Epilepsia , 33(2):376-388, 1992 Raven Press, Ltd., New York 0 International League Against Epilepsy

Alterations of Ballistic Movements in Epileptic Patients with Phenytoin Intoxication F. Benvenuti, S. Bandinelli, M. A. Mencarelli, M. L. Lunardelli, *R. Campostrini, *G. Zaccara, and tT. Pantaleo Department of Rehabilitation, Ospedale “ I Fraticini,” I.N.R.C.A., National Research Institute, and Departments of *Neurology and ?Physiological Sciences, University of Florence, Florence, Italy

Summary: We assessed the effects of phenytoin (PHT) overdosage on ballistic arm abduction movements in nine epileptic patients receiving long-term PHT treatment. During the overdosage period, all but one showed clinical abnormalities referable to impaired cerebellar function; one also had slowness of movement. Ballistic movements showed abnormalities in all of the patients although a great variability was present in the type and severity of abnormalities. In four patients, kinematic and EMG recordings differed least from the normal, in four they resembled those described in patients with cerebellar deficits, and in one those described in patients with Parkinson

disease. The type and severity of clinical disturbances of voluntary motor control as well as alterations of ballistic movements were not related to specific PHT plasma concentrations. One month after the adjustment of PHT dosage, the patients who had clinical abnormalities completely recovered or markedly improved. Previously observed kinematic and EMG abnormalities completely disappeared or improved markedly. Key Words: Anticonvulsants-Phenytoin-Drug-induced abnormalitiesEpilepsy-Arm movements-ElectromyogramHumans.

Phenytoin (PHT) is used to treat partial and generalized seizures. It has been suggested that the antiepileptic effect of PHT involves not only the cerebral cortex but also numerous subcortical structures (Bittencourt and Richens, 1980; Laxer et al., 1980; Mameli and Tolu, 1984; Mameli et al., 1985). In particular, it has been shown that the antiepileptic effect of PHT is reduced in cerebellectomized animals (Julien and Halpern, 1972; Laxer et al., 1980). Motor disturbances have been reported to be related to PHT toxicity (Dam, 1970; Reynolds, 1975). The most characteristic alterations are those due to cerebellar dysfunction such as nystagmus, tremor, and ataxia (Dam, 1970). The occurrence of these complications has been proved to be related to blood PHT concentrations although there exist great individual differences (Buchthal et al., 1960; Kutt et al., 1964; Idelstrom et al., 1972; Booker and Darcey, 1973; Dodrill, 1975).

Extrapyramidal motor disturbances, albeit more rarely, have been described in association with PHT treatment. Such alterations include dyskinesias, choreoathetoid movements, dystonia (Kooiker and Sumi, 1974; McLellan and Swash, 1974; Hamad et al., 1975; Chadwick et al., 1976), and bradykinesia (Prensky et al., 1971), which have been interpreted as related to PHT effects on cerebral dopamine systems (Chadwick et al., 1976; Snider and Snider, 1977). In recent years, the study of fast or ballistic movements performed at a single joint has been used as a useful tool to obtain further insight into the pathophysiology of different movement disorders including those due to basal ganglia (Hallett and Khoshbin, 1980; Baroni et al., 1984; Benvenuti et al., 1988) or cerebellar disturbances (Hallett et al., 1975b). Ballistic movements are operationally defined as the movements performed “as rapidly and accurately as possible” in a step-tracking task. A triphasic pattern of electromyographic (EMG) activity in the agonist and antagonist muscles has long been recognized to underlie fast or ballistic limb movements in humans (Wachholder and Haltenburger,

Received May 1991; revision accepted July 1991. Address correspondence and reprint requests to Dr. F. Benvenuti at Ospedale I.N.R.C.A. “I Fraticini,” via dei Massoni 21, 50139 Firenze, Italy.

376

ARM MOVEMENTS AND PHEN YTOlN INTOXICATION

377

listic arm abduction movements were investigated in epileptic patients, both during PHT overdosage and after the proper adjustment of the therapy.

1926; Angel, 1974; Hallett et al., 1 9 7 5 ~ Hallett ; and Marsden, 1979; Pantaleo et al., 1988). The sequence consists of an initial burst of activity in the agonist muscle (Agl), followed by a burst of activity in the antagonist muscle (Antl), and finally by a small, not constant, second agonist burst (Ag2). Furthermore, an inhibition in the antagonist muscle (AntIn) occurs before the onset of Agl (as much as 50 ms for fast elbow flexion movements) and continues for the whole duration of Agl itself when this muscle is tonically active in the period preceding the motor task (Hallett et al., 19752). It has been suggested (Hallett and Marsden, 1979; Hallett and Khoshbin, 1980) that any movement can be fully characterized in terms of energizing (the selection of proper muscles and inhibition of inappropriate ones) and timing (the order in which the proper muscles are activated and sequenced). These two descriptors are considered to be two separate functions: the energizing mainly controlled by the basal ganglia and the timing mainly controlled by the cerebellum (Hallett and Khoshbin, 1980). In this context, EMG alterations reflecting inappropriate energizing of muscle activation have been observed in parkinsonian patients (Hallett and Khoshbin, 1980; Baroni et al., 1984; Benvenuti et al., 1988), whereas inappropriate timing has been observed in patients with cerebellar disorders (Hallett et al., 197%). To obtain insight into the motor deficits due to PHT toxicity, kinematic and EMG variables of bal-

METHODS

Nine epileptic patients (six male and three female; aged 22-52 years, mean of 34.6 years) receiving long-term PHT treatment (3-34 years) who had high plasma PHT concentrations (2 1-5 1 p,g/ml) were studied. General characteristics of patients, antiepileptic drug (AED) regimens, and clinical evaluations of motor disability are shown in Tables 1 and 2. The intoxication was caused by selfadministration of higher PHT dosages (patients 1 , 4 , 5 , and S), marked reduction of body weight for dietary restraint (patients 2 and 9), excessive PHT intake due to misunderstanding of the prescription (patients 3 and 6), and interaction with other recently prescribed AEDs (patient 7). Plasma AED concentrations were measured by gas-liquid chromatography (Riva et al., 1980). The clinical assessment and the analysis of ballistic arm abduction movements were performed during the overdosage period and 1 month after the adjustment of the PHT dosage (plasma concentration below 20 pg/ml). All patients had folic acid concentrations above 6 ng/ ml. None showed peripheral neuropathy on nerve conduction and EMG investigations. Twenty healthy control subjects (10 male and 10 female;

TABLE 1. General characteristics of putients with epilepsy treated with PHT Duration of disease (years)

Type of seizures

Patient

Sex

Age (years)

1

F

27

12

Partial, tonic-clonic

2

M

36

21

Tonic-clonic

3

M

22

16

Partial, tonicxlonic

4

M

46

42

Partial

5

M

31

6

6

F

36

21

7

M

22

9

8

M

52

39

Partial, tonic-clonic Tonic-clonic

9

F

40

10

Partial

Partial, tonic-clonic Tonic-clonic

Duration of PHT treatment (years)

CT of cerebrum

Previous overdosage periods

History

Normal

0

9

Porencephaly (right frontal)

0

6

Normal

0 1

3

Porencephaly (left frontal), mild cerebellar cortical atrophy Normal

0

6

Normal

1

4

Normal

0

-

Widespread cerebral cortical atrophy Slight widespread cerebral cortical atrophy

0

-

0

-

10

15

34 8

Glue intoxication (toluene) (17 years old) Prematurity and difficult parturition Severe hyperthermia of unknown origin (2 years old) Postvaccinal encephalitis (6 years old) -

Occipitoparietal trauma (4 years old)

Epilepsia, Vol. 33, No. 2, 1992

378

F . BENVENUTI ET AL. TABLE 2. Antiepileptic treatments and clinical evaluations of motor abnormalities During PHT overdosage

Patient

Antiepileptic medication“ (mg/day)

Drug plasma concentrations“ Wml)

PHT 250

PHT 51

PHT PB PHT PB PHT PB PHT PB PHT PB

PHT PB PHT PB PHT PB PHT PB PHT PB

250 170 350 150 400 300 350 25 400 150

37 30 32 27 21 25 32 4 40 20

PHT 400 PRM 250 PB 150 PHT 300 PRM 500

PHT 40 PRM 3 PB 30 PHT 44 PRM 3 PB 20

PHT 400

PHT 43

“ Antiepileptic

After PHT dosage reduction Clinical assessment

Drowsiness, nystagmus, mild gait ataxia Drowsiness, mild gait ataxia Normal Severe gait ataxia Mild gait ataxia Drowsiness, nystagmus, moderate gait ataxia, dysmetria Drowsiness, nystagmus, severe gait ataxia, dysmetria Drowsiness, nystagmus, severe gait ataxia, severe dysmetria, kinetic tremor Drowsiness, moderate gait ataxia, slowness of movement

Antiepileptic medication“ (mg/day)

Drug plasma concentrations“ ol.g/mU

PHT 200

PHT 20

Normal

PHT PB PHT PB PHT PB PHT PB PHT PB

PHT PB PHT PB PHT PB PHT PB PHT PB

17 24 14 25 15 20 19 6 10 19

Normal

PHT 300 PRM 250 PB 150 PHT 200 PRM 500

PHT 15 PRM 4 PB 26 PHT 13 PRM 3 PB 16

Normal

PHT 300

PHT 18

Normal

200 150 250 150 300 200 325 25 250 150

Clinical assessment

Normal Mild gait ataxia Normal Mild gait ataxia

Mild gait ataxia, mild dysmetria

drugs: PHT, phenytoin; PB, phenobarbital; PRM, primidone.

aged 22-56 years, mean of 37.5 years) were studied for reference. All subjects were right handed. The experimental apparatus used to study ballistic movements has been previously described (Baroni et al., 1984). Briefly, subjects were seated looking at a translucent screen and grasped a movable handle, keeping their arm extended (directed horizontally forward) and mechanically unsupported. In the screen, two target lights (5 mm diameter spots, 10 cm apart on a horizontal line) and the response light (5 mm diameter spot) were projected. Target lights could be switched on in turn by a remote control at 3-6 s intervals. The handle was connected mechanically to the response light and could slide along a horizontal track; any horizontal displacement of the handle produced an equal horizontal displacement of the response light. Subjects were required to align the response light “as rapidly and as accurately as possible” with whichever target light was on at any time (steptracking task). Arm abduction movements in the horizontal plane involving the deltoid muscle (posterior fibers) as agonist and the pectoralis major muscle as antagonist were considered. Action potentials, derived from agonist and antagonist muscles by surface electrodes, were amplified and fed to a multipen recorder. The muscular action potentials were also full-wave rectified and passed through a “leaky” integrator (time constant of 20 Epilepsiu, Vol. 33, No. 2, 1992

ms). The “integrated” activity was fed to the pen recorder together with the signals of the hand movement (monitored as changing voltage by a linear potentiometer connected to the movable handle), and of the switching on of the target lights. After a brief period of practice, sufficient to make the subject understand the task (10-15 trials), 10 successive right arm abduction movements were recorded in each session for each subject. Kinematic and EMG variables of right arm abduction ballistic movements were measured from paper recordings. We chose these variables as their significance had been previously investigated in studies dealing both with the physiology (see, for example, Wachholder and Haltenburger, 1926; Angel, 1974; Hallett et al., 1 9 7 5 ~ Flowers, ; 1976; Hallett and Marsden, 1979; Baroni et al., 1984; Pantaleo et al., 1988) of fast voluntary movements and with their alteration in some neurological diseases (Hallett et al., 197%; Flowers, 1976; Hallett and Khoshbin, 1980; Baroni et al., 1984; Benvenuti et al., 1988). The following kinematic variables were considered: reaction time (the time from the switching on of the target light to the onset of the arm movement), mean velocity of the initial movement (initial movement was considered to last from the start of the response until it changed slope or stopped), error of the initial movement (the distance between the position of the response light and that

ARM MOVEMENTS AND PHENYTOIN INTOXICATION of the target light at the end of the initial movement), and duration of corrective movements (the time from the end of the initial movement to the achievement of a final stable position of the response light). From the IEMG recordings, we measured the time to onset of Agl, duration of Agl, duration of the AntIn, and the time interval between the onsets of AntIn and Agl. As a rule, the beginning of Agl was the onset of IEMG activity in the agonist muscle. Alternatively, when a marked ongoing resting activity was present, Agl onset was taken as the time at which the IEMG reached a magnitude greater than 10% of its peak amplitude. The end of Agl was, in all instances, taken as the time at which the amplitude declined below 10% of the peak amplitude. AntIn was considered to last from the onset of the silent period to the onset of the first antagonist burst; on the other hand, when inhibition did not lead to a silent period, AntIn onset was indicated by a 30% decline in the level of the ongoing resting activity; AntIn end was considered as the time when IEMG activity again reached 30% of control resting activity. In our experimental conditions (Baroni et al., 1984; Pantaleo et al., 1988), postural constraints (arm extended and mechanically unsupported) imposed some tonic basal activity, namely in the antagonist muscle, thus making it possible that subjects' IEMGs displayed AntIn (Hallett et al., 1975~). Individual means and standard deviations were calculated. For each variable, a patient's mean values were considered abnormal when they deviated more than 2 SDs from the corresponding healthy control subjects' mean (Table 3 )

379

TABLE 3. Kinematic and EMG variables of fast right arm abduction movements in control subjects (n = 20) Variables Kinematic Reaction time (ms) Mean velocity of initial movement (mm/s)" Error of initial movement (mm) Duration of corrective movements (ms)b Electromyographic Time to onset of Agl (ms) Duration of Agl (ms) Duration of initial antagonist inhibition (ms) Time interval between the onsets of AntIn and Agl

Mean

Standard deviation

337

52

674

1I04

8

4

149

73

204 127

40 14

123

19

32

8

a Initial movement was considered from the start of the response until it abruptly changed slope or stopped. The time from the end of the initial movement to the achievement of a final stable position of the response light.

RESULTS

terns underlying ballistic performance, taking into account previous observations made both in normal subjects and patients with neurological diseases. Consequently, we will treat separately the results of the patients listed in Tables 1, 2, 4, and 5 : (a) the four patients whose recordings differed least from the normal (Baroni et al., 1984; Pantaleo et al., 1988), hereinafter designated normal-like (patients 1 to 4); (b) the four patients with alterations resembling those recorded in patients with cerebellar deficits (Hallett et al., 1975b), hereinafter designated cerebellar-like (patients 5 to 8); and (c) the patient with kinematic and EMG features recalling those observed in patients with Parkinson disease (Hallett and Khoshbin, 1980; Baroni et al., 1984; Benvenuti et al., 1988), hereinafter designated parkinsonianlike (patient 9).

The clinical abnormalities observed during the overdosage period are summarized in Table 2. No clear relationship between PHT plasma concentrations and the type and severity of symptomatology could be found; in particular, no critical specific PHT plasma concentration was observed that caused the same disturbances of voluntary motor control in all the patients. Compared to control subjects (Table 3, Fig. l), all patients' ballistic motor performance and underlying EMG patterns showed abnormalities. Patients' alterations in some kinematic and EMG variables are summarized in Tables 4 and 5 , respectively. Great variability was observed in the type and severity of patients' abnormalities. We therefore considered it useful for presentation of results to divide patients according to the features of their EMG pat-

Normal-like patients During the overdosage period (Table 2 ) , three patients showed mild to severe gait ataxia, associated with drowsiness in two and nystagmus in one. On the other hand, one patient did not show any clinical abnormality. Ballistic movements showed (Table 4) normal to slightly prolonged reaction time with normal or mildly reduced mean velocity of the initial movement. The accuracy of the initial movement was similar to that observed in normal subjects (Flowers, 1976; Baroni et al., 1984; Pantaleo et al., 1988); patients could reach the target accurately or overshoot (more frequently) or undershoot it. In the latter cases, one or two corrective movements were required. The duration of corrective movements was either normal or slightly prolonged. Epilepsia, Vol. 33, N o . 2, 1992

