Eye movement abnormalities in myotonic dstrophy

Electroencephalography and clinical Neurophysiology 109 (1998) 184–190

Eye movement abnormalities in myotonic dstrophy M. Versino*, A. Romani, R. Bergamaschi, R. Callieco, S. Scolari, R. Poli, S. Lanfranchi, G. Sandrini, V. Cosi Fondazione ‘Istituto Neurologico C. Mondino’, Universita` di Pavia, Via Palestro 3 - 27100 Pavia, Italy Accepted for publication: 22 November 1997

Abstract We studied saccade and smooth pursuit eye movements in 31 patients suffering from myotonic dstrophy (MD). On the basis of mean value comparisons, saccades were slower and hypometric and smooth pursuit eye movements performed worse in MD patients than in controls. On an individual basis, saccade duration was prolonged in 67.7%, saccades were hypometric in 19.4%, saccade latency was delayed in 9.7%, and the smooth pursuit performance index was decreased in 9.7% of patients. Eye movement abnormalities did not correlate with those detectable by visual, brain-stem auditory and somatosensory evoked potentials. We attempted to classify eye movement abnormalities as myogenic or neurogenic on the basis of differences in combination of eye movement abnormalities and the occurrence of D5/D35 dissociation; the latter consists of a prolonged duration for large (35°) but not for small (5°) saccades. Since D5/ D35 dissociation occurred in 26/33 multiple sclerosis patients with increased saccade duration, we considered it to be a neurogenic pattern attributable to a central nervous system (CNS) dysfunction. A prolonged duration without dissociation especially in combination with saccade hypometria, is interpreted as a myogenic pattern, although the lack of dissociation may also occur with CNS impairment in case of a marked increase in saccade duration. Accordingly we classified the oculomotor abnormalities detected as neurogenic in 11 MD patients and as myogenic in another 10, but in some subjects belonging to the second group concomitant CNS impairment is not to be excluded.  1998 Elsevier Science Ireland Ltd. Keywords: Saccades; Smooth pursuit; Evoked potentials; Myotonic dystrophy

1. Introduction Myotonic dystrophy (MD) is an autosomal dominant multisystem disorder of variable penetrance, and is usually expressed between 15 and 40 years of age. Almost all patients show an unstable cytosine-thymine-guanine trinucleotide repeat, located within the MD gene on chromosome 19 (Brook et al., 1992; Shelbourne and Johnson, 1992). Skeletal muscles show a delayed relaxation after contraction (myotonia), and there is progressive atrophy of the face, neck and extremities with distal preponderance. Although MD patients rarely complain of oculomotor symptoms or signs other than lid drop, the subclinical involvement of the oculomotor system has been reported by all

* Corresponding author: Tel.: +39 382 380340; fax: +39 382 380286; e-mail: [email protected]

0924-980X/98/$19.00  1998 Elsevier Science Ireland Ltd. All rights reserved PII S0924-980X (97)0008 2-9

studies based on eye movement recording (von Noorden et al., 1964; Emre and Henn, 1985; Oohira et al., 1985; ter Bruggen et al., 1990, 1992, 1993; Bollen et al., 1992; Hansen et al., 1992; Verhagen et al., 1992; Anastasopoulos et al., 1996; Di Costanzo et al., 1997). Eye movement abnormalities in MD share some common features, but there are some differences concerning the impairment of smooth pursuit eye movements. Moreover, whether the origin of these abnormalities is myogenic or neurogenic (peripheral or central nervous system) is still a matter of debate. In MD, extraocular muscle pathology shows myopathic changes (Davidson, 1961; Junge, 1966; Burns, 1969; Kuwabara and Lessel, 1976), and extraocular myotonia is detectable both with electromyography (Davidson, 1961; Lessel et al., 1971; Oohira et al., 1985; ter Bruggen et al., 1990) and with saccadic eye movement recording (Hansen et al., 1992), although myotonia is not considered as a main factor in the determination of eye movement abnormalities (Anasta-

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sopoulos et al., 1996). On the other hand, the central nervous system (CNS) involvement in MD has been documented by means of neuropsychological testing, electroencephalography and evoked potentials and neuroradiological investigations. The various authors tried to classify eye movement abnormalities as myogenic or neurogenic on the basis either of the pattern of these abnormalities or of the combination with concomitant non-oculomotor alterations. The present report investigates saccade and smooth pursuit eye movement alterations which are classified as myogenic or neurogenic on an individual basis.

2. Methods and materials We recorded saccade and smooth pursuit eye movements in 31 MD patients (26 families; 13 males and 18 females; mean age: 38.51 years; age range: 15–63 years) and in 36 age- and sex-matched controls. In addition, we considered 33 age- and sex-matched multiple sclerosis patients, all of whom presented with slow saccades at eye movement recording. We included this third group on the assumption that CNS impairment might be responsible for a saccade slowing pattern. The patients were diagnosed as having MD on the basis of clinical and electrophysiological criteria (Sandrini et al., 1986), and visual acuity greater than 4/10 in both eyes was a prerequisite for inclusion in the study. None of the patients presented with clinically evident disconjugate oculomotor abnormalities, nor did any complain of diplopia. 2.1. Eye movement recording and analysis Both in patients and in controls, we recorded reflexive saccade and triangular ramp smooth pursuit eye movements by means of the bitemporal electrooculographic technique (EOG). The signal was filtered (bandpass: DC-40 Hz), sampled at a frequency of 250 Hz and stored for off-line analysis by specifically designed software (Versino et al., 1992; Versino et al., 1993a). We elicited reflexive saccades by means of 15 light emitting diodes (LEDs) placed every 5° from +35° (right) to −35° (left) from the subject’s midsagittal plane. The LEDs were then lit in a pseudo-random sequence (two blocks of 29 trials). We considered the following parameters. 2.1.1. Amplitude-duration relationship D = a + b*A, where D is the duration in milliseconds and A is the amplitude in degrees. The relationship found for each subject was used for the computation of D20, which corresponds to the expected duration value as computed for a mid-range amplitude of 20°. For individual subject evaluation, D20 was considered abnormal (increased duration) if in excess of the 95th percentile of control distribution, which was equal to 88.59 ms. We also com-

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puted the duration for both the 5 and the 35° amplitudes (D5 upper normal limit: 47.66 ms; D35 upper normal limit: 136.77 ms). 2.1.2. Amplitude-peak velocity relationship Vp = A/(c + d*A) where Vp is the peak velocity in degrees/s and max = 1/d corresponds to the maximum (saturation) Vp value reached when A is infinite. For individual subject evaluation, Vmax was considered abnormal (decreased velocity) if below the 5th percentile of control distribution, which was equal to 496.77°/s. As for duration, we also computed the velocity for 5° amplitudes (V5, lower normal limit: 165.04°/s). 2.1.3. Precision P = A/TS where TS is the target step in degrees. For individual subject evaluation, the mean precision value P¯ was considered abnormal (hypometric saccades) if below the 5th percentile of control distribution, which was equal to 0.89. 2.1.4. Latency (L) Latency (L) is the period of time from LED activation to the beginning of the saccade. For individual subject evaluation, the mean latency value L¯ was considered abnormal (prolonged latency) if in excess of the 95th percentile of control distribution, which was equal to 347 ms. 2.1.5. Target velocity-performance index relationship In the following we will refer to D20, Vmax, P¯ and L¯ as ‘saccade parameters’. We elicited smooth pursuit eye movements by moving a target (LED) at a constant velocity and through a 60° amplitude (+30 and −30° back and forth). We used target velocities that ranged from 10 to 50°/s. Each subject performed 58 ramps. We considered the following relationship: PI = m − n*V, where PI is the performance index expressed as a percentage and V is target velocity in degrees/s. PI is a way to represent smooth pursuit system performance after catch-up saccades have been removed, and is computed as the ratio between the amplitude of (smooth pursuit) eye displacement and the amplitude of target displacement (Versino et al., 1993a). The equation PI = 100, where m = 100 and n = 0, is intended to represent a perfect smooth pursuit which is able to match any target velocity and does not need the cooperation of saccades. PI25 (i.e., mid-range V equal to 25°/s) was computed in the same way as described for the amplitude-duration relationship, and was rated as abnormal (decreased PI) if below the 5th percentile of control distribution, which was equal to 48.48. In the following we will refer to PI25 as ‘smooth pursuit parameter’. 2.2. Multimodal evoked potentials The detailed description of evoked potential stimulation, recording and analysis procedures can be found in a paper

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(Cosi et al., 1992) that involved some of the patients who participated in the present study Briefly we studied pattern reversal visual evoked potentials (VEPs) in 30 patients, brain-stem auditory evoked potentials (BAEPs) in 29 patients, and somatosensory evoked potentials (SEPs) in 30 patients. VEPs were considered abnormal when P100 was not detectable, or when its latency exceeded 125 ms at least in one eye. BAEPs were considered abnormal when peak III or peak V was absent, or when the I-V inter-peak latency (IPL) exceeded 4.41 (females) or 4.67 ms (males) in at least one ear. Right median nerve SEPs were considered abnormal when peak N20 was absent or when the N13-N20 interval exceeded the upper normal limits, which vary on the basis of subject age. 2.3. Statistical analyses We based comparison between the MD and control groups on the parameter mean values (Student’s t-test). We looked for significant association between the occurrence of abnormal eye movement and evoked potential parameters (two-tailed Fisher’s exact test). Finally, we looked for a positive correlation between the average of right and left eye P100 and saccade latency.

3. Results 3.1. Eye movements in MD The mean value comparisons (Table 1) show that reflex-

ive saccades were slower (longer duration, lower maximum peak velocity) and slightly hypometric but with normal latency as compared with controls. The abnormal duration and peak velocity is detectable both for small (see D5 and V5) and, to a greater extent, for large saccades (see D35 and Vmax). Fig. 1 compares the respective tracings of a 35° saccade from an MD patient and a normal subject. Although mean m and n parameters differed very little between MD patients and controls, the significantly reduced PI25 mean values show smooth pursuit as impaired (Table 1). The degree of impairment was less for smooth pursuit than for saccades. On the basis of individual patient evaluation (Table 2), D20 was prolonged in 21 (67.7%) patients, all of whom but one also showed reduced Vmax. Precision was abnormal in 6 (19.4%) patients, all of whom presented with hypometric saccades, and latency was delayed in 3 (9.7%) patients. In 11 patients, D5/D35 dissociation, namely normal duration for small saccades (D5) and prolonged duration for large saccades (D35), was detectable (Table 2). The smooth pursuit performance index was reduced in 3 (9.7%) patients; moreover, in one of these the performance index values were very low for all target velocities, and the performance index target velocity relationship was not computable. Hypometric saccades were invariably associated with a prolonged saccade duration and a reduced peak velocity, in 2/6 patients with D5/D35 dissociation, and in one patient with a reduced smooth pursuit performance index. Saccade latency delay combined with an abnormal sac-

Table 1 Saccade and smooth pursuit parameter mean and standard deviation (SD) values in 31 MD patients and 36 controls Patients

a b D20 D5 D35 c × 104 d × 104 Vmax V5 V35 P¯ L¯ m n PI25

Controls

Mean

SD

Mean

SD

23.47 4.14 106.43 44.21 168.65 175.42 27.37 430.65 167.11 342.29 0.91 249.554 94.61 1.01 69.38

4.91 1.52 30.61 8.84 53.28 30.51 12.11 177.57 31.32 113.92 0.07 37.03 13.58 0.25 12.52

26.08 2.61 78.23 39.12 117.35 178.76 15.62 656.17 196.12 487.59 0.95 248.45 99.21 0.93 75.94

3.73 0.31 5.94 3.47 10.11 26.56 2.48 103.68 17.01 49.86 0.032 29.27 10.59 0.24 11.53

t

P

2.46 5.53 5.05 3.01 5.28 0.5 5.31 6.22 4.66 6.67 3.42 0.13 1.55 1.28 2.21

0.016 ,0.0001 ,0.0001 0.005 ,0.0001 0.634 ,0.0001 ,0.0001 ,0.0001 ,0.0001 0.002 0.89 0.127 0.207 0.031

The last two columns show the t and probability (P) value derived from mean value comparison. a and b are the amplitude-duration relationship coefficients. D20 is saccade duration value computed for 20° saccade. c and d are the amplitude-peak velocity relationship coefficients. Vmax is the theoretical maximum saccade peak velocity. P¯ is mean saccade precision. L¯ is mean saccade latency. m and n are the target velocity-performance index relationship coefficients. PI25 is the smooth pursuit performance index when target velocity is 25°/s.

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M. Versino et al. / Electroencephalography and clinical Neurophysiology 109 (1998) 184–190 Table 2 The occurrence of eye movement, visual evoked potential (VEP) and brain-stem auditory evoked potential (BAEP) abnormalities in 31 MD patients Case no.

D20

Vmax

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

Normal Normal Normal + + Normal Normal Normal Normal + + + + + + Normal + + + + + Normal + + + + + + Normal + +

Normal Normal Normal − + Normal Normal Normal Normal + + + + + + Normal + + + + + Normal + + + + + + Normal + +

D35/D5 dissociation

+ −

− + − + − + + − + − + − − − − + + + +

P¯

L¯

PI25

VEP

BAEP

Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal + Normal Normal + + Normal + + Normal Normal Normal +

Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal + Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal + Normal Normal + Normal Normal Normal Normal

Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal + Normal Normal Normal Normal Normal Normal + Normal Normal Normal Normal + + Normal Normal Normal

Normal Normal Normal Normal Normal Normal Normal + Normal NP Normal Normal Normal + Normal Normal Normal Normal Normal Normal Normal + Normal Normal Normal Normal + + Normal Normal Normal

NP Normal Normal + + Normal HL Normal Normal NP Normal Normal Normal Normal Normal Normal Normal Normal + Normal Normal Normal Normal + Normal + + Normal + Normal Normal

N/M

N M?

M? N M? N M? N N M? N M N M M+N M M N N N N

D20 is saccade duration value computed for 20° saccade. Vmax is the theoretical maximum saccade peak velocity. D5/D35 dissociation is a prolonged duration for 35° but not for 5° saccade in patients with abnormal D20. P¯ is mean saccade precision. L¯ is mean saccade latency. PI25 is the smooth pursuit performance ¯ index when target velocity is 25°/s. N/M is the hypothesized neurogenic or myogenic origin of the ocular motor abnormalities. The + sign in the D20, Vmax, P, ¯ VEP and BAEP columns stands for abnormal. In the D5/D35 dissociation column the + sign means that the dissociation is detectable, and the − sign means L, that the dissociation is not detectable. HL, peripheral hearing loss; M, myogenic; M?, possibly myogenic (a neurogenic impairment can not be excluded); N, neurogenic; NP, not performed.

cade duration and peak velocity in one patient, with the abnormality of all saccade parameters in another patient and with the abnormality of all saccade and smooth pursuit parameters in a further patient. Finally, the reduction of smooth pursuit performance was associated in all the patients with D5/D35 dissociation. Eighteen patients showed normal smooth pursuit and abnormal saccades. 3.2. Multimodal evoked potentials in MD VEPs were abnormal in 7/30 (23.3%) patients: P100 latency was delayed bilaterally in 3 and unilaterally in 4 patients. BAEPs were abnormal in 8/29 (27.6%) patients: the I-V IPL was prolonged in 7 patients (bilateral in two, unilateral in 5 patients), whereas a very severe hearing loss prevented the detection of the entire BAEP components and the detection of a possible brain-stem auditory impairment

in another patient. Median SEPs were normal in all the 30 patients tested. In only one patient both VEPs and BAEPs proved to be abnormal. Six out of the 7 patients with abnormal BAEPs also showed an abnormal saccade duration, but this figure did not prove to be significant (r = 0.17; Fisher’s exact test, P = 0.36). Finally, the average value of P100 latency did not correlate significantly with saccade latency (r = −0.14; P = 0.45). 3.3. Patterns of saccade slowing in multiple sclerosis Twenty-six out of 33 (78.78%) multiple sclerosis (MS) patients with slow saccades, i.e., with increased D20 and reduced Vmax, showed a D5/D35 dissociation. In contrast, a dissociation in velocity values occurred in 19/33 (57.57%) patients. The 7 patients without D5/D35 dissociation

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Fig. 1. A 35° saccade position (up) and velocity tracings (bottom) from a control (left) and an MD patient (right).

included those in whom impairment of saccade duration and velocity was very severe and in whom the dissociation in velocity values did not appear either. Their mean duration value was 145.61 ms, which is significantly higher than the 105.24 ms mean duration value detectable in the 26 patients with D5/D35 dissociation (P , 0.0001).

