Cardiac abnormalities in myotonic dystrophy

Cardiac abnormalities in myotonic dystrophy

Journal of the Neurological Sciences, 1987, 80:259-268 259 Elsevier JNS 02869 Cardiac abnormalities in myotonic dystrophy Electrocardiographic and ...

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Journal of the Neurological Sciences, 1987, 80:259-268

259

Elsevier JNS 02869

Cardiac abnormalities in myotonic dystrophy Electrocardiographic and echocardiographic findings in 65 patients and 34 of their unaffected relatives. Relation with age and sex and relevance for gene detection Axel R. W i n t z e n I and J o h a n J. S c h i p p e r h e y n 2 Departments of ~Neurology and 2Cardiology, University Hospital Leiden, Leiden (The Netherlands)

(Received 14 October, 1986) (Revised, received 31 March, 1987) (Accepted 31 March, 1987)

SUMMARY Sixty-five patients with a definite diagnosis of myotonic dystrophy (MD) and 34 of their presumably unaffected relatives were examined cardiologically, including ECG in all and echocardiography in 61 and 32 persons respectively, in order to investigate the frequency of cardiac abnormalities, their clinical importance and their potential value as a preclinical marker in the diagnosis of MD. Atrioventricular conduction (AVC) abnormalities were found in 18/33 (54~o) of affected males and in only 5/32 (16~o) of affected females (P = 0.0025). Intraventricular (IVC) conduction abnormalities were encountered with similar frequency in both sexes: in 12/33 ( 3 6 ~ ) of affected males and 10/32 (31 ~ ) of affected females. Mitral valve prolapses (MVP) were seen more often in affected females: 9/31 (29~o) of affected males vs 15/30 (50~o) of affected females have MVP (P -- 0.16). A previously undescribed finding was that of pericardial effusions in 5 affected and in 1 unaffected person. All affected males with MVP also had conduction abnormalities, but cardiac findings were not interrelated otherwise. None of the cardiac abnormalities mentioned were age-related. Only 8/65 (12~o) of patients had cardiac symptoms, all of which were the result of conduction defects. As far as can be judged from a transversal study, the value of cardiac examination of this kind as a preclinical test for the diagnosis of MD is modest. It is argued that IVC-abnormalities, but not AVC-disturbances or MVP, in clinically

Correspondenceto: A.R. Wintzen, M.D., Dept. of Neurology,UniversityHospital Leiden, Rijnsburgerweg 10, 2333 AA Leiden, The Netherlands. 0022-510X/87/$03.50 © 1987 Elsevier Science Publishers B.V. (Biomedical Division)

260 unaffected relatives may indicate that they are preclinical heterozygotes. The significance of pericardial effusion for the diagnosis of MD awaits further evaluation.

Key words: Myotonic dystrophy; Cardiac conduction abnormalities; Mitral valve prolapse; Pericardial effusion; Distribution over sex and age; Preclinical gene detection

INTRODUCTION

The nature and frequency of cardiac involvement in myotonic dystrophy is important for different reasons. First, cardiac abnormalities may cause symptoms and require treatment. Second, their occurrence may provide insight into the disease process if related to age and other manifestations of the disorder. Third, they might be valuable in identifying as heterozygotes clinically unaffected relatives. The latter two issues, of course, are closely connected; they were the main topics of this prospective study. The former issue is out of the scope of a neurologist and will only be mentioned briefly. Cardiac involvement in myotonic dystrophy is common but its reported frequency varies considerably. ECG-abnormalities were found to vary from 38 (Orndahl et al. 1964) to 100 ~o (Schmitt and Schmidt 1975), and the frequencies of reported detection ofmitral valve prolapses (MVP) range between 0 and 80~o (Beulcke et al. 1979; Winters et al. 1976). Conduction abnormalities were found to be restricted to particular families in one series (Hawley et al. 1983), an as yet unconfLrmed (Moorman et al. 1985) finding. Whether these differences in frequency are the result of heterogeneity of the disorder, differences of age, sex or stage of the disease, observers' bias, or a combination of these, is unclear. Furthermore, detailed information regarding the occurrence of cardiac abnormalities in relatives of MD patients is scarce (Bundey and Carter 1970; Winters et al. 1976; Gottdiener et al. 1982). The question whether ECG or echocardiographic abnormalities, alone or in combination, may serve as a preclinical test has not yet been unequivocally answered. The present paper reports on the frequency of cardiac abnormalities in a large group of patients and their clinically unaffected relatives. PATIENTS, DEFINITIONS AND METHODS

