Electroencephalography and clinical Neurophysiology, 83 (1992) 83-86
83
© 1992 Elsevier Scientific Publishers Ireland, Ltd. 0013-4649/92/$05.00
E E G 90601 Short communication
Electrophysiological
f i n d i n g s in a c a s e of s e v e r e i n t r a t h e c a l b a c l o f e n o v e r d o s e
Markus Kofler a, Leopold Saltuari a, Erich Schmutzhard a, Klaus Berek a, Holger Baumgartner b, Lothar Russegger c and Franz Aichner a " Department of Neurology, b Institute of Biochemical Pharmacology, and " Department ofNeurosurgery, Innsbruck Uni~'ersity, Innsbruck (Austria) (Accepted for publication: 18 March 1992)
Summary Multimodality evoked potentials were examined in a case of serious accidental intrathecal baclofen overdose in a patient who suffered from severe spasticity due to a traumatic brain lesion. Electrophysiological findings during, before and after the intoxication were compared. Transcranial electrical stimulation up to 750 V did not evoke any responses in thenar muscles on the first day of intoxication. An improvement to normal values was observed within 3 days, paralleled by an amelioration of the patient's clinical condition. Cervical electrical stimulation was largely unaffected by baclofen. Median nerve somatosensory and brain-stem acoustic evoked potentials revealed few or no differences during intoxication compared to pre- and post-intoxication responses. Key words: Evoked potentials; Baclofen; lntrathecal drug overdose
There are very few reports available on baclofen's influence on evoked potentials in h u m a n s (Miiller et al. 1987). We had the unique opportunity of testing mulfimodality evoked responses in a case of serious accidental intrathecal baclofen overdose leading to coma and respiratory arrest. Clinical and therapeutic aspects of this case have been previously reported (Saltuari et al. 1990).
Case report and methods A 16-year-old male with a 6 m o n t h history of head injury with right hemispheric contusional and subdural hematoma, brain e d e m a and transient compression of the brain-stem received baclofen intrathecally by m e a n s of a mechanical drug device. He suffered from severe spastic tetraparesis unresponsive to oral antispastic treatment which included up to 100 mg baclofen, 12 mg tizanidine, and 20 mg diazepam per day. During a refilling procedure of the p u m p reservoir 10 weeks after the implantation, a 10 mg bolus of baclofen was inadvertently delivered into the intrathecal space. Within 80 rain the patient presented with nystagmus, flaccidity, absence of tendon jerks, and coma and had to be intubated and artificially ventilated due to complete respiratory arrest. Within 6 days of symptomatic therapy including intravenous physostigmine, diazepam, phenytoin, clonazepam, ceftriaxon and subcutaneous heparin, the patient recovered gradually and regained the same neurological condition as before the intoxication. Multimodality evoked responses were tested regularly during the course of intoxication. They are compared to results obtained before and after the poisoning. Motor evoked potentials were obtained by bipolar transcranial and cervical electrical stimulation using a Digitimer D180. For transcranial stimulation electrical impulses of 750 V and a decay time of 50 tzsec were delivered through silver-silver chloride surface electrodes (diameter 10 mm) placed at Cz (cathode) and C3 (anode)
according to the 10-20 system. Neck stimulation was performed with electrodes placed over the fourth (anode) and seventh (cathode) cervical vertebra with a stimulus intensity of 525 V. Impedance was kept below 2 k J2. C o m p o u n d muscle action potentials (CMAPs) were recorded from the right thenar eminence with skin square electrodes (9 by 9 ram) attached to belly and tendon of the abductor pollicis brevis muscle (APB) and amplified 1000 times (transcranial evoked response) and 250 times (cervical evoked response), using an A A 6 Mklll amplifier. The low filter was set at 10 Hz, the high filter at 3000 Hz. Somatosensory evoked potentials were elicited by bipolar stimulation of the median nerve at the wrist. Electrical unipolar square waves with a duration of 0.2 msec were delivered at a rate of 5 Hz with an intensity of 10% above motor threshold. Recordings were obtained with silver-silver chloride disk electrodes (diameter 9 ram) placed over Erb's point using the contralateral side as reference and over the seventh cervical vertebra and the hand area of the contralateral sensory cortex (2 cm posterior to C 3 / C 4 according to the 10-20 system), both recorded with Fz as reference. Impedance was kept below 2 kg2. Three series of 512 responses were averaged over a period of 50 msec and amplified 10,000 or 25,000 times (Erb's point), 25,000 times (cervical), and 50,000 or 100,000 times (cortical), using an A A 6 MklII amplifier system. The low filter was set at 10 Hz, the high filter at 3000 Hz. Brain-stem acoustic evoked potentials were recorded bilaterally between mastoid and Fz with silver-silver chloride surface electrodes (diameter 9 m m ) after monaural stimulation with broad-band click impulses of 0.1 msec duration, alternating polarity, and an intensity of 80 dB H L at a repetition rate of 10 Hz. Two series of 1024 responses were averaged over a period of 10 msec and amplified 100,000 times using an A A 6 MklII amplifier system with the low filter set at 30 Hz and the high filter set at 1500 Hz.
Results
Correspondence to: Markus Kofler, M.D., D e p a r t m e n t of Neurology, Innsbruck University, Anichstrasse 35, A-6020 Innsbruck (Austria). Tel.: 0512 5044273; Fax: 0512 582339.
Two months before the patient's intoxication - during daily intrathecal application of 300 p.g baclofen - C M A P s of the right APB were obtained after contralateral transcranial stimulation of the
84
M. K O F L E R ET AL.
Stimulation
Cortical
I0
A Cervical
C
B
ms
D
Stimulation
iO
m8
Fig. 1. Motor evoked potentials (MEPs) of the right A P B muscle after electrical transcranial (upper traces) and cervical (lower traces) stimulation (two responses are superimposed). A: normal MEPs 2 months before intoxication. B: absent MEPs after transcranial stimulation and normal MEPs after neck stimulation on day 1 of intoxication. C: normal MEPs on day 3 of intoxication. D: normal MEPs 4 months after intoxication. Note different calibrations for transcranial and cervical evoked responses.
motor cortex with a latency of 21.5 msec, and a peak-to-peak amplitude of 3.7 inV. Neck stimulation revealed C M A P s of 7.8 mV with a latency'0f 15.0 msec (Fig. 1A and Table I).
On the day of the baclofen intoxication, 14 h after the acute event when the patient was comatose, electrical transcranial stimulation did not elicit any C M A P s over the right APB, whereas neck
TABLE 1 Latencies and amplitudes of motor evoked potentials (MEPs) obtained from the right APB muscle after electrical transcranial and cervical stimulation compared with normal values of 16 healthy subjects, and latencies and amplitudes of somatosensory evoked potentials (SSEPs) following right median nerve stimulation at the wrist (mean of 3 repetitions) compared with normal values of 24 healthy subjects. Time
MEPs 2 months pre-intoxication Intoxication day 1 Intoxication day 3 4 m o n t h s post-intoxication
Normal values (n = 16)
Cortical stimulation
Cervical stimulation
Latency (msec)
Peak-to-peak amplitude (mV)
Latency (msec)
Peak-to-peak amplitude (mV)
21.5 22.0 21.5
3.70 1.43 3.00
15.0 17.0 14.5 15.5
7.80 7.80 7.60 6.60
21.8 _+2.85 (R_+3 S.D.)
0.38-9.80 (range)
13.7+_3.54 (R + 3 S.D.)
1.52-13.70 (range)
Cervical response
Cortical response Latency (msec)
Peak-to-peak amplitude (uV)
Latency (msec)
Peak-to-peak amplitude (~V)
SSEPs 2 months pre-intoxication Intoxication day 3 4 months post-intoxication
20.4 21.5 20.5
1.79 0.83 1.58
14.2 14.2 14.2
2.13 0.63
Normal values (n = 24)
19.18 _+ 1.6 (~_+ 2.5 S.D.)
1.63-8.05 (range)
13.49 + 1.6 (~+ 2.5 S.D.)
1.73-5.33 (range)
1.83
SEVERE INTRATHECAL BACLOFEN OVERDOSE stimulation revealed similar responses as in the previous recording (Fig. 1B and Table I). Sixty-two hours after the incident right APB responses were obtained with a latency of 22.0 msec after transcranial and 14.5 msec after neck stimulation. The amplitude after transcranial stimulation had increased to 1.43 mV (Fig. 1C and Table I). At that particular time the patient was able to perform non-purposeful movements in response to noxious stimuli. The muscle tone was slightly higher than the previous day, tendon jerks had reappeared, and weaning from the respirator had just been commenced. A control examination on the sixth day after the intoxication showed no significant changes of amplitudes or latencies after transcranial or neck stimulation. In the meantime, the patient had regained consciousness, breathed spontaneously, and muscle tone and tendon jerks had increased to the same extent as before intrathecal baclofen treatment. Four months later no significant changes in the APB responses after electrical transcranial or neck stimulation were observed (Fig. 1D and Table I). Somatosensory evoked potentials examined 2 m o n t h s prior to the intoxication during intrathecal baclofen therapy revealed an absent cortical response over the right hemisphere and a left cortical response with a latency of 20.4 msec (Fig. 2A and Table I). No relevant differences were found 4 m o n t h s after intoxication (Fig. 2C and Table I). On the third day post intoxication, however, the amplitude of the cervical response (peak-to-peak N13 to the following positivity) and the left cortical response (N20 to P25) were decreased after right median nerve stimulation (Fig. 2B and Table I). Some cortical activity was obtained from the right hemisphere which was also noted in the follow-up evaluation. Brain-stem acoustic evoked potentials had already been abnormal before the intoxication due to a traumatic ponto-mesencephalie lesion and remained unchanged on the third day of the intoxication, as well as in a follow-up 4 m o n t h s later.
85 p,g and during continuous infusion of 150-600 p,g baclofen. To our knowledge, no observations have been published so far regarding baclofen's effect on evoked potentials in a dose exceeding the therapeutic range. Other GABA-related drugs, e.g., benzodiazepines and barbiturates, have been found to influence latencies and amplitudes in various ranges (Beric5 and Prevec 1984; Loughnan et al. 1987; Kochs and Schulte am Esch 1988; Koht et al. 1988; Rumpl et al. 1988; Kochs et al. 1989; Russ et al. 1989; Sch6nle et al. 1989; Z e n t n e r et al. 1989). The absence of transcranial motor evoked potentials during high dose intrathecal baclofen application, as we observed in our case, can be theoretically attributed to inhibition of the (1) segmental afferent sensory input, (2) spinal interneuron system (spinal premotor center), (3) anterior horn cells, and (4) corticospinal tract. Presynaptic inhibition of afferent sensory input in the dorsal horn is well documented (Zieglg~insberger et al. 1988), in higher concentrations baclofen has also been found to act postsynaptically (Davidoff 1985). A transient toxic effect on the anterior horn cells may also be possible. An axonal effect of baclofen seems unlikely, since amplitudes after neck stimulation remained unchanged. W h e t h e r a pure spinal effect would be sufficient to explain a complete loss of transcranial motor evoked potentials remains uncertain. An additional supraspinal influence seems likely, since the patient became comatose and developed respiratory failure. The changes in transcranial motor evoked responses were followed by an improvement in the patient's clinical condition: on the third day the electrophysiological findings were the same as before the intoxication with the clinical recovery from this event being completed by the sixth day. Muscle tone and tendon jerks had markedly increased to values obtained before intrathecal baclofen treatment. Neither clinical nor electrophysiological long-term adverse effects were noted up to 4 months after the intoxication. O u r observations suggest that high dose intrathecal baclofen has substantially more effect on motor evoked than on somatosensory or acoustic evoked potentials. W h e t h e r a supraspinal site of action contributes to these findings is not yet clear.
Discussion
Mi~ller et al. (1987) reported no changes of multimodality evoked potentials in 3 cases after intrathecal bolus applications of 100-400
The authors are grateful to Dr. A. Beri6, Baylor College of Medicine, Houston, TX, U.S.A., for his advice and revision of the manuscript.
Cortical
A
B
c
lOrns
Fig. 2. Somatosensory evoked potentials (SSEPs) following right median nerve stimulation at the wrist. U p p e r traces: cortical responses, lower traces: cervical responses (two responses are superimposed). A: SSEPs 2 m o n t h s before intoxication. B: SSEPs on day 3 of intoxication. C: SSEPs 4 m o n t h s after intoxication.
86 References
Berid, A. and Prevec, T.S. Effects of valium on the tibial nerve SEP. Pain, 1984, Suppl. 2: S162. Davidoff, R.A. Antispasticity drugs: mechanisms of action. Ann. Neurol., 1985, 17: 107-116. Kochs, E. and Schulte am Esch, J. Neurophysiologisches Monitoring (Elektroenzephalogramm, evozierte Potentiale) und Benzodiazepinwirkung. An~isth. Intensivther. Notfallmed., 1988, 23: 145152. Kochs, E., Wust, P., Blanc, I. and Schulte am Esch, J. Acoustic and somatosensory evoked cortical potentials in sedation with midazolam and drug antagonism with flumazenil. Aniisth. Intensivther. Notfallmed., 1989, 24: 49-56. Koht, A., Schlitz, W., Schmidt, G., Schramm, J. and Watanabe, E. Effects of etomidate, midazolam, and thiopental on median nerve somatosensory evoked potentials and the additive effects of fentanyl and nitrous oxide. Anesth. Analg., 1988, 67: 435-441. Loughnan, B.L., Sebel, P.S., Thomas, D., Rutherfoord, C.F. and Rogers, H. Evoked potentials following diazepam or fentanyl. Anaesthesia, 1987, 42: 195-198. Miiller, H., Zierski, J., Dralle, D., B6rner, U. and Hoffmann, O. The effect of intrathecal baclofen on electrical muscle activity in spasticity. J. Neurol., 1987, 234: 348-352.
M. KOFLER ET AL. Rumpl, E., Prugger, M., Battista, H.J., Badry, F., Gerstenbrand, F. and Dienstl, F. Short latency somatosensory evoked potentials and brain-stem auditory evoked potentials in coma due to CNS depressant drug poisoning. Preliminary observations. Electroenceph. clin. Neurophysiol., 1988, 70: 482-489. Russ, W., Kling, D., Schwandt, H.J., Krumholz, W. and Hempelmann, G. Effects of thiopentone and etomidate on median nerve somatosensory evoked responses. Neurol. Res., 1989, 11: 51-56. Saltuari, L., Baumgartner, H., Kofler, M., Schmutzhard, E., Russegger, L., Aichner, F. and Gerstenbrand, F. Failure of physostigmine in treatment of acute severe intrathecal baclofen intoxication. New Engl. J. Med., 1990, 322: 1533-1534. Sch6nle, P.W., Isenberg, C., Crozier, T.A., Dressier, D., Machetanz, J. and Conrad, B. Changes of transcranially evoked motor responses in man by midazolam, a short acting benzodiazepine. Neurosci. Lett., 1989, 101: 321-324. Zentner, J., Kiss, 1. and Ebner, A. Influence of anesthetics - nitrous oxide in particular - on electromyographic response evoked by transcranial electrical stimulation of the cortex. Neurosurgery, 1989, 24: 253-256. Zieglg~insberger, W., Howe, J.R. and Sutor, B. The neuropharmacology of baclofen. In: H. Miiller, J. Zierski and R.D. Penn (Eds.), Local-Spinal Therapy of Spasticity. Springer, Berlin, 1988: 37-49.
83
© 1992 Elsevier Scientific Publishers Ireland, Ltd. 0013-4649/92/$05.00
E E G 90601 Short communication
Electrophysiological
f i n d i n g s in a c a s e of s e v e r e i n t r a t h e c a l b a c l o f e n o v e r d o s e
Markus Kofler a, Leopold Saltuari a, Erich Schmutzhard a, Klaus Berek a, Holger Baumgartner b, Lothar Russegger c and Franz Aichner a " Department of Neurology, b Institute of Biochemical Pharmacology, and " Department ofNeurosurgery, Innsbruck Uni~'ersity, Innsbruck (Austria) (Accepted for publication: 18 March 1992)
Summary Multimodality evoked potentials were examined in a case of serious accidental intrathecal baclofen overdose in a patient who suffered from severe spasticity due to a traumatic brain lesion. Electrophysiological findings during, before and after the intoxication were compared. Transcranial electrical stimulation up to 750 V did not evoke any responses in thenar muscles on the first day of intoxication. An improvement to normal values was observed within 3 days, paralleled by an amelioration of the patient's clinical condition. Cervical electrical stimulation was largely unaffected by baclofen. Median nerve somatosensory and brain-stem acoustic evoked potentials revealed few or no differences during intoxication compared to pre- and post-intoxication responses. Key words: Evoked potentials; Baclofen; lntrathecal drug overdose
There are very few reports available on baclofen's influence on evoked potentials in h u m a n s (Miiller et al. 1987). We had the unique opportunity of testing mulfimodality evoked responses in a case of serious accidental intrathecal baclofen overdose leading to coma and respiratory arrest. Clinical and therapeutic aspects of this case have been previously reported (Saltuari et al. 1990).
Case report and methods A 16-year-old male with a 6 m o n t h history of head injury with right hemispheric contusional and subdural hematoma, brain e d e m a and transient compression of the brain-stem received baclofen intrathecally by m e a n s of a mechanical drug device. He suffered from severe spastic tetraparesis unresponsive to oral antispastic treatment which included up to 100 mg baclofen, 12 mg tizanidine, and 20 mg diazepam per day. During a refilling procedure of the p u m p reservoir 10 weeks after the implantation, a 10 mg bolus of baclofen was inadvertently delivered into the intrathecal space. Within 80 rain the patient presented with nystagmus, flaccidity, absence of tendon jerks, and coma and had to be intubated and artificially ventilated due to complete respiratory arrest. Within 6 days of symptomatic therapy including intravenous physostigmine, diazepam, phenytoin, clonazepam, ceftriaxon and subcutaneous heparin, the patient recovered gradually and regained the same neurological condition as before the intoxication. Multimodality evoked responses were tested regularly during the course of intoxication. They are compared to results obtained before and after the poisoning. Motor evoked potentials were obtained by bipolar transcranial and cervical electrical stimulation using a Digitimer D180. For transcranial stimulation electrical impulses of 750 V and a decay time of 50 tzsec were delivered through silver-silver chloride surface electrodes (diameter 10 mm) placed at Cz (cathode) and C3 (anode)
according to the 10-20 system. Neck stimulation was performed with electrodes placed over the fourth (anode) and seventh (cathode) cervical vertebra with a stimulus intensity of 525 V. Impedance was kept below 2 k J2. C o m p o u n d muscle action potentials (CMAPs) were recorded from the right thenar eminence with skin square electrodes (9 by 9 ram) attached to belly and tendon of the abductor pollicis brevis muscle (APB) and amplified 1000 times (transcranial evoked response) and 250 times (cervical evoked response), using an A A 6 Mklll amplifier. The low filter was set at 10 Hz, the high filter at 3000 Hz. Somatosensory evoked potentials were elicited by bipolar stimulation of the median nerve at the wrist. Electrical unipolar square waves with a duration of 0.2 msec were delivered at a rate of 5 Hz with an intensity of 10% above motor threshold. Recordings were obtained with silver-silver chloride disk electrodes (diameter 9 ram) placed over Erb's point using the contralateral side as reference and over the seventh cervical vertebra and the hand area of the contralateral sensory cortex (2 cm posterior to C 3 / C 4 according to the 10-20 system), both recorded with Fz as reference. Impedance was kept below 2 kg2. Three series of 512 responses were averaged over a period of 50 msec and amplified 10,000 or 25,000 times (Erb's point), 25,000 times (cervical), and 50,000 or 100,000 times (cortical), using an A A 6 MklII amplifier system. The low filter was set at 10 Hz, the high filter at 3000 Hz. Brain-stem acoustic evoked potentials were recorded bilaterally between mastoid and Fz with silver-silver chloride surface electrodes (diameter 9 m m ) after monaural stimulation with broad-band click impulses of 0.1 msec duration, alternating polarity, and an intensity of 80 dB H L at a repetition rate of 10 Hz. Two series of 1024 responses were averaged over a period of 10 msec and amplified 100,000 times using an A A 6 MklII amplifier system with the low filter set at 30 Hz and the high filter set at 1500 Hz.
Results
Correspondence to: Markus Kofler, M.D., D e p a r t m e n t of Neurology, Innsbruck University, Anichstrasse 35, A-6020 Innsbruck (Austria). Tel.: 0512 5044273; Fax: 0512 582339.
Two months before the patient's intoxication - during daily intrathecal application of 300 p.g baclofen - C M A P s of the right APB were obtained after contralateral transcranial stimulation of the
84
M. K O F L E R ET AL.
Stimulation
Cortical
I0
A Cervical
C
B
ms
D
Stimulation
iO
m8
Fig. 1. Motor evoked potentials (MEPs) of the right A P B muscle after electrical transcranial (upper traces) and cervical (lower traces) stimulation (two responses are superimposed). A: normal MEPs 2 months before intoxication. B: absent MEPs after transcranial stimulation and normal MEPs after neck stimulation on day 1 of intoxication. C: normal MEPs on day 3 of intoxication. D: normal MEPs 4 months after intoxication. Note different calibrations for transcranial and cervical evoked responses.
motor cortex with a latency of 21.5 msec, and a peak-to-peak amplitude of 3.7 inV. Neck stimulation revealed C M A P s of 7.8 mV with a latency'0f 15.0 msec (Fig. 1A and Table I).
On the day of the baclofen intoxication, 14 h after the acute event when the patient was comatose, electrical transcranial stimulation did not elicit any C M A P s over the right APB, whereas neck
TABLE 1 Latencies and amplitudes of motor evoked potentials (MEPs) obtained from the right APB muscle after electrical transcranial and cervical stimulation compared with normal values of 16 healthy subjects, and latencies and amplitudes of somatosensory evoked potentials (SSEPs) following right median nerve stimulation at the wrist (mean of 3 repetitions) compared with normal values of 24 healthy subjects. Time
MEPs 2 months pre-intoxication Intoxication day 1 Intoxication day 3 4 m o n t h s post-intoxication
Normal values (n = 16)
Cortical stimulation
Cervical stimulation
Latency (msec)
Peak-to-peak amplitude (mV)
Latency (msec)
Peak-to-peak amplitude (mV)
21.5 22.0 21.5
3.70 1.43 3.00
15.0 17.0 14.5 15.5
7.80 7.80 7.60 6.60
21.8 _+2.85 (R_+3 S.D.)
0.38-9.80 (range)
13.7+_3.54 (R + 3 S.D.)
1.52-13.70 (range)
Cervical response
Cortical response Latency (msec)
Peak-to-peak amplitude (uV)
Latency (msec)
Peak-to-peak amplitude (~V)
SSEPs 2 months pre-intoxication Intoxication day 3 4 months post-intoxication
20.4 21.5 20.5
1.79 0.83 1.58
14.2 14.2 14.2
2.13 0.63
Normal values (n = 24)
19.18 _+ 1.6 (~_+ 2.5 S.D.)
1.63-8.05 (range)
13.49 + 1.6 (~+ 2.5 S.D.)
1.73-5.33 (range)
1.83
SEVERE INTRATHECAL BACLOFEN OVERDOSE stimulation revealed similar responses as in the previous recording (Fig. 1B and Table I). Sixty-two hours after the incident right APB responses were obtained with a latency of 22.0 msec after transcranial and 14.5 msec after neck stimulation. The amplitude after transcranial stimulation had increased to 1.43 mV (Fig. 1C and Table I). At that particular time the patient was able to perform non-purposeful movements in response to noxious stimuli. The muscle tone was slightly higher than the previous day, tendon jerks had reappeared, and weaning from the respirator had just been commenced. A control examination on the sixth day after the intoxication showed no significant changes of amplitudes or latencies after transcranial or neck stimulation. In the meantime, the patient had regained consciousness, breathed spontaneously, and muscle tone and tendon jerks had increased to the same extent as before intrathecal baclofen treatment. Four months later no significant changes in the APB responses after electrical transcranial or neck stimulation were observed (Fig. 1D and Table I). Somatosensory evoked potentials examined 2 m o n t h s prior to the intoxication during intrathecal baclofen therapy revealed an absent cortical response over the right hemisphere and a left cortical response with a latency of 20.4 msec (Fig. 2A and Table I). No relevant differences were found 4 m o n t h s after intoxication (Fig. 2C and Table I). On the third day post intoxication, however, the amplitude of the cervical response (peak-to-peak N13 to the following positivity) and the left cortical response (N20 to P25) were decreased after right median nerve stimulation (Fig. 2B and Table I). Some cortical activity was obtained from the right hemisphere which was also noted in the follow-up evaluation. Brain-stem acoustic evoked potentials had already been abnormal before the intoxication due to a traumatic ponto-mesencephalie lesion and remained unchanged on the third day of the intoxication, as well as in a follow-up 4 m o n t h s later.
85 p,g and during continuous infusion of 150-600 p,g baclofen. To our knowledge, no observations have been published so far regarding baclofen's effect on evoked potentials in a dose exceeding the therapeutic range. Other GABA-related drugs, e.g., benzodiazepines and barbiturates, have been found to influence latencies and amplitudes in various ranges (Beric5 and Prevec 1984; Loughnan et al. 1987; Kochs and Schulte am Esch 1988; Koht et al. 1988; Rumpl et al. 1988; Kochs et al. 1989; Russ et al. 1989; Sch6nle et al. 1989; Z e n t n e r et al. 1989). The absence of transcranial motor evoked potentials during high dose intrathecal baclofen application, as we observed in our case, can be theoretically attributed to inhibition of the (1) segmental afferent sensory input, (2) spinal interneuron system (spinal premotor center), (3) anterior horn cells, and (4) corticospinal tract. Presynaptic inhibition of afferent sensory input in the dorsal horn is well documented (Zieglg~insberger et al. 1988), in higher concentrations baclofen has also been found to act postsynaptically (Davidoff 1985). A transient toxic effect on the anterior horn cells may also be possible. An axonal effect of baclofen seems unlikely, since amplitudes after neck stimulation remained unchanged. W h e t h e r a pure spinal effect would be sufficient to explain a complete loss of transcranial motor evoked potentials remains uncertain. An additional supraspinal influence seems likely, since the patient became comatose and developed respiratory failure. The changes in transcranial motor evoked responses were followed by an improvement in the patient's clinical condition: on the third day the electrophysiological findings were the same as before the intoxication with the clinical recovery from this event being completed by the sixth day. Muscle tone and tendon jerks had markedly increased to values obtained before intrathecal baclofen treatment. