Ps_ychiatr_v Research: ~eur~~magi~g, 50:93-99 Elsevier

93

Positron Emission Tomography in Myotonic Dystrophy

Ruediger Mielke, Karl Herholz, Gereon Fink, Dirk Flitter, and Wolf-Dieter Heiss

Received July 17,1992; revised version received December 12, 1992; accepted January 5, 199.3’.

Abstract. Regional cerebral glucose metabolism (rCMRG1) was studied in three patients with myotonic dystrophy by positron emission tomography with laF-2- fluoro-2~eoxy-D-glucose as the radiotracer. Clinically, all patients presented an organic personality syndrome. Impairment of rCMRG1 was found in all cortical and subcortical regions, particplarly in the frontal cortex and the lentiform nucleus. The results suggest that the organic personality changes that occur in myotonic dystrophy reflect widespread cerebral pathology. The metabolic pattern was similar to that seen in normal aging but was qualitatively more severe and is therefore consistent with the classification of myotonic dystrophy as a progeric disease.

Key Words. Regional cerebral glucose metabolism, aging, fluorodeoxyglucose, frontal cortex. lentiform nucleus.

Myotonic dystrophy is the second most common muscular dystrophy with autosomal dominant inheritance and characte~sti~ appearance of dystrophi~ changes in nonmuscular tissue. The disorder usually begins in adolescence and adult life until the third decade, sometimes in infancy, and rarely as a severe, often fatal form, in the neonate. It manifests clinically with atrophy of distal muscles, associated myotonia, cataracts, cardiac involvement, gonadal atrophy, and other endocrine deficiencies. The central nervous system is commonly involved. Thus, patients often are characterized by mental retardation, personality changes, apathy, and lack of initiative. In studies using computed tomography or magnetic resonance imaging, cerebral involvement has been documented by ventricular enlargement, peri- ventricular hyperintensities (Glantz et al., 1988), and basal ganglia calcification (Avrahami et al., 1987). Histological changes, such as the presence of Alzheimer’s neuro~brillary tangies, have repeatedly been reported (Kuroda et al., 1988; Yoshimura et al., 1990; Kiuchi et al., 1991).

Because of the close relationship of neuropsychological function to cerebral

Ruediger Mielke, M.D., is Neurologist and Neuropsychiatrist, Max-Planck-lnstitut fiir Neurologische Forschung and Universittisklinik fiir Neurologie, K6ln, Germany. Karl Herholz, M.D., is Neurologist, Max-Planck-Institut fiir Neurologische Forschung and UniversiCtsklinik fiir Neurologie, K61n, Germany. Gereon Fink, M.D., is Postdoctoral Fellow, Max-Planck-Institut fiir Neurologische Forschung, K61n, Germany. Dirk Ritter, M.D., is Postdoctoral Fellow, Universitetsklinik fiir Neurologie, Ktiln, Germany. Wolf-Dieter Heiss, M.D., is Professor of Neurology and Director, Max-Planck-lnstitut fiir Neurologische Forschung and Universitiitsklinik fiir Neurologie, K6In, Germany. (Reprint requests to Dr. W.-D. Heiss, Max-Planck-Institut fiir Neurologische Forschung, Gleueler Str. 50, D-5000 KBln 41, Germany.)

0165-1?81~93/$04,~ Q f993 Elsevier Scientific Publishers Ireland Ltd.

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energy metabolism, we performed positron emission tomography (PET) with rsF-2- fluoro-&deoxy-D-glucose (FDG) (Reivich et al., 1979) in three patients (two men and one woman) with myotonic dystrophy. In particular, we studied changes of regional glucose metabolic rates.

