Effects of chronic high serum levels of phenobarbital on evoked potentials in epileptic children

Electroencephalography and clinical Neurophysiology, 92 (1994) 11- 16 © 1994 Elsevier Science Ireland Ltd. 0168-5597/94/$07.00

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EEP 93518

Effects of chronic high serum levels of phenobarbital on evoked potentials in epileptic children M. Brinciotti Istituto di Neuropsichiatria Infantile, Universit3 "La Sapienza," Via dei Sabelli 108, 00185 Rome (Italy)

(Accepted for publication: 6 August 1993)

Summary We studied VEP and BAEP in 8 epileptic children with chronic high serum levels of phenobarbital. Records were obtained when the drug serum level was more than 40 mg/I and repeated when serum concentration was within the normal range. During the periods of high levels, P2 latency of the VEP was abnormally increased in all cases but one. The mean P2 latency decreased according to the reduction of the serum level of phenobarbital (139.6 msec vs. 110.1 msec, P = 0.002), and a significant regression coefficient (r = 0.546, P = 0.0271) was also noted between P2 latency and drug serum concentration. BAEPs were normal in all cases but one, who had a coexisting high level of phenytoin. All these findings suggest that the pharmacological effect of phenobarbital may be detected by VEPs and may result in delay of the P2 component. Key words: Evoked potentials; Phenobarbital; Intoxication; Epilepsy; (Children)

High serum levels of antiepileptic drugs ( A E D ) are usually associated with signs and symptoms of intoxication, but the level at which clinical manifestations appear varies among patients (Plaa 1975; Reynolds and Trimble 1985). The primary dose-related side-effects of phenobarbital (Pb) are drowsiness, double vision, nystagmus, ataxia and slurred speech. Moreover, several changes of neurophysiological parameters have also been noted in the CNS as well as in peripheral nerve functions in relation to high serum levels of Pb (Shorvon and Reynolds 1982; Reynolds and Trimble 1985), but there are no systematic reports on evoked potentials (EP). In the present study we have analyzed the effects of chronic high levels of Pb on cortical and brain-stem EPs in children with epilepsy. Materials and m e t h o d s

We studied visual evoked potentials (VEP) and brain-stem auditory evoked potentials (BAEP) in 8 epileptic children with high serum concentrations of Pb (more than 40 m g / l ) . All children were treated with a long-term anticonvulsant therapy (range 4 - 1 3 years, mean 8.9 years); at the time of our examination, all patients had high levels of Pb from 1 to 6 months, as understood from the history and the review of previous medical reports. Each patient underwent an initial evaluation, including physical and neurological examiSSDI 0013-4694(93)E0208-N

nation, E E G , urinalysis and complete hematological and biochemical profiles (including renal and liver function, SGOT, SGPT, g a m m a - G T , sodium, potassium, calcium, phosphorus). Serum levels of all antiepileptics were measured for all patients, and the specific time of drug ingestion was noted when the blood sample was taken. All laboratory data were repeated according to the clinical course in each patient. Clinical and laboratory data of all patients are shown in Table I. At the first examination, 3 children (cases 2, 6 and 7) did not have any clinical evidence of Pb intoxication, despite the high serum level of the drug. Even if standard neuropsychological tests were not systematically applied, all patients showed subtle changes in behavior and cognitive functions related to high Pb levels (Table II). The cause of high levels of Pb was reduction of body weight without corresponding dose adjustment in 4 patients (cases 1, 3, 5 and 7; m e a n weight loss = 5400 g), liver disease or other metabolic disorders in 3 (cases 2, 4 and 6), and drug-drug interaction in 1 case (no. 8). In all patients neurophysiological parameters (EEG, VEP, BAEP) were obtained on at least 2 occasions: the first recording was performed during the period of high Pb levels (phase A), and the second when serum levels of Pb were within the normal range of 15-40 m g / l (phase B). The method we used allowed us to make within-subject comparisons of recorded parameters, while controlling for practice effects.