4. Discussion We detected a very high occurrence of abnormal saccade parameters: 67.7% of the patients showed at least one abnormal parameter that invariably included a prolonged saccade duration. These figures are in keeping with those reported previously by other authors (Oohira et al., 1985; ter Bruggen et al., 1990, 1992; Bollen et al., 1992; Hansen et al., 1992; Verhagen et al., 1992; Anastasopoulos et al., 1996; Di Costanzo et al., 1997). Differences in analytical design possibly explain why there is less agreement about the occurrence of smooth pursuit abnormalities. Values in the literature range from 100% (von Noorden et al., 1964) to 0% (Verhagen et al., 1992) of patients; the latter case series excluded patients with any other visual or oculomotor deficit that might have been responsible for the smooth pursuit impairment. On the basis of mean value comparison, smooth pursuit has variably been reported as similar to (Bollen et al., 1992) and different from control values (ter Bruggen et al., 1990). Our results on smooth pursuit lie in the middle. Our patients showed a slight but significant reduction in PI25 mean values. However, on an individual basis, only 3 (9.7%) of them proved to be abnormal. Differences in opinion about the origin of oculomotor impairment in MD partly stem from the controversy about smooth pursuit impairment. With a case series of 10 MD

patients, von Noorden et al. (1964) recorded smooth pursuit eye movements that proved to be abnormal at visual inspection because of the occurrence of catch-up saccades; saccade latency and accuracy were normal in 9/10 patients and fixation was normal in all patients. For 10 MD patients, Bollen et al. (1992) reported reduced gain but normal saccade latency as compared with controls; fixation was normal, and there was no correlation with muscular weakness and/or myotonic grip. Anastasopoulos et al. (1996) found a reduced mean smooth pursuit gain that paralleled the capacity to suppress the vestibulo-ocular (VOR) reflex by means of visual stimuli. They also reported the occurrence of normal VOR, decreased saccade peak velocity, a delayed latency for centrifugal saccade with short interstimulus interval and normal saccade accuracy. For 40 MD patients, Di Costanzo et al. (1997) reported a decreased saccade peak velocity, whereas saccade accuracy and latency were both normal. In all 4 studies, along with a case report by Emre and Henn (1985) the authors stated that eye movement abnormalities derived from a ‘neurogenic’ impairment. Oohira et al. (1985) compared the oculomotor findings in 7 MD patients with those in 16 patients with an ophthalmoparesis and in 7 patients with ocular myopathy. Smooth pursuit was abnormal in 3/7 (44.55%) MD patients, and appeared in combination with a particular pattern of saccade peak velocity reduction that the authors classified as myogenic, since it occurred both in small and in large amplitude saccades, as in ocular myopathies, and not in large saccades alone as in ocular motor nerve palsies. In addition, EMG and extraocular muscle pathology detected myopathic, and EMG myotonic alterations in one patient. In 26 MD patients, ter Bruggen et al. (1990) detected normal smooth pursuit with normal saccade latency and precision, but with reduced peak velocity (on an individual basis, 83% of patients showed this reduction) and in combination with

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EMG myopathic and myotonic features in ocular muscles. In both these studies the authors stated that eye movement abnormalities derived from a ‘myogenic’ impairment. Verhagen et al. (1992) made an extensive investigation of the ocular motor, vestibular and auditory systems. Individual basis evaluation showed saccade slowing in 77% of the 13 patients, whereas smooth pursuit was normal in all patients but two; these latter also presented poor visual acuity, divergent strabismus and convergence paralysis. The authors stated that the abnormalities could derive from a central or peripheral dysfunction. Overall, there is disagreement in the literature about the origin of ocular motor impairment in MD due both to different results and to their interpretation since, a priori, a neurogenic or a myogenic dysfunction may lead to the same oculomotor abnormalities. As to the origin of ocular motor impairment, none of our patients complained of diplopia, nor did any of them show the classical pattern of ocular motor impairment that is attributable to an ocular nerve palsy. Accordingly, we apply the ‘neurogenic’ label to CNS ocular motor impairment and the ‘myogenic’ label to myopathic impairment of ocular motor muscle. The BAEP abnormalities here described (I-V IPL prolongation) demonstrated a brain-stem impairment in 7 patients, but although 6 of them also showed an increased saccade duration, the correlation was not statistically significant. A significant positive correlation would have provided an indirect way to support the neurogenic hypothesis, but the lack of correlation does not deny it. We might add two more comments. Firstly, the abnormal saccade latency in MD is not secondary to a delay along visual pathways, since there is no correlation with VEP abnormalities, or with P100 latency. The occurrence of abnormal eye movement parameters is much higher than the occurrence of EP abnormalities and, unless these two neurophysiological technique prove to differ substantially in sensitivity and specificity, it seems reasonable to suppose that eye movement abnormalities do not derive exclusively from CNS involvement. The data from the MS patients suggest that D5/D35 dissociation is a feature of CNS impairment-induced saccade slowing. Oohira et al. (1985) reported a similar dissociation for saccade peak velocity in ocular motor palsies. He also reported the lack of this dissociation as a hallmark of saccade slowing in ocular myopathy, a finding which contrasts with our data, since saccade peak velocity was reduced both for small and for large saccades in 14/33 MS patients. On the other hand, the lack of dissociation was less frequent for duration values (7/33 MS patients), and occurred in patients with very severe saccade duration impairment. Moreover, when there was no dissociation in duration, there was none in velocity either. Accordingly, myopathic slowing as identified by Oohira et al. (1985) should be detectable by means of duration in the place of velocity. Dissociation between small and large saccade duration is in keeping with the findings by Abel et al. (1978) and by Snow et al. (1985),

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who demonstrated that an increase in duration is an adaptive process used by the saccadic system to compensate for an inadequate saccade size, which in turn is induced by a peripheral lesion. Thus, if an increase in saccade duration in ocular myopathy is an adaptive process to maintain saccade size, duration values should be prolonged for any saccade size. Horizontal saccade velocity depends on saccade amplitude (the main sequence) (Bahill et al., 1975), and is related to the paramedian pontine reticular formation excitatory burst neuron firing rate (Van Gisbergen et al., 1981). It is likely even for small saccades that peak firing rate and peak velocity will be affected more than average velocity (saccade duration) by a dysfunction that involves burst neurons or their afferences. Moreover, saccade duration proved to be more reliable than peak velocity (Versino et al., 1993b). Accordingly, we decided to consider D5/D35 dissociation as a sign of neurogenic saccade slowing, and the lack of dissociation as a sign of possible myopathic saccade slowing. Since the lack of dissociation is detectable in MS patients also, the myogenic hypothesis is more likely to be true if strengthened by the concomitant occurrence of saccade hypometria. D5/D35 dissociation was detectable in 11 patients, who we classify as ‘neurogenic’. This group included the 3 patients with reduced PI25 and two other patients with a saccade latency delay. Saccade latency delay invariably derives from CNS impairment which involves either the structures concerned with saccade programming or the projections of such structures to the burst generator. The other 10 patients with prolonged saccade duration but without D5/D35 dissociation should be labeled as having a ‘possibly myopathic’ ocular motor deficit. However, the MD patients without D5/D35 dissociation also showed significantly prolonged saccade duration (137.86 ms) in comparison with those without the dissociation (107.85 ms), and we know from MS patients that in this situation the lack of D5/D35 dissociation should be interpreted cautiously. In 4 patients without D5/D35 dissociation, saccades were also hypometric, and this combination (slow saccades of restricted amplitude) strengthens the ‘myogenic’ hypothesis. In all these patients either VEPs or BAEPs or both were abnormal, and in one of them saccade latency was delayed, thus suggesting a CNS impairment involving regions not directly or preeminently concerned with saccade velocity generation. In the other patients, the ‘myogenic’ hypothesis is weaker since saccade precision was normal and a concomitant CNS involvement cannot be excluded. For instance, one patient showed abnormal BAEPs, and another two patients showed abnormal VEPs. In all the patients without D5/D35 dissociation, smooth pursuit eye movements were normal and this finding would suggest both a sparing of ocular motor muscle and a saccadic system impairment located at a CNS level (Emre and Henn, 1985). This argument too is inconclusive, however, since saccades are a more demanding task

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for extraocular muscles than is smooth pursuit, and it is possible that MD affects the global layer fibers which are more involved in saccade more than it does the orbital layer fibers which are more involved in smooth pursuit (Spencer and Porter, 1988; ter Bruggen et al., 1990). In conclusion, MD patients frequently show saccade and, to a lesser extent, smooth pursuit eye movement abnormalities that originate either from a central nervous system dysfunction and/or from an extraocular muscle dysfunction.

Acknowledgements The authors are grateful to Mr. Roberto Alloni and to Mrs. Laura Delnevo for their technical assistance.

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