380

F. BENVENUTI ET A L .

Ant. IEMG Ant. EMG FIG. 1. Fast right arm abduction movement in a healthy control subject. Organization of the traces (from top to bottom): “integrated” EMG of the antagonist muscle (Ant. IEMG); EMG of the antagonist muscle (Ant. EMG); “integrated” EMG of the agonist muscle (Ag. IEMG); EMG of the agonist muscle (Ag. EMG); signal of switching on of the target light (Light); and signal of hand movement (Position). The subject displays the triphasic EMG pattern characteristic of ballistic movements. Note in particular the sequence of agonist-antagonist activation without coactivation phenomena and the occurrence of antagonist inhibition preceding the onset of the first agonist burst. Calibration bars: 1 mV, 10 cm, 500 ms.

tA

Ag. IEMG Ag. EMG

Light Posit ion

These patients showed “triphasic” EMG patterns (Fig. 2) similar to those recorded in normal subjects (Fig. 1). As a rule, a reciprocal activation of agonist and antagonist muscles was clearly present although some degree of coactivation could occur in the final part of the movement. The time to onset of Agl was normal or slightly increased; the duration of Agl and AntIn were also within normal limits. On the other hand, the time between the onset of AntIn and Agl was always reduced (Table 5 ) ; in particular, in two patients, this time interval was virtually absent or, in some trials, the onset of AntIn followed the beginning of Agl. One month after the adjustment of the PHT dos-

age, the three patients who showed clinical abnormalities completely recovered or markedly improved (Table 2). The previously observed kinematic and EMG abnormalities completely disappeared or markedly improved (Tables 4 and 5). In particular, it seems worth noting that the time between the onset of AntIn and AgI became normal in all of these patients. An example of recovery after the adjustment of PHT dosage is shown in Fig. 2. Cerebellar-like patients During the overdosage period, cerebellar-like patients (Table 2) presented mild to severe gait ataxia,

TABLE 4. Some kinematic variables of fast arm abduction movements in epileptic patients treated with PHT Mean velocity of initial movement

Reaction time Patient

During overdosage

1

2 3 4 5 6 7 8 9

Error of initial movement

Duration of corrective movements

After overdosage

During overdosage

After overdosage

During overdosage

After overdosage

During overdosage

After overdosage

N

N

N

111

11

N N N

N

N N

N N

tt N tt ttt tttttt tt

N

N

N

N

N

N

N

N N N

tt N N

N N N

111 c1

N N N N N

N N

N

N

N

N

1J11 111

11

tf

tt

11

N

N

N

N N N

Tt

N

N

N

N

N

ttttt tttttt tt

N

f t t t t N

N , normal values; i.e., control subjects’ mean 2 2 SDs. Upward arrows indicate abnormally increased values. Downward arrows indicate abnormally decreased values. Two to six arrows indicate that the values were greater or smaller than normal subjects’ mean plus or minus 2, 3, 4, 5 , or 6 SDs, respectively. Epilepsia, Vol. 33, NO. 2, 1992

N

tt tt N

N N N N

N

tttttt ttt Tt ttttt tt tttt ttttt

1111

111 11

11

111111 111.11

11 N

N N N N

1.1 N N N

N N N

N N

f t t t

1.11111 1111 11J.lil

1111.1 N N

N

N

N N

11 N

11 N

N

11 .11.1.11 11 N N

N

N

11

11 N

N

6 8 L 9

s

P

E 2

NOILV3IXOLNI NIOLXNZHd QNV SLNZNZAOJV WtIV

18E

382

F . BENVENUTI ET AL.

A Ant. IEMG

~

Ant. EMG Ag. IEMG Ag. EMG Light

I \

Position

B Ant. IEMG

A

-

--

Ag. IEMG

-w-1

?

Ag. EMG

Light Position

FIG. 2. Examples of fast right arm abduction movements recorded in a normal-like patient who did not show any clinical abnormality during the overdosage period (patient 3): during the overdosage period (A); 1 month after the adjustment of PHT dosage (B).For organization of traces, see Fig. 1. In A, the triphasic EMG pattern is preserved and displays reciprocal activation of agonist and antagonist muscles. Note that the onset of antagonist (Antln) did not precede but accompanied the onset of agonist muscle (Agl). In B, the EMG patterns display characteristics similar to those observed in normal subjects. Calibration bars: 0.5 mV, 10 cm, 500 ms.

Ballistic performances were severely altered, with a longer reaction time, a lower mean velocity of the initial movement, and a longer duration of corrective movements (Table 4). EMG activity at rest (i.e., when grasping the handle, before the beginning of the movement) looked like ongoing tremor, although no tremor could be observed clinically. The patient did not show the triphasic EMG pattern characteristic of ballistic movements (Fig. 5). The initial agonist activity (i.e.,

Epilepsia, Vol. 33, No. 2, 1992

the activity preceding or accompanying the onset of movement) did not consist of a single burst but of multiple bursts, usually with a trend towards progressively increasing amplitude that continued after the beginning of the motor act. In particular, a longer latency and shorter duration of Agl (i.e., the first agonist burst after the switching on of the target light that showed a clear-cut increase compared to the ongoing bursting activity) were observed (Table 5).

-

ARM MOVEMENTS A N D PHENYTOIN INTOXICATION

A Ant. IEMG Ant. EMG

--

A g IEMG

383

1-

Ag. EMG

m-

Light Position

B Ant. IEMG

I

Ant. EMG Ag. IEMG

I

EMG Light

n A .

Position .\

--=-,.I

FIG. 3. Examples of fast right arm abduction movements recorded in a cerebellar-like patient who showed mild gait ataxia during the overdosage period and who clinically recovered following PHT dosage adjustment (patient 5): during the overdosage period (A); 1 month after the adjustment of PHT dosage (6). For organization of traces, see Fig. 1. EMG patterns underlying ballistic movements are severely altered in A. Note the dramatic increase in the duration of both agonist and antagonist bursts and the reduction in the time interval between the onset of antagonist muscle (Antln) and agonist muscle (Agl). Partial overlapping of agonist and antagonist bursts also appears to be a common feature. In 6 , EMG patterns closely resemble those recorded in normal subjects. Calibration bars: 0.5 mV, 10 cm, 500 ms.