12

M. BRINCIOJTI

V E P s w e r e e l i c i t e d by f l a s h ( i n t e n s i t y 0.3 J o u l e ; frequency 2/sec; d i s t a n c e f r o m e y e s 25 c m ) ; b o t h binocular and monocular records were obtained, and at l e a s t t w o t r i a l s o f 100 a r t i f a c t - f r e e r e s p o n s e s w e r e recorded within 512 msec after stimulus. Peak latency and amplitude values of the P2 component were analyzed. B e c a u s e o f t h e p o o r c o o p e r a t i o n o f t h e p a t i e n t s , VEPs by pattern-reversal stimulation could not be obtained. Particular care was used to minimize the effects

o f i n a t t e n t i o n a n d m o v e m e n t a r t i f a c t , a n d to c h e c k t h e s t a t e o f a l e r t n e s s d u r i n g r e c o r d i n g , a c c o r d i n g to T a y l o r a n d M c C u l l o c h (1992). BAEPs to independent left and right ear stimulation w e r e e l i c i t e d t h r o u g h h e a d p h o n e s ( a l t e r n a t e click; int e n s i t y 70 + 2 d B SL; f r e q u e n c y l l / s e c ) ; at least two trials of 2000 artifact-free responses were recorded w i t h i n 10 m s e c . A b s o l u t e a n d i n t e r - p e a k l a t e n c y a n d amplitude values of components were evaluated. Nor-

TABLE I Clinical and laboratory data of patients related to Pb levels. Case

(sex, age)

Epilepsy

Neurological examination

EEG

Therapy (mg/kg/day)

--*

Serum level (rag/l)

Partial

Foc

Pb (5_8) PHT (13.3)

~ -,

52.0 26.1

Partial

Drowsiness Nystagmus Ataxia Hypotonia Hypotonia

Foc

Pb PHT

(3.3) (8.0)

-~ -,

28.6 9.8

Lennox-Gastaut

Hemiplegia

Multifoc

Lennox-Gastaut

Hemiplegia

Multifoc

Pb (2.8) VPA (15.6) Pb (1.6) VPA (15.6)

-~ ~ -, -~

47.8 50.6 32.5 57.0

Generalized

Tetraplegia Sialorrhea Drowsiness Tetraplegia

Multifoc

Pb

(6.0)

-*

41.0

Multifoc

Pb

(3.0)

-~

18.0

Foc

Pb

(3.6)

-*

53.0

Partial

Hemiplegia Drowsiness Nystagmus Hemiplegia

Foc

Pb

(1:8)

-~

36.6

Partial

Drowsiness

Multifoc

Partial

Normal

Multifoc

Pb PHT Pb PHT

(8.0) (4.0) (2.7) (2.0)

~ ~ --, ~

53.4 4.5 28.7 5.2

(F, 12.9 yrs) N6 Phase A Phase B

Generalized Generalized

Hypotonia Hypotonia

Multifoc Multifoc

Pb Pb

14.1 ) t3.3)

-~ ~

43.8 26.5

(M, 10 yrs) N7 Phase A Phase B

Partial Partial

Normal Normal

Normal Normal

Pb Pb

17.11) /5.0)

~ -~

48.0 25.0

(M, 8.9 yrs) N8 Phase A

Partial

Tetraplegia Nystagmus Ataxia Sialorrhea Tetraplegia

Multifoc

Pb (5.3) PHT (5.0) PRM (17.0) VPA (33.0) Pb (5.0) PHT (6.6)

---, --* -, ~ -, -~

80.0 3.0 10.5 81.0 35.7 6.0

NI (M, 18 yrs) * Phase A

Phase B (F, 17.8 yrs) N2 Phase A Phase B (F, 17 yrs) N3 Phase A

Phase B N4 (F, 16.8 yrs) Phase A

Phase B (F. 13 yrs) N5 Phase A Phase B

Phase B

Generalized Partial

Partial

Multifoc

Pb = phenobarbital; PHT = phenytoin; PRM = primidone; VPA = valproate; phase A = serum level of Pb more than 40 mg/l; phase B = serum level of Pb within range (15-40 mg/l). * Coexisting high levels of Pb and PHT.

13

PHENOBARBITAL AND EVOKED POTENTIALS TABLE 1I Changes on behavior and cognitive functions related to Pb serum concentration. Patient

N1

N2 N3

N4 N5

N6 N7

N8

Pb serum level > 40 m g / l

< 40 m g / l

Hyperkinesis Hyperactivity Irritability Poor visuo-motor coordination Poor manual motor skills Irritability Aggressive behavior Tantrums Poor visuo-motor coordination Anxiety Sadness Affective disorders Poor visuo-motor coordination Poor visuo-motor coordination Poor manual motor skills Hyperactivity Irritability Poor visuo-motor coordination Poor manual motor skills Poor alertness