Methods

Patients. Case 1. Since childhood, a 42-year-old man noted a progressive weakness and wasting of

all muscles, starting in the proximal muscles of the arm. He was now unable to rise from a squatting position. His speech became slurred. Previously he had a spontaneous thrombosis in the left leg and underwent operations for bilateral cataracts. Physical examination revealed small testes, frontal balding, myopathic facies, and nasal dysarthria. There was a generalized atrophic paresis. Reflexes were weak; sensation was normal. The psychopathoIo~c~ status showed an organic personality syndrome with lack of initiative and emotional indifference. General myotonic discharges and polyphasic motor unit potentials were noted in electromyog- raphy (EMG). A biopsy of the quadriceps muscle showed disseminated atrophy of muscle fibers and numerous internal nuclei. Cerebral computed tomography (CT) was normal.

Case 2. A 50-year-old man was said to have been weak since childhood. Over the last 15 years, muscle force had deteriorated further; gait and speech also became abnormal. Members of his father’s family were reported to be weak but were not examined. At admission, the patient showed a high arched palate, small testes, a funnel chest, loss of hair on the forehead, bilateral ptosis, impaired gaze, marked wasting, and paresis of all muscles. The proximal muscles and those of the face and neck were most severely affected. Myotonic reactions were obtained. Reflexes and sensation were normal. Psy~hopatholo~c~ly the patient appeared slow, rigid, and mentally retarded. EMG showed myotonic discharges and shortened, polyphasic action potentials in all investigated muscles. Muscle biopsy revealed myopathic changes with multiple internal nuclei. CT was normal.

Case 3. A 59-year-old women was admitted to the ophthalmological clinic because of bilateral cataracts and ptosis. Rue to muscle weakness involving the distal upper and lower limbs, she was transferred to the neurological department. In her history she had two fetal wastages. Muscle weakness was first noted in the third decade. Her grandmother was said to have had died of paresis. Clinical examination additionally revealed slurring of speech, second degree heart block, and only mild myotonia. Reflexes were weak, and sensation was normal She appeared to be emotionally indifferent and of low intelligence. EMG showed myotonic discharges and increased insertion activity. Muscle biopsy showed myopathic changes with increased central nuclei in chains. Basal ganglia calcification was observed in the CT scan, but there were no findings of atrophy.

PET. A four-ring S~~ditronix scanner was used to obtain transaxial images of brain glucose metabolism with the FDG method (Reivich et al., 1979). After an intravenous bolus injection of 185 MBq FDG in normal sahne solution, the patient rested in a supine position, with eyes closed, in a quiet room with dimmed lights. Details of the measurement protocol have been described by Heiss et al. (1984). Quantification of regional cerebral glucose metabolic rates (rCMRG1) was based on multiple arterialized venous blood samples and transaxial tomograms parallel to the canthomeatal line recorded from 30 to 50 minutes after tracer injection with adjustment of the rate constants K, and K3 to measured tissue activity (Wienhard et al., 1985). Fourteen slices with a center to center distance of 6.85 mm were analyzed, Regions of interest were adapted to major functional-anatomical structures according to a standard scheme using a semiautomatic computer-assisted mapping procedure (Herholz et al., 1985).

The rCMRG1 was evaluated by comparison with mean values and 95% prediction limits of an age-matched sample of 39 healthy control subjects (16 women and 23 men). Average vaiues

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are given as means f standard deviations. Ail statistical procedures were performed using the SAS software package (SAS Institute, Cary, NC).

Results

Table 1 presents the mean values and standard deviations of rCMRG1 of the three patients with myotonic dystrophy and an age-matched control group of 39 healthy subjects. Cortical as well as subcortical metabolic rates of glucose were generally below the 95% confidence limits of control values. To study the regional distribution of these changes further, we normalized rCMRG1 by subtraction of global brain metabolism in each ~dividual. Normalized values (Table 2) were below the 95% confidence limits of control values in the frontal cortex and lentiform nucleus, suggesting that these structures were affected most severely. There were no abnormal asymmetries.