In the antagonist muscle, an abnormally prolonged silent period preceded and accompanied the initial activity of the agonist muscle; it was followed by multiple bursts alternating with those of the agonist muscle. One month after the adjustment of PHT dosage, the patient recovered. Ballistic performance improved and displayed features similar to those recorded in normal subjects. All of the kinematic variables improved markedly (Table 4). Correspondingly, EMG patterns assumed a triphasic aspect similar to that recorded in normal subjects (Fig. 5 ) . The initial agonist activity could consist either of a single burst of normal or prolonged duration, or of

two nearly fused bursts; AntIn duration was correspondingly reduced (Table 5). DISCUSSION In the present study, all but one of the patients showed neural clinical disturbances referable to PHT toxicity during the overdosage period. The symptomatology displayed a great range of variability. In particular, the type and/or severity of disturbances of voluntary motor control did not appear to be related to any specific PHT plasma level (Table 2). This great individual variability in the susceptiEpilepsia, Vol. 33, No. 2, 1992

F. BENVENUTI ET AL.

384 A Ant IEMG Ant EMG

Ap

IEMG

Ag

EMG

a

4 A

tight Position

I

h

Ant IEMG

I

Ant EMG

Ag

IEMG

AQ

EMG

I I

tight Posltlon

A

A ’

\

\I

FIG. 4. Fast right arm abduction movements in an epileptic patient who showed gait ataxia, dysmetria, and kinetic tremor during the overdosage period and who clinically improved following PHT dosage adjustment (patient 8). For organization of traces, see Fig. 1. During the overdosage period (A), EMG patterns were characterized by long-lasting activation of both agonist (Ag) and antagonist (Antln) muscles. Antln started after the onset of Agl and was never complete (i.e., a true silent period was never observed). Partial overlapping (coactivation) of agonist and antagonist bursts was also present. One month after the adjustment of PHT dosage (B), motor performances improved. Correspondingly, underlying EMG patterns partially recovered and displayed features that at least in part recalled those recorded in healthy subjects; note, for example the appearance of a prominent burst in the agonist muscle preceding the movement as well as the presence of a complete or a nearly complete inhibition in the antagonist muscle. Calibration bars: 0.5 mV, 10 crn, 500 ms.

bility to the PHT toxic effects is well known (Dam, 1970) and has been ascribed to differences in local conditions (alterations of circulation, histological or histochemical changes, variations in the bloodbrain barrier, and presence of abnormal metabolites) (Kutt et al., 1964), in protein binding (Booker and Darcey, 1973), in drug metabolism (Kutt et al., 1964), and to the presence of comedications (Kutt, 1982). It may be argued that since some patients (nos. 2, 4, 8, 9, Table 1) had computed tomography (CT) scan abnormalities, the value of the results of the present study are weakened as these lesions might themselves affect voluntary motor function. However, comparing the results obtained during PHT intoxication with those obtained 1 month after adjustment of the therapy, we observed a clear-cut improvement or even recovery in both clinical status and kinematic and EMG variables of ballistic Epilepsia, Vol. 33, No. 2 , 1992

movements. This clearly indicates that the alterations observed during PHT intoxication were related to the PHT overdosage. It may also be objected that the observed abnormalities and improvement or recovery after the adjustment of the therapy could be related, at least in part, to phenobarbital (PB) comedication since seven of the nine patients (nos. 2, 3, 4, 5 , 6, 7, and 8, Table 2) were receiving PHT with PB or primidone (PRM). In addition (Table 2), after the adjustment of therapy, PB plasma concentrations were slightly decreased not only in the two patients (nos. 2 and 4, Table 2) with PB dosage reduction but also in the other patients with unchanged PB or PRM dosages. However, we do not think that PB played a major role in causing either the motor abnormalities observed during the intoxication period or their improvement or recovery after the adjustment of the therapy since variations in PB plasma concentrations were small com-

ARM MOVEMENTS AND PHENYTOIN INTOXICATION

385

A Aiit. IEMG

f l

Ant. E M G

f l

Ag. IEMG

I

Ag. E M G

Light Position

4

I

Light

~

Po sit ion

I

FIG. 5. Fast right arm abduction movements in the epileptic patient designated as parkinsonian-like (patient 9) during the overdosage period (A) and 1 month after the adjustment of PHT dosage (B). This patient, who exhibited gait ataxia and slowness of movement during the overdosage period, clinically recovered following the adjustment of the therapy. For the organization of the traces, see Fig. 1. In A, note in particular that the initial agonist activity (i.e., before and at the onset of movement) does not consist of a single burst but of multiple bursts with a trend towards increasing intensity and that the initial antagonist inhibition was abnormally prolonged. However, reciprocal activation of agonist and antagonist muscles was as a rule maintained. In B,the patient showed EMG patterns similar to those underlying ballistic performance in healthy subjects. Calibration bars: 0.5 mV, 500 ms, 10 cm.

pared to those observed for PHT plasma concentrations. In fact, in the seven patients also treated with PB or PRM, PB plasma concentrations (mean k standard error) decreased from 22.3 3 to 19.4 k 3 pg/ml after the adjustment of AED therapy, whereas in the same seven patients PHT plasma concentrations decreased from 35.1 ? 3 to 15.3 k 1 p,g/ml. During the overdosage period, patients displayed a wide range of variability in the type and severity