I I I R I NC I R I NC NC NC R I I R I R I I

I

0

5oo

MSEC

Fig. 1. Example of abnormal VEP (case 4) recorded during the phase of high serum level of Pb (up); delay of the major positive peak (latency = 143.0 msec), that achieved normal limits (down) when Pb serum concentration was 36.6 mg/l. In this figure and in Fig. 2, for each recording (binocular stimulation) 1st trace = O2-Fz, 2nd trace = O1-Fz (vertical calibration = 2/2V; positivity is down).

amplitude of the responses. Analysis of residuals was also performed. The Student's 2-tailed t test for paired data was used to compare

l = improvement; R = remission; NC = no changes.

mean values. Differences

w e r e c o n s i d e r e d s i g n i f i c a n t a t P = 0.05 o r less.

mative values of VEP and BAEP were obtained using

Results

t h e s a m e p r o c e d u r e in a c o n t r o l g r o u p o f 25 c h i l d r e n , matched for sex and age.

P2 latency of the VEP

Least-square linear regression analysis was used to determine

the

effect of drug

level o n

(more

latency and

than

2.5 S . D .

was abnormally increased

above the mean

value

TABLE III Latency of the main component of VEP and BAEP in relation to serum level of Pb. Patient

Phase

Latency (msec) VEP

BAEP

P2 N 1 ** N2 N3 N4 N5 N6 N7 N8 Controls

A B A B A B A B A B A B A B A B

148.0 106.0 126.0 107.0 175.0 140.0 143.0 124.0 143.0 100.0 99.0 101.0 130.0 102.5 153.0 100.0

Mean (S.D.)

103.2 (9)

I * *

III

2.00 * 1.76 1.90 1.60

4.56 * 3.84 4.00 3.65

1.52 1.53 1.38 1.40 1.39 1.46

3.66 3.63 3.50 3.49 3.64 3.62

1.61 (0.15)

3.72 (0.19)

* * * *

* *

V

I-III

6.40 * 5.64 6.04 5.73 Not available Not available Not available Not available 5.36 5.28 5.36 5.50 5.00 4.90 Not available Not available 5.02 (0.28)

I-V

2.56 * 2.08 2.10 2.05

4.40 * 3.88 4.14 4.18

2.14 2.10 2.12 2.09 2.25 2.16

3.83 3.75 3.72 4.10 3.61 3.44

2.11 (0.11)

3.97 (0.17)

Phase A = Pb serum level more than 40 mg/I; phase B = Pb serum level within normal range (15-40 rag/l). * Abnormal latency (more than 2.5 S.D. from mean control value). * * Coexisting high levels of Pb and PHT.

of the

14

M. B R I N C I O T T I

Discussion

: \

L'

I

0

~oo

usEc

Fig. 2. Changes in wave form and latency of VEP (case 8): during the phase of high serum levels of Pb (up) large positive wave with increased latency that achieved normal values (down) when P b serum concentration was 35.7 m g / I . (Traces and calibration as in Fig. 1 .)

control group) in all patients but one, when Pb levels were more than 40 m g / 1 (Table III). When Pb concentrations were within the normal range, the mean P2 latency decreased significantly (phase A 1139.6 + 22 msec vs. phase B 110.1 + 14 msec; t = 4.784, P = 0.002) and values achieved normal limits in 7 patients (Figs. 1 and 2). A significant positive regression coefficient was noted between the Pb serum concentration and P2 latency (r = 0.546; P = 0.0271; Fig. 3). BAEP records were not available in 3 cases (3, 7 and 8) because of poor cooperation of the patients. During the period of high levels of Pb (phase A), BAEPs were normal in all remaining cases but one (case 1) in which an increase of absolute and inter-peak latencies was observe& In this patient a coexisting high serum level of phenytoin (PHT) was also noted; BAEP recording was normal in phase B, when both Pb and P H T serum concentrations were within normal range.

P2 latency (msec) 25O

2o01

+

150

_.._~-~w¢+

0

20

+

40

60

Pb serum concentration

80

t00

(rag/l)

Fig. 3. Significant positive regression between Pb serum concentrations and P2 latency of VEPs ( Y = 0.851X+90.204; r = 0.546; P = 0.0271).