During the period 1977 upto and including 1986 we examined 65 patients with a definite diagnosis of myotonic dystrophy. As we encouraged examination of their families, 34 of their relatives were examined in the same way, including cardiologic and ophthaimologic screening. The patients and their relatives belonged to 35 different kinships. The diagnosis of myotonic dystrophy was posed on the basis of at least two of the following criteria: muscular weakness with appropriate distribution (60 patients), muscular atrophy (47), clinical myotonia (51), cataract (36), or evidence from the pedigree (57). Two elderly patients were free of signs and symptoms of the disease but

26l were obligatory heterozygotes in view of pedigree data. With the exception of five second degree relatives in one sibship, all relatives examined were first degree family members of an affected person and thus had an a priori risk of being heterozygous of 0.5. All patients and relatives were examined by one neurologist (ARW) and one cardiologist (JJS). The cardiological examination included auscultation of the heart, a 12-lead electrocardiogram and an echocardiogram in 63 out of 65 patients as well as in 32 out of 34 relatives. First degree (PR-interval equal to or longer than 0.20 s) or higher degree atrioventricular block, as well as recurrent AV-nodal tachycardia was classified as AV conduction (AVC) abnormality. Complete bundle branch block, right bundle branch block and left axis deviation suggesting left anterior partial bundle branch block were classified as intraventricular conduction (IVC) abnormality. The echocardiograms were made with an Organon Technika 003 echocardiograph, with a two-dimensional linear array system. M-mode scans were made through the third, fourth or fifth intercostal space in the left recumbent position. Recordings were made on a Honeywell LS6 fibre-optic recorder, at a paper speed of 50 mm/s. From the recording the end-systolic diameter of the left atrium, the end-systolic and end-diastolic diameter of the left ventricle and the thickness of the septal and the posterior wall were measured (Henry et al. 1980). Patients with a late-systolic or holosystolic apical murmur or mid-systolic click and more than 2 mm systolic posterior movement of the mitral valve leaflets on the echocardiogram were considered to have a MVP. All patients and their relatives were examined by an ophthalmologist, especially for cataract. RESULTS

There were 33 males and 32 females affected; unaffected females (24) outnumbered the unaffected males (10) for no apparent reason. The age-distribution was similar for these four groups (Table I). Abnormal AVC was found iri over half of the affected males, irrespective of their ages. By contrast, abnormal AVC was relatively rare in affected females: 5 out of 32 patients (P = 0.0025, chi-square test). One unaffected male and two unaffected female relatives had an abnormal AVC. No sex difference was found for IVC abnormalities (Table 1): affected males and females both had a rate of approximately 1 : 3, with no apparent variation with age. IVC abnormalities were found in two male and one female unaffected relatives. AVC and IVC abnormalities occurred independently from each other: the frequency of their combined manifestation roughly equalled the product of the frequencies of the individual phenomena (Table 1, col. 5). The resulting prevalence of all conduction abnormalities was 2 : 3 for affected men and 1 : 3 for affected women; accordingly the rate of these abnormalities for males was twice that for females (Table 1, column 6) (P = 0.04, chi-square test). Excluding a few patients with long-standing hypertension the echocardiographic dimensions of the left atrium and left ventricle as well as the wall thickness of the left ventricle were normal in all patients and their relatives.

65

32

5 17 9 1

33

5 14 13 1

23

5

2 3 .

18

3 8 6 1

.

22

10

2 3 5

12

2 3 6 1

.

.

9

2

2

7

2 4 1

AVC + IVC dist.

36

13

2 5 6

23

3 11 8 1

Total pat. with cond. abnorm,

34

24

4 10 8 2

10

1 9 . .

. .

Total pers.

IVC dist.

Total pat.

AVC dist.

Unaffected

3

2

. 2 . .

1

. 1 . .

. .

.

. . .

3

1

1

2

2

. .

.

.

IVC dist.

CONDUCTION

AVC dist.

AND INTRAVENTRICULAR

Affected

OF ATRIOVENTRICULAR

. .

. .

.

.

2

1

1

1

1

AVC + IVC dist.

AND

4

2

2

2

2

T o t a l pat. w i t h cond. abnorm.

FOR MD-PATIENTS

A V C dist. = atrioventricular c o n d u c t i o n d i s t u r b a n c e ; IVC dist. = i n t r a v e n t r i c u l a r c o n d u c t i o n d i s t u r b a n c e ; M D = m y o t o n i c d y s t r o p h y ; A V C + I V C dist. = b o t h A V C and IVC d i s t u r b a n c e s ; total pat. with cond. abnorm. = total of patients with c o n d u c t i o n abnormalities.

Total patients

Total females

Females 0-19 20-39 40-59 60 +

Total males

Males 0-19 20-39 40-59 60 +

Age (years)

SEX- A N D A G E - S P E C I F I C A B N O R M A L I T I E S THEIR UNAFFECTED RELATIVES

TABLE 1

to

263 TABLE 2 SEX- AND AGE-SPECIFIC RATES OF CONDUCTION ABNORMALITIES AND MITRAL VALVE PROLAPSE FOR MD PATIENTS AND THEIR UNAFFECTED RELATIVES

Age (years)

Total pat.

Total pat. conduct, abn.

Pat. ECG + Echo

Id. with conduct, abn.

5 14 13 1

3 11 8 1

5 13 12 1

3 10 7 -

33

23

31

5 17 9 1

2 5 6 -

32

1 9 . .

MD males 0-19 20-39 40-59 60 + Total m a l e s M D females 0-19 20-39 40-59 60 + Total females M D relatives-males 0-19 20-39 40-59 60 + Total m a l e s

Id. w i t h b o t h cond. abn. + M V P

Id. all cardiac abn.

3 4 2

3 4 2

3 10 7

20

9

9

20

5 16 8 1

2 4 5 -

3 9 3

1 2 1

4 11 7

13

30

11

15

4

22

2

1 8

2

3

-

5

3

-

5

4

1

5

1

-

1

1

-

1

6

1

7

. .

. .

. .

10

2

9

2

M D relatives-females 0-19 4 20-39 10 40-59 8 60+ 2

2 -

4 10 7 2

2 -

2

23

2

Total females

24

Id. with MVP

M V P = m i t r a l valve p r o l a p s e ; M D = m y o t o n i c d y s t r o p h y ; pat. E C G + Echo = n u m b e r of p a t i e n t s w h o h a d both E C G a n d e c h o c a r d i o g r a p h y .

Mitral valve prolapse (MVP) was encountered more often in affected females than in affected males (Table 2): in half (15/30) of the females and almost one third (9/31) of the males. The difference is not significant (P = 0.16, chi-square test). No apparent relation with age was found for its presence. MVP was less frequent in unaffected sibs, but still occurred in 3/9 males and 6/23 females. A second, and surprising, echo-cardiographic finding was that of pericardial effusions in 5 affected persons (4 males, 1 female) and in one unaffected female. It was not related to other cardiac or clinical abnormalities. Although conduction abnormalities were twice as frequent as MVP in affected men, all males who had MVP also had ECG abnormalities, an association not seen in women (Table 2) (P = 0.002, chi-square test).

264 In all families, who had three or more affected members examined, both conduction abnormalities and MVP's were encountered. There were 11 families each with only 2 affected members examined. Among the 22 patients concerned there were 4 women belonging to 2 families without conduction abnormalities. Three families with 2 patients each examined, comprising 2 males and 4 females, did not display MVP. Finally, there were 17 families, concerning 10 males and 7 females, each with only one patient fully examined: 6 patients (2 males, 4 females) had no conduction abnormality, 10 patients (7 males, 3 females) had no MVP. Although conduction-abnormalities and MVP were less frequent in unaffected family members, their occurrence deserves special attention. Four relatives, considered to be unaffected, had cardiac conduction defects (Table 3, persons 1-4). Of these, persons 1, 3 and 4, who had IVC disturbances, had an a priori risk of 0.5 and had equivocal clinical signs or symptoms suggesting that they might be affected indeed. One person (No. 2) who had an abnormal AVC as an isolated sign, had an a priori risk of 0.25, no signs in her 4 sibs or her mother of being affected and no clinical signs or symptoms suggestive of the disease itself. Nine supposedly unaffected relatives had MVP (Nos. 3 and 5-12). All of them had an a priori risk of 0.5, but, with the exception of No. 3, just mentioned, and No. 6, who had slight atypical lenticular opacities, were free of suggestive signs or symptoms otherwise. In this series, only one patient had had cardiac symptoms as a presenting and a single clinical abnormality for many years. It concerned a 38-year-old male who had intermittent tachycardias of atrioventricular nodal origin since his teen-age. He was examined in his early twenties because of an affected parent. No muscular or ophthalmological abnormalities were found. On his last visit, he complained of loss of dynamic drive and hypersomnia; on examination, the orbicularis oculi muscles were overtly paretic. In view of the high rate of conduction abnormalities in the present group of patients, it is remarkable that relatively few had cardiac symptoms: only 8 out of 65 patients had sought medical advice or were medically treated at some time for this reason. In all instances symptoms were attributable to conduction disturbances; they will not be described in detail. MVP was asymptomatic in all cases. The 6 patients with pericardial effusions also did not have cardiac symptoms. DISCUSSION Almost all MD patients in this study had muscular signs. Only a few patients lacked muscular symptoms and were diagnosed on the basis of cataracts and/or evidence from the pedigree. Thus, the frequency of cardiac abnormalities reported here largely represents that of a group of patients who already have muscular symptoms. Abnormalities of AVC had an overall frequency of about 1 in 3, a figure agreeing with that of others (Orndahl et al. 1964; Church 1967; Moorman et al. 1985; Perloff et al. 1984). The marked sex difference, males being affected about 4 times as often as

F

M M M F F M F

F

F

3

4 5 6 7 8 9 10

11

12

65

26

29 32 31 34 40 20 23

29

37 24

Age (years)

+

+ +

AVC dist.

+

+

+

IVC dist.

See Tables 1 and 2 for abbreviations; N D = not done.

M F

Sex

1 2

Patient No.

+

+

+ + + + + +

+

MVP

+

+

ND

Slight atypical lenticular opacities

Hypersomnia; inconsistent slight weakness Hypersomnia

Baldness since age 17

Clinical signs/symptoms

UNAFFECTED RELATIVES WITH CARDIAC ABNORMALITIES: A D D I T I O N A L F I N D I N G S

TABLE 3

One affected sister At least two affected sibs Brother affected Brother affected Two sibs affected Two sibs affected At least one affected sib Same sibship as previous Same sibship as previous Mother of previous sibs

Two sisters and one brother affected All four sibs unaffected; 2 sibs of unaffected mother MD

Evidence from pedigree

O~

266 females, has, however, not been reported before. IVC defects were observed with an equal rate of 1 in 3 for both sexes, i.e. approximately the same order of magnitude as reported by others (Church 1967; Perloff et al. 1984). Although conduction defects may occur at a fairly young age (Schmitt and Schmidt 1975; Griggs et al. 1975; Harper 1979), it has never been explicitly stated that their presence seems to be completely age-independent: in the present series all patients who had skeletal muscular signs had an equal risk of also having cardiac conduction abnormalities. The reported frequency of MVP in myotonic dystrophy patients varies: the lowest rate is reported by Beulcke (1979) (0/10 patients; 1), the highest by Winters (1976) (8/10 patients: 19). The largest series reported up to now (Moorman et al. 1985) comprised 46 patients with a MVP-rate of 17/46 (37 ~o), similar to ours 24/61 (39~o). The relation with sex and age remains largely obscure (Gottdiener et al. 1982; Reeves et al. 1980; Moorman et al. 1985). Our data suggest that the expression of MVP in myotonic dystrophy resembles that of"idiopathic" MVP in so far as it is related to sex: it is more common in females (Devereux et al. 1982). The relation with age, however, implying a higher frequency of idiopathic MVP for adults than for children, was not a feature in our material (Devereux et al. 1982). The occurrence of pericardial effusion has not been reported in myotonic dystrophy before. As it was also found in one unaffected relative, it does not seem to be a disease specific finding. However, its relatively high rate, 5 in 61 affected persons who had echocardiography, suggests an etiological relationship with myotonic dystrophy. Hawley et al. (1983), on the basis of analysis of 18 families, including 30 patients with myotonic dystrophy and 17 unaffected relatives who were examined by the authors and complemented with data on 34 family members living elsewhere, suggested that cardiac conduction disturbances are restricted to particular families; this would imply genetic heterogeneity. Our findings do not support this: the lack of conduction disorders in 8 out of 35 families can be fully accounted for by the sex-specific frequencies of these disturbances in the whole group and the small sample sizes in the families concerned. As Hawley et al. dit not specify the sex of their probands and relatives, and the number of persons involved in each family seems to be very small, their findings might be caused by chance. A more recent study (Moorman et al. 1985) did not confirm the finding either. One of the aims of the present study was to find out whether ECG and echocardiography could contribute to the diagnosis of myotonic dystrophy in patients without unequivocal muscular signs. This has been suggested by some for conductionabnormalities (Cannon 1967; Spurney and Woolf 1962) but refuted by others (Harper 1979; Gottdiener et al. 1982, Bundey and Carter 1970). With regard to the presence of MVP, it has been investigated by Gottdiener et al. (1982): they encountered MVP (and conduction disturbances) in 24 affected persons only and never in the 21 unaffected relatives and concluded that "cardiac manifestations of myotonia are not transmitted independently of neurologic abnormality", a conviction also reached by Harper (1979) with respect to ECG abnormalities alone. Although our findings largely support this

267 opinion, we court some reserve for two reasons: first, in this rather large group of patients we have encountered one male whose atrial arrhythmia by long preceded the appearance of the first sign of muscular weakness. He may serve as the rare exception to the rule. Second, we encountered three supposedly unaffected relatives (Nos. 1, 3 and 4 in Table 3) with equivocal signs or symptoms, who showed abnormal IVC. Although it is impossible to prove without follow-up we feel that the finding of IVC abnormalities in these patients adds to the probability of their being affected. On the other hand, this probability does not appear to be increased by an isolated t'mding of AVC or MVP, both because, in this series, they were found in persons without the slightest suggestion of being affected, and because they are not rare in healthy people. Mitral valve prolapse, according to criteria used in this study, is found in 5 ~o of the general population, and even in 17~ of young females (Savage et al. 1983). Low degree AV-conduction block is not uncommon in the healthy young population, especially in well-trained sportsmen, whereas IVC disorders in persons without obvious systemic disease or ischemic or valvular heart disease are rare and are found mainly in the elderly. Accordingly, we concluded that the possible contribution of cardiac investigation to the detection of preclinical heterozygotes is small and limited to the finding of IVC disturbances only. It cannot compete with but may complement ophthalmological investigation. In the present era of D N A technology, clinical methods for gene detection tend to be neglected or underestimated. In the case of myotonic dystrophy, however, all clinical indications in family members at risk should be considered with great care, because DNA linkage studies are impossible in many instances, as the number of available and/or cooperative affected an/or unaffected family-members is too small, and as is illustrated in the present study. Moreover, up to now, the accessibility of this technique is limited. The relative rarity of symptoms of cardiac abnormalities has been stressed in all previous reports. The largest series was described by Church (1967): he found 16~o (41/252 cases from the literature) of patients with MD to have symptoms. Of these, 6 had pulmonary, not cardiac problems, leaving 14~ with cardiac complaints. In our series 8 out of 65 patients (12~o) had symptoms. Like in other studies, all symptoms were due to conduction abnormalities, the MVPs being asymptomatic. ACKNOWLEDGEMENTS Statistical advice was obtained from Theo Stijnen, PhD.; Henk Veenema, MD is most gratefully acknowledged for his critical comments. REFERENCES Beulcke, G., F. Casazza, B. Colombo, M. Morpurgo and G. Scannavini (1979) On some cardiological aspects of Steinert's disease. Z. Kardiol., 68: 848-854. Bundey,S. and C. O. Carter (1970)Earlyrecognitionofheterozygotesfor the genefor dystrophiamyotonica. J. Neurol. Neurosurg. Psych., 33: 279-293. Cannon, P.J. (1967) The heart and lungs in myotonicmuscular dystrophy.Ann. J. Med., 32: 765-775. Church, S.C. (1967) The heart in myotonia atrophica. Arch. Int. Med., 119: 176-180.

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