*

of the abnormalities of their ballistic motor performance, both from the kinematic and EMG viewpoints, without any evident relationship with PHT plasma levels. However, it is noteworthy, even if expected from the clinical symptomatology of the patients, that the most frequent alterations were similar to those observed in patients with cerebellar deficits (Hallett et al., 1975b), namely related to the proper timing of activation of agonist and antagonist muscles. In fact, alterations of this type were

Epilepsia, Vol. 33, N o . 2 , 1992

386

F . BENVENUTI ET AL.

present in the recordings of both cerebellar-like and normal-like patients. Thus, the division of the patients into these two groups may appear to some extent artificial. Nevertheless, given the great variability in the type and severity of the alterations of EMG patterns underlying ballistic performances, we considered such division useful, not only for the presentation of results but also for subsequent discussion. It has been suggested that the cerebellum is involved in the control of fast voluntary movements through segregated circuits with different functions (Brooks and Tach, 1981). In particular, there is evidence that lateral cerebellar hemisphere and dentate nucleus discharge before the onset of movement and therefore they are believed to be involved in initiating movement. On the other hand, the intermediate cerebellum and the interpositus nucleus fire later during the execution of volitional movements and are exquisitely sensitive to rapid feedback from the movement; therefore, they are considered to play a part in the final, corrective part of the movement (Brooks and Tach, 1981). In our study, normal-like patients presented alterations involving mainly the initial part of the EMG ballistic pattern (reduced time interval between the onset of AntIn and Agl). On the other hand, cerebellar-like patients displayed severe alterations concerning not only the EMG pattern underlying the initial part of the movement (reduced time interval between the onset of AntIn and Agl, prolonged duration of Agl and AntIn) but also its subsequent corrective phase (marked coactivation of Antl and Agl and/or Antl and Ag2). It could be speculated that in the former group of patients it is mainly the neural system in which the lateral cerebellum is involved that is affected, whereas in the latter group it is not only the lateral cerebellum that is affected but also the neural system in which the intermediate cerebellum is involved. It could also be speculated that the effect on the lateral cerebellum is greater in the second group of patients than in the first. Why PHT overdosage caused such different effects in the two groups of patients is not clear. It could reflect individual differences in the anatomic or functional status of the neural systems involved in planning fast movements, and these differences might have been present already before the overdosage period. It could also reflect differences in pharmacokinetic and pharmacodynamic factors. Furthermore, the present data seem to imply that the lateral cerebellar system has a greater susceptibility to PHT toxic effects.

Epilepsia, Vol. 33, No. 2 , 1992

It is noteworthy that one patient who clinically presented nystagmus, gait ataxia, and slowness of movement showed EMG alterations similar to those observed in patients with Parkinson disease (Fig. 5). The interpretation of this observation is not obvious. The multiple pharmacologic properties of the drug (Woodbury, 1980) could lead to different effects on those central neural mechanisms involved in motor control including the nigrostriatal pathways. In this context, it should be recalled that PHT has dopamine antagonist properties (Chadwick et al., 1976; Snider and Snider, 1977) as well as inhibiting calcium- and calmodulin-dependent protein phosphorylation and neurotransmitter release (De Lorenzo, 1980). These latter properties recall the effects of the calcium antagonist flunarizine in producing parkinsonism (Chouza et al., 1986; Micheli et al., 1987; Benvenuti et al., 1988). One month after the adjustment of PHT dosage, only three patients showed a complete normalization of both kinematic and EMG variables while the others still presented alterations referable to impaired cerebellar or extrapyramidal functions, although in a less marked degree. The absence of a complete recovery could be ascribed to pre-existent central nervous system alterations, possibly due to the epilepsy itself (Dam, 1970; Salcman et al., 1978), andlor to a not complete reversibility of damage due to PHT intoxication after the adjustment of therapy (Selhorst et al., 1972; Ghatak et al., 1976). However, other hypotheses cannot be discarded. The reversibility of the disturbances could take periods longer than those monitored in the present study, as it has been observed that the neurological manifestations of PHT may long outlast the presence of the drug in serum, sometimes by many months (Ahamad et al., 1975). Finally, the persistence of the alterations could be due to interference of interictal and/or subclinical epileptic discharges with neural systems involved in motor planning (Smith et al., 1986). To answer these questions, longitudinal studies would be necessary, carried out before and after starting PHT treatment. Our results show that PHT intoxication causes alterations of kinematic and EMG variables of ballistic movements although a great variability in the type and severity of abnormalities is observed. These abnormalities may decrease or even disappear after appropriate adjustment of PHT dosage. The present study further indicates that the kinematic and EMG analysis of fast arm movements may be a useful tool in the follow-up of epileptic patients treated with PHT and possibly in the early detection of drug-induced motor abnormalities.

ARM MOVEMENTS AND PHEN YTOIN INTOXICATION Acknowledgment: We thank Dr. Mark Hallett for help in revising the manuscript.