It is well known that primary dose-related side-effects of Pb usually appear when the serum concentration is more than 40 rag/l, but there are noteworthy individual variations, especially in children. In this clinical situation, the value of measuring A E D levels is well recognized, and rapid A E D assay has been recently available for immediate dose adjustment (Cosgrove et al. 1990; Houtman et al. 1990). Toxic symptoms are rarely seen in patients with chronic antiepileptic therapy when serum concentrations are less than 30 m g / l , even though a child with severe signs of Pb toxicity at a serum level of 23.4 mg/1 has been reported (Kang and Shinnar 1990). As the minimum toxic level is approached or exceeded, side-effects increase in intensity, an exacerbation of seizures may also occur, and stupor or coma can result. The literature abounds with reviews of side-effects of Pb on clinical. E E G and peripheral nerve function (Schmidt 1982; Oxley et al. 1983; Reynolds and Trimble 1985: Drake et al. 1987: Vining et al. 1987; Trimble 1990). but there are no systematic reports on EP. Drake et al. (1989) reported an increase of latencies in visual and brain-stem EPs of epileptics on polypharmacy more than in patients on monotherapy; even if interference by polytherapy could be considered in 4 of our cases. the remaining patients were on Pb monotherapy, However. the observed changes of VEP seem to be closely related to Pb more than other drugs; in fact. a linear relationship was noted between P2 latency and Pb serum concentrations. Martinovi6 et al. (1990) noted that the P100 latency of the pattern-reversal VEP was prolonged, but not at a significant level, in long-term treated patients with poor seizure control, while significant changes of wave form were found by correlation analysis. Recently, Salas-Puig et al. (1992) reported a prolonged Nt9-P25 interval of the somatosensory EP in patients with idiopathic generalized epilepsy as compared with both controls and patients with juvenile myoclonic epilepsy, and these differences appeared more closely related to A E D than to other factors. Significant changes of EPs have been observed during anesthesia with barbiturates or other general anesthetics (Domino et al. 1963: Garcia-Larrea et al. 1993): major latency and amplitude changes of BAEPs. progressing to complete abolition of responses, have been noted during combined infusion of high doses of lidocaine and thiopental (Garcia-Larrea et al. 1988). Furthermore, Nogawa et al. (1991) reported significant changes of the VEP following the administration of anesthetics, with a drastic and sensitive prolongation of latency from the awake state to the stage where the E E G showed high voltage slow waves, and complete restoration to preanesthetic values after recovery from

PHENOBARBITAL AND EVOKED POTENTIALS anesthesia. In the present study, the effect of a chronic high Pb level in children with long-term antiepileptic therapy appears to be similar. In fact, we observed an abnormally increased value of the P2 latency of the V E P when serum concentration of Pb was more than 40 m g / l . These abnormal responses appear to be closely related to the effect of the drug, since the attainment of a normal serum concentration was associated with a normal P2 latency in all children but one. In this patient (case 3) the P2 latency decreased according to the reduction of the Pb serum level, but did not achieve normal limits; in this case, the abnormalities of VEPs were probably due to the presence of severe brain damage. One of the most interesting aspects of our observation was that 3 children with high serum levels of Pb did not show any clinical signs or symptoms of overt intoxication, while their VEPs had consistent delay of the P2 component. These abnormalities disappeared when serum concentrations of Pb were within normal limits. However, all patients showed subtle changes in behavior and cognitive functions during the period of high Pb levels; these aspects improved when the Pb serum concentration was reduced. The relationship between psychiatric symptoms and A E D s is still debated; recently, G e r e z and Tello (1992) studied the clinical relevance of topographic analysis of E E G and EP in psychiatric patients, by evaluating responses to some A E D s (carbamazepine, valproic acid, but not Pb), and found that subtle focal changes predicted good responses to treatment. In our sample, according to Trimble and Cull (1988), high levels of Pb seem to exacerbate existing behavioral problems, particularly hyperkinesis. Furthermore, poor visuo-motor coordination and slowing of information processing are specially mentioned as central effects of AEDs, particularly P H T and Pb, possibly induced by slowed central conduction (Green et al. 1982). In an early study, Hutt et al. (1968) gave Pb to normal volunteers for up to 1 month and found impairment of various measures of perceptual-motor performance which correlated with blood concentrations of the drug. In our sample, 5 patients showed poor performances on visuo-motor coordination during high Pb levels with improvement or remission when Pb levels decreased; in previous studies on epileptic children treated with Pb monotherapy we observed that the m e a n P2 latency was significantly longer during treatment than after drug withdrawal (Benedetti et al. 1986; Brinciotti et al. 1987). In the present sample, we found a positive regression coefficient between a high Pb serum concentration and P2 latency. Similar results have been noted in children with Pb serum levels within the normal range (Brinciotti et al. 1989). All these features support the hypothesis that the pharmacological effect of inhibition due to Pb may be detected by VEPs, and it may result in the

15 delay of the P2 component. According to ManonEspaillat et al. (1991), among central nervous structures the oculo-motor and vestibulo-cerebellar systems seem to be the most vulnerable and sensitive to high Pb levels. A prolonged P2 latency of the V E P could contribute to explain disturbances of visuo-motor coordination; these subtle side-effects of Pb may be related to changes of central conduction throughout the visual pathways, and VEPs appear sufficiently sensitive to discover these changes, even if clinical manifestations of overt drug toxicity are not yet evident. On the basis of our observations, in selected cases with high-dose Pb therapy, the recording of VEPs may be proposed as an additional non-invasive neurophysiological monitoring, since it appears to be more sensitive than clinical examination to show drug-related effects. On the contrary, no significant changes were noted in BAEPs in relation to Pb serum concentration, and all children but one had normal BAEPs during the period of Pb intoxication. Abnormal responses were observed only in case 1, who had a coexisting high level of PHT; in this patient, it seems likely that the abnormalities of the B A E P were due to the effect of this drug more than to Pb. In fact, the distribution of P H T in CNS is especially high in brain-stem and cerebellar structures (Laxer et al. 1980; Mameli et al. 1982), and abnormal BAEPs have been reported in epileptic patients treated with P H T (Green et al. 1982; Rodin et al. 1982). In conclusion, we emphasize the usefulness of a complete clinical, biochemical and neurophysiological study of patients with chronic high serum levels of Pb; the P2 latency of the VEP seems to be a sensitive p a r a m e t e r for monitoring subtle drug-related changes, and it may assist in the evaluation of subclinical sideeffects of the drug.

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M. BRINCIOTTI Martinovi6, ]',., Ristanovi6, D., Doki6-Ristanovi6, D. and Jovanovid, V. Pattern-reversal visual evoked potentials recorded in children with generalized epilepsy. Clin. Electroenceph., 1990, 21: 233-243. Nogawa, T., Katayama, K., Okuda, H. and Uchida, M. Changes in the latency of the maximum positive peak of visual evoked potentials during anesthesia, Nippon Geka Hoka, 1991, 61): 143153. Oxley, J.. Janz. D. and Meinardi. H. (Eds.). Chronic toxicity of Antiepileptic Drugs. Raven Press. New York. 1983. Ptaa. G.L. Acute toxicity of antiepileptic drugs. Epilepsia. 1975. 16: 183-191. Reynolds, E.H. and Trimble. M.R Adverse neuropsychiatric effects of anticonvulsant drugs. Drugs, 1985. 29: 570-581. Rodin. E.. Chavasirisobhon. S. and Klutke, G. Brainstem auditory evoked potential recording m patient with epilepsy. Clin. Electroenceph., 1982. 13: 154-161. Salas-Puig, J.. Tufion. A.. Diaz. M. and Lahoz. C.H. Somatosensory evoked potentials in juvenile myoclonic epilepsy. Epilepsia. 1992. 33: 527-530. Schmidt. S.D. (Ed.). Adverse Effects of Antiepileptic Drugs. Raven Press, New York, 1982. Shorvon. S.D. and Reynolds. E.H Anticonvulsant peripheral neu ropaty: a clinical and electrophysical study of patients on single drug treatment with phenytoin, carbamazepine or barbiturates. J. Neurol. Neurosurg. Psychiat., 1982.45: 620-626. Taylor, M.J. and McCulloch. D.L. Visual evoked potentials in infants and children. J. Clin. Neurophysiol., 1992, 9: 357-372. Trimble. M.R. Antiepileptie drugs, cognitive function, and behavior m children: evidence from recent studies. Epilepsia. 1990. 31 (Suppl. 4): $30-$34. Trimble. M.R. and Cull C. Children of school age: the influence of antiepileptic drugs on behavior and intellect. Epilepsia. 1988. 29 (Suppl. 3): S15-S19 Vining, EP.G.. Mellits, D.. Dorsen, M.M. et al. Psychok~gic and behavioural effects of antiepileptic drugs in children: a doubleblind comparison between phenobarbital and valproic acid Paediatrics. 1987. 80:165-174