited thymectomy. During this period myasthenia gravis appeared to be advancing. On May 19, 1981 she had a sudden hematemesis, for which 1200 ml of blood was transfused. Diffuse hemorrhagic gastritis was found by gastrofibroscopy, and was appropriately treated. It was noteworthy, however, that after blood transfusion the
Fig. 1. A : Percussion myotonia of the tongue, and B: of the thenar muscles.
85 myasthenia considerably improved for a period of 1 week. On June 8, 1981 she had the thymus removed. Histological examination failed to show lymphoid follicle hyperplasia. Four months after the operation she began to show progressive improvement of the myasthenia without apparent changes in myotonia congenita, although she had been on the same dose of distigrnine bromide.
Fig. 2. A : Complete ptosis of the right eyelid and mild ptosis of the left eyelid. B: An intravenous injection of 2 mg edrophonium chloride brought about a prompt improvement of ptosis.
-?
Fig. 3. Pedigree of family showing members affected by myotonia. The arrow indicates the present case. The dotted members are in unknown condition in relation to myotonia.
86
Fig. 4. A: Positive sharp waves, and B: Percussion myotonia obtained from the thenar muscles. The calibration indicates 1 mV and 10 ms.
DISCUSSION
There is a definite link between myasthenia gravis and a number of diseases that are believed to be related to immunological disturbances, and thymoma is a well-known association with myasthenia gravis. In contrast there has been no close association reported in myotonia congenita. Since some authors have suggested that myotonia congenita is part of a continuous spectrum of diseases including myotonic dystrophies and paramyotonia (Maas and Paterson 1950), from that standpoint one can refer to various associations of myotonic dystrophy. Namely, cataracts, frontal baldness, cardiac abnormalities and less frequently hypogammaglobulinemia have been well-recognized in myotonic dystrophy. There is 1 case report available dealing with the definite combination of myasthenia gravis and myotonic dystrophy in a 13-year-old girl (Schon 1977). The combination of these 2 diseases is said to occur in approximately 1 person in 700 million, assuming that the combination of the 2 diseases is detected by chance alone (Schon 1977). Myotonia congenita is less frequently seen than myotonic dystrophy. The prevalence rate of myotonia congenita has been reported to be between 0.3 and 0.6/100000 persons (Rowland and Layzer 1981a), while that of myotonic dystrophy has been reported to be 2.4 and 4.9/100 000 persons (Rowland and Layzer 1981b). Therelbre, a chance combination of myasthenia gravis and myotonia congenita in the same individual is thought to be astronomically rare, even allowing for some geographical differences in the prevalence rates. The electrical refractoriness associated with repetitive myotonic bursts can elicit pseudomyasthenia in patients with myotonia characterized by decrease in the voltage of successive responses with repetitive stimulation (Borenstein and Desmedt 1973). Therefore, an amplitude decrement alone may not be enough to prove the presence of myasthenia in the present case. Our patient, however, showed diurnal fluctuation of diplopia and ptosis which responded to the anticholinesterase agent and also, retrospectively, to thymectomy. The above clinical feature cannot be expected in myotonia, and consequently the concomitant occurrence of myotonia and myasthenia gravis is reliably supported.
87 To the best of our knowledge, the present case is the first case in which myasthenia gravis and myotonia congenita exist concomitantly, and is the second case if she is a sufferer of myotonic dystrophy rather than of myotonia congenita. We believe, however, that she has myotonia congenita of the autosomal dominant mode of inheritance, since she did not have cataracts, endocrine abnormalities, hypogammaglobulinemia or any features of muscular dystrophy. Neither were her family members found to have these complications. Muscle fiber membrane hyperirritability appears to be responsible for myotonia (McComas and Mrozek 1968; Lipicky et al. 1971; Gruener 1977), and no neuromuscular transmission abnormality has been demonstrated (Hofmann et al. 1966). On the other hand, neostigmine, an anticholinesterase agent, has been reported to aggravate myotonic dystrophy and myotonia congenita (Russel and Stedman 1936; Kennedy and Wolf 1938). In fact, we found that the patient was sensitive to edrophonium chloride injections, and therefore, we selected thymectomy as the first choice of therapy, since thymectomy can have a beneficial effect on the course of myasthenia gravis (Genkins et al. 1975). Serum anti-acetylcholine-receptor antibodies are detectable in 85-90~ of patients with myasthenia gravis (Lindstrom et al. 1976; Engel et al. 1977). The titer of anti-acetylcholine-receptor antibody of our patient, obtained 6 months after thymectomy, was within normal limits. The significance of this is unknown, however, since the preoperative titer could not be measured due to technical problems. In reviewing the clinical course, the following points are of interest. Firstly, a transient improvement of myasthenia gravis was observed when the patient received blood transfusion for hematemesis, which may imply the usefulness of incidental blood exchange as well as plasmapheresis. Secondly, she began to show some progressive improvement from 4 months after thymectomy despite the absence of follicular hyperplasia of the thymus. This fact supports the importance of early thymectomy for myasthenia gravis even in cases with no detectable autoantibodies in serum. ACKNOWLEDGEMENT
The authors thank Dr. Nobutada Tachi, Department of Pediatrics, for performing enzyme histochemical and electron-microscopic studies of the muscle. REFERENCES Borenstein, S. and J.E. Desmedt (1973) New diagnostic procedures in myasthenia gravis. In: J.E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 1, Karger, Basel, pp. 350-374. Engel, A.G., E.H. Lambert and F.M. Howard, Jr. (1977) Immune complexes (IgG and C3) at the motor end-plate in myasthenia gravis - - Ultrastructural and light microscopic localization and electrophysiologic correlations, Proc. Mayo Clin., 52: 267-280. Genkins, G., A.E. Papatestas, S.H. Horwitz and P. Kornfeld (1975) Studies in myasthenia gravis Early thymectomy Electrophysiologic and pathologic correlations, Amer. J. Med., 58: 517-524. Gruener, R. (1977) In vitro membrane excitability of diseased human muscle. In: L. P. Rowland (Ed.), Pathogenesis of Human Muscular Dystrophies, Excerpta Medica, New York, NY, pp. 242-258.
88 Hoffmann, W.W., W. Alston and G. Rowe (1966) A study of individual neuromuscular junctions in myotonia, Electroenceph. clin. Neurophysiol., 21: 521-537. Kennedy, F. and A. Wolf (1938) Quinine in myotonia and prostigmine in myasthenia, J. Amer. med. Ass., 110:198 201. Lindstrom, J. M., M.E. Seybold, V.A. Lennon, S.D. Whittingham and D.D. Duane (1976) Antibody to acetylcholine receptor in myasthenia gravis Prevalence, clinical correlates and diagnostic value, Neurology (Minneap.), 26: 1054-1059. Lipicky, R.J., S.H. Bryant and J. H. Salomon (1971) Cable parameters, sodium, potassium, chloride and water content, and potassium efflux in isolated external intercostal muscle of normal volunteers and patients with myotonia congenita, J. clin. Invest., 50:2091 2103. Maas, O. and A.S. Paterson (1950) The identity of myotonia congenita, dystrophia myotonica and paramyotonica, Brain, 73:318 336. McComas, A. J. and K. Mrozek (1%8) The electrical properties of muscle fibre membrane in dystrophia myotonica and myotonia congenita, J. Neurol. Neurosurg. Psychiat, 31 : 441-452. Rowland, L.P. and R.B. Layzer (1981a) Muscular dystrophies, atrophies, and related diseases. In: A.B. Baker and L.H. Baker (Eds.), Clinical Neurology, Vol. 3, Harper and Row, Hagerstown, MD, Ch. 37, p. 47. Rowland, L.P. and R.B. Layzer (1981b) ibid., p. 27. Russel, W. R. and E. Stedman (1936) Observation on myotonia, Lancet, ii: 742--743. Schon, R.T. (1977) Myasthenia gravis and myotonic dystrophy in a 13-year-old girl, Neurology (Minneap.), 27 : 546-549.