REFERENCES Angel RW. Electromyography during voluntary movement: the two burst pattern. Electroencephalogr Clin Neurophysiol 1974;36:493-8. Baroni A, Benvenuti F, Fantini L, Pantaleo T, Urbani F. Human ballistic arm abduction movements: effects of L-dopa treatment in Parkinson’s disease. Neurology 1984;34:868-76. Benvenuti F, Baroni A, Bandinelli S , Ferrucci L, Corradetti R, Pantaleo T. Flunarizine-induced parkinsonism in the elderly. J Clin Pharmacol 1988;28:600-8. Bittencourt PRM, Richens A. Assessment of antiepileptic drug toxicity by eye movements. Electroencephalogr Clin Neurophysiol 1980;36(suppl):467-81. Booker HE, Darcey B. Serum concentrations of free diphenylhydantoin and their relationship to clinical intoxication. Epilepsia 1973;14:177-84. Brooks VB, Tach WT. Cerebellar control of posture and movement. In: Brooks VB, ed. Handbook of physiology, Vol. 2 , The nervous system ZZ. Bethesda: American Physiological Society, 198 1 :877-946. Buchthal F , Svensmark 0, Schiller PJ. Clinical and electroencephalographic correlations with serum levels of diphenylhydantoin. Arch Neurol 1960;2:624-30. Chadwick D, Reynolds EH, Marsden CD. Anticonvulsantinduced dyskinesias: a comparison with dyskinesias induced by neuroleptics. J Neurol Neurosurg Psychiarry 1976;39: 1210-8. Chouza C, Scaramelli A, Caamano JA, De Medina 0, Aljanati R, Romero S . Parkinsonism, tardive dyskinesias, akathisia, and depression induced by flunarizine. Lancet 1986;l:13034. Dam M. Phenytoin: toxicity. In: Woodbury DM, Penry JK, Pippenger CE, eds. Antiepileptic drugs. New York: Raven Press, 1970:247-56. De Lorenzo RJ. Phenytoin: calcium- and calmodulin-dependent protein phosphorylation and neurotransmitter release. In: Glaser GH, Penry JK, Woodbury DM, eds. Antiepileptic drugs: mechanisms of action. New York: Raven Press, 1980:399-414. Dodrill CB. Diphenylhydantoin serum levels, toxicity, and neuropsycological performance in patients with epilepsy. Epilepsia 1975;16593-600. Flowers KA. Visual “closed-loop’’ and “open-loop’’ characteristics of voluntary movement in patients with parkinsonism and intention tremor. Brain 1976;99:269-3 10. Ghatak NR, Santoso RA, Mac Kinney WM. Cerebellar degeneration following long-term phenytoin therapy. Neurology 1976;26:818-20. Hallett M, Khoshbin S. A physiological mechanism of bradykinesia. Brain 1980;103:301-14. Hallett M, Marsden CD. Ballistic flexion movement of the human thumb. J Physiol (Lond) 1979;294:33-50. Hallett M, Shahani BT, Young RR. EMG analysis of stereotyped voluntary movements in man. J Neurol Neurosurg Psychiatry 1975a;38:1154-62. Hallett M, Shahani BT, Young RR. EMG analysis of patients with cerebellar deficits. J Neurol Neurosurg Psychiatry 1975b;38:1163-9. Hamad S, Laidlaw J, Houghton GW, Richens A. Involuntary movements caused by phenytoin intoxication in epileptic patients. J Neurol Neurosurg Psychiatry 1975;38:225-331. Idelstrom CM, Schalling D, Carlquist U, Sjoquist F. Behavioural and psychophysiological studies: acute effects of diphenylhydantoin in relation to plasma levels. Psycho1 Med 1972;2: 1 1 1-20. Julien RM, Halpern LM. Effect of diphenylhydantoin and other antiepileptic drugs of epileptiform activity and Purkinje cell discharge rate. Epilepsia 1972;13:3871100.

387

Kooiker JC, Sumi SM. Movement disorders as a manifestation of diphenyhydantoin intoxication. Neurology 1974;24:68-71. Kutt H. Phenytoin: interaction with other drugs. In: Woodbury DM, Penry JK, Pippenger CE, eds. Antiepileptic drugs, 2nd ed. New York, Raven Press, 1982:22740. Kutt H, Winters W, Kokenge R, Mac Dowel F. Diphenylhydantoin metabolism, blood levels and toxicity. Arch Neurol 1964; 11:642-8. Laxer KD, Robertson LT, Julien RM, Dow RS. Phenytoin: relationship between cerebellar function and epileptic discharges. In: Glaser GH, Penry JK, Woodbury DM, eds. Antiepileptic drugs: mechanisms of action. New York: Raven Press, 1980:415-27. MacLellan DL, Swash M. Choreoathetosis and encephalopathy induced by phenytoin. Br Med J 1974;2:20&5. Mameli 0, Tolu E. Further observations on the action of phenytoin on the cerebellum in rats: involvement of the lateral reticular nucleus. Epilepsia 1984;25:363-7. Mameli 0 , Tolu E, Caria MA, Melis F, Sechi GP. Effects of phenytoin administration on vestibular function in the rat. Epilepsia 1985;26:262-7. Micheli F, Pardal MF, Gatto M, et al. Flunarizine-and cinnarizine-induced extrapyramidal reactions. Neurology 1987;37: 88111. Pantaleo T, Benvenuti F, Bandinelli S , Mencarelli MA, Baroni A. Effects of expected perturbations on the velocity control of fast arm abduction movements. Exp Neurol 1988;101:31326. Prensky AL, De Vivo DC, Polkes H. Severe bradykinesia as a manifestation of toxicity to antiepileptic medications. i Pediatr 1971:78:7004. Reynolds EH: Chronic antiepileptic toxicity: a review. Epilepsia 1975 ;16:319-52. Riva R, Albani F, Baruzzi A. Rapid quantitative determination of underivatized carbamazepine, phenytoin, phenobarbital and p-hydroxyphenobarbital in biological fluids by packed column gas chromatography. J Chromatogr 1980;221:75-84. Salcman M, Defendini R, Correll J , Gilman S. Neuropathological changes in cerebellar biopsies of epileptic patients. Ann Neurol 1978;3:10-9. Selhorst JB, Kaufman B, Horwitz SJ. Diphenylhydantoininduced cerebellar degenerations. Arch Neurol 1972;27: 453-6. Smith DB, Bruce RC, Collins J, Mattson RH, Cramer JA, The VA Cooperative Study Group 118. Behavioural characteristics of epilepsy patients compared with normal subjects. Epilepsia 1986;27:760-8. Snider SR, Snider RS. Phenytoin and cerebellar lesions: similar effects on cerebral catecholamine metabolism. Arch Neurol 1977;34:162-7. Wachholder K, Haltenburger H. Beitrage zur Physiologie der willkurlichen Bewegung. X . Mitteilung. Einzelbewegungen. Pfliigers Arch Ges Physiol 1926;214:642-61. Woodbury DM. Phenytoin: proposed mechanisms of anticonvulsivant action. In: Glaser GH, Penry JK, Woodbury DM, eds. Antiepileptic drugs: mechanisms of action. New York: Raven Press, 1980:447-71.

RfiSUME Nous avons CvaluC les effets du surdosage de la diphknylhydantohe (PHT) sur les mouvements balistiques d’abduction du bras chez neuf patients Cpileptiques sous traitement au long cours avec PHT. Pendant la pCriode de surdosage tous les patients sauf un ont montrC anomalies cliniques a mettre sur le compte de function ctrkbelleuse compromise; un patient avait ralentissement moteur. Les mouvements balistiques Ctaient alt6rCs chez tous les patients mais on a observe une grande variabilitC dans le type et dans la sCvCritC des anomalies. Chez quatre patients les enregistrements cinkmatiques e t Clectromyographiques n’ktaient pas tr&s differents de ceux des normaux; chez quatre ils ressemblaient a ceux dCcrits chez des patients Epilepsia, Vol. 33, No. 2 , 1992

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avec des dCficits cerkbelleux; chez un autre patient les enregistrements ressemblaient ? ceux i dCcrits dans la maladie de Parkinson. Le type et la sBvCrit6 des anomalies cliniques du contrble du mouvement volontaire et les alterations des mouvements balistiques n’Ctaient pas en rapport avec une concentration plasmatique specifique de la PHT. Un mois apres l’ajustement du dosage de la PHT, les patients qui avaient des anomalies cliniques ont completement rCcupCrC ou ils Ctaient tres ameliork. Les anomalies cinematiques et Clectromyographiques observees pendant la phiode de surdosage ont disparu conpletement ou elles one CtC tres ameliores. (Translatioiz supplied b y authors)

RESUMEN Hemos estudiado 10s efectos de la sobredosis de difenilhidantoina (PHT) en nueve pacientes epilkpticos que eran sometidos a tratamiento cronico con este farmaco. Durante todo el periodo de la sobredosis, todos 10s pacientes except0 uno presentaron sintomas de leves o graves alteraciones de la funci6n del cerebelo. Uno de ellos present6 enlencimiento motorio. Los movimientos balisticos mostraban alteraciones en todos 10s pacientes si bien bas alteraciones eran diversas en tipo y gravedad. Las variables cinematicas y EMG se presentaron en cuatro pacientes con diferencias minimas en relacion a individuos normales. Cuatro pacientes presentaron alteraciones similares a las descritas en pacientes con enfermedad del cerebelo y un paciente tenia alteraciones parecidas a quellas observadas en pacientes con enfermedad de Parkinson. El tipo y gravedad de 10s disturbios del control del movimiento voluntario asi como las alteraciones de 10s movimientos balisticos no estaban relacionados con las concentraciones plasmaticas de la PHT. Despues de un mes de haber reducido el dosaje de PHT, en 10s pacientes se observo un

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notable mejoramiento o completa desaparicih de 10s sintomas. Paralelamente, las alteraciones cinematicas y EMG de 10s movimientos balisticos desaparecieron o mejoraron notablemente. (Trunslution supplied by authors)

ZUSAMMENFASSUNG Wir haben die Auswirkungen der Uberdosierung von Difenylidantoin (PHT) in epileptischen Patienten, die mit diesem Pharrnakurn auf lange Zeit behandelt wurden, untersucht. Wahrend der Zeit der Uberdosierung zeigten alle Patienten, bis auf einen, eine Symptomatik, die auf veranderte cerebellare Funktion zuruckzufuhren ist; bei einem Patienten wurde auch eine motorische Verlangsamung festgestellt. Die ballistischen Bewegungen waren, trotz der gropen Unterschiede der Art und der Schwere der Veranderungen, in allen Patienten abnormal. Die kinetischen Aufzeichnungen und das EMG zeigten bei vier Patienten minimale Unterschiede im Vergleich zu normalen Patienten, bei weiteren vier Veranderungen, wie sie bei Patienten mit cerebellaren Storungen beschrieben werden und bei einem Veranderungen, wie man sie bei Patienten mit Parkinson’scher Krankheit beobachtet. Art un Schweregrad der Storungen der willkiirlichen motorichen Kontrolle wie auch die Veranderungen der ballistichen Bewegungen waren nicht an eine spezifische Plasmakonzentration des PHT gebunden. Einen Monat nach der Verringerung der Dosis von PHT konnte bei den Patienten ein volliges Verschwinden oder eine beachtliche Besserung der Symptomatik festgestellt werden. Die kinematischen Veriinderungen und die Abnormalitaten des EMG waren vollig verschwunden oder weitgehend verbessert. (Translation supplied by authors)