Discussion

Onset of muscle symptoms in our patients was in childhood and the third decade. They did not show any focal neurological findings such as hemiparesis or sensory loss. Diagnosis was made on the basis of clinical features and typical changes in EMG and biopsy. Patients fulfilled DSM4II-R criteria (American Psychiatric Association, 1987) for organic personality syndrome, characterized by impaired social judgment, apathy, and emotional indifference, which have consistently been

Table 1. Absolute regional glucose metabolic rates ~mol/lOO g/minute) of patients with myotonic dystrophy and age-matched control subjects

Left side Right side

Patients Controls A Patients Controls A Region (n=3) (r)’ 39) (%) (n=3) (n= 39) (%)

Frontal

Sensorimotor

Temporal

Parietal

Occipital

Visual

lnsula

Limbic

Caudate

Lentiform

Thalamus

Brainstem

Cerebellum

Subcortical white 16.6 f 2.92 20.1 f 2.46 17 16.9 f 3.13 20.3 It 2.52

A = difference between patients and control subjects in percent. Data are presented as mean f SD.

* = absolute value below 95% confidence limits of control subjects.

28.8 k 1.64’

28.1 f 1.42’

26.5 f 2.26

27.8 f 1.59’

26.7 f 3.08’

26.5 f 3.04*

29.0 f 1 Q6’

21.9 f 0.71’

31 .o f 0.82’

31.2 f 2.47’

33.8 zk 2.96

22.3 k 0.57*

24.8 f 2.29

39.7 rt 4.98

38.2 jc 4.28

35.0 f 3.65

36.0 f 4.85

36.5 + 4.19

36.9 f 6.55

39.6 rt 4.76

29.0 It 3.45

42.5 i 4.71

43.3 * 5.07

39.0 1 4.95

27.0 f 3.41

32.3 f 3.40

27 28.9 f 2.26*

26 29.6 * 1.80’

24 26.9 zt 2.02*

23 27.9 f 2.01’

27 26.5 i 2.80

28 27.9 f 4.62

27 27.8 f 2.37*

25 21.4 f 1.81.

27 29.8 zk 0.29*

28 31.6 k 2.21 l

13 34.5 * 2.60

17 22.Q + 0.93

23 25.0 f 2.66

39.8 f 5.00 39.1 i 4.70 36.0 f 3.74 36.7 i 4.81 36.6 It 4.06 37.1 f 6.25 39.2 xt 5.08 28.8 f 3.48 42.0 zt 4.58 43.0 * 5.44 40.2 * 5.05 27.7 * 3.32 32.5 z!z 3.32

27

24

25

19

28

25

29

26

29

27

14

17

23

17

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reported as striking features in myotonic dystrophy (Bird et al., 1983; Garron et al., 1986; Harper, 1988; Perini et al., 1989) in about 70% of affected patients (Calderon, 1966). There was no evidence of dementia. CT scans showed calcification of basal ganglia in one case but revealed no other abnormalities or atrophy. Normal CT findings have also been reported by Bird et al. (1983), while other authors (Avrahami et al., 1987; Glantz et al., 1988) found an increased incidence of cerebral atrophy and white matter abnormalites in myotonic dystrophy (Glantz et al., 1988) or basal ganglia calcification and microcephaly (Avrahami et al., 1987).

We compared rCMRG1 of the three patients with myotonic dystrophy with that of an age-matched control group. Hypometabolic areas with the most prominent changes were found in the frontal cortex and lentiform nucleus (Table 2). Predominant frontal metabolic impairment corresponds to the patients’ psychiatric syndrome, which was characterized by marked apathy and lack of initiative.

Global brain glucose metabolic rates were generally low (Table I). These findings are consistent with the findings of Fiorelli et al. (1992), who reported lower values for global brain MRGl in 11 patients with myotonic dystrophy than in 14 healthy control subjects. These authors did not focus their analysis on regional changes of CMRGl. The present results indicate a more general cerebral pathology in myotonic dystrophy. In this context, recent neuropatholog~ca~ examinations provided evidence of specific histological changes in myotonic dystrophy. Yoshimura et al. (1990) reported the occurrence of neurofibrillary tangles with a quite different cerebral distribution than is seen in Alzheimer’s disease. While neurofibriilary

Table 2. Normalized regional glucose metabolic rates ~mol/lOO g/minute) of patients with myotonlc dystrophy and agre-matched control subjects

Left side Right side

Patients Controls Patients Controls - Rsgion (n= 3) (n = 39) (n= 3) (n = 39)

Frontal 3.3 + 0.33 6.0 f 2.21 3.4 rt 0.37’ 6.1 F 2.31

Senaorimotor 2.6 * 1.02 4.5 i 1.84 4.1 + 0.90 5.4 f 1.40

Temporal 1 .O f 0.76 1.3 + 1.56 1.4 rt 0.67 2.3 i 1.81

Parietal 2.3 k 1.19 2.3 t 2.48 2.4 t 1.35 3.0 + 2.34

Occipital 1.2 + 1.24 2.8 + 1.44 1 .O I 0.88 2.9 + 1.34

Visual 1 .O rt 1.63 3.2 i 4.51 2.4 rt I .97 3.4 f 3.97

lnsula 3.5 k 1.05 5.9 i 2.47 2.3 + 1.37 5.5 -t 2.76

Limbic -3.6 4 1.61 -4.7 + 2.43 -4.1 k 1.97 -4.9 f 2.62

Caudate 5.5 f 2.69 8.8 * 2.21 4.3 f 1.91 8.3 i 2.07

Lentiform 5.7 + 0.19’ 9.6 rir 2.71 6.1 j, 0.12” 9.3 f 3.06

Thalamus 8.3 f f.96 5.3 + 2.97 9.0 f 1.63 6.5 + 3.19

Brainstem -3.2 i: 1.87 -6.7 + 2.86 -2.6 i: 2.26 -6.0 f 2.33

Cerebellum -0.7 * 1.17 -1.4 + 2.57 -0.5 + 1.38 -1.2 + 2.53

Subcortical white -8.9 + 1.14 -13.6 f 1.78 -8.6 i 1.21 -13.4 * 1.79

Note. Data are presented as mean f SD.

* = normalized value below 95% confidence limits of control subjects.

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Fig. 1. Positron emission tomographic (PET) images of a patient with myotonic dystrophy and a control subject at three levels

PET images obtained in a 42-year-old patient with myotonic dystrophy [case 1, bottom) show globally reduced metabolism with relative frontal hy~meta~l~sm in comparison to PET images from a healthy 50-year-old man (top).

tangles in Alzheimer’s disease are often distributed in the neocortex, Yoshimura et al. (1990) noted a preferential affection of the limbic system. Kiuchi et al. (1991) reported a large number of neurofibrillary tangles in the hippocampal region. They argued that this distribution pattern, together with the typical clinical features, might point to a progeric disease (Martin, 1978), since the findings are similar to the pattern seen in normal aging. Our PET findings support this hypothesis since a moderate decline of frontal metabolism may also be found in normal aging (Kuhl et al., 1982; Mielke et al., 1992). Impairment of frontal metabolism was also seen in progressive supranuclear palsy (Blin et al., 1990; Karbe et al., 1992). Major metabolic impairment of brainstem structures, as has been observed in progressive supranuclear palsy (Karbe et al., 1992), was not present in myotonic dystrophy. The findings in myotonic dystrophy were clearly different from the temporoparietal metabolic impairment typically seen in degenerative dementia of the Alzheimer type (Benson et al., 1983; Friedland et al., 1983; Duara et al., 1986).

In conclusion, our PET study demonstrated cerebral involvment in myotonic dys- trophy. Frontal predominance of metabolic impairment corresponds to the organic personality syndrome and is compatible with clinical and pathological signs of ac- celerated aging.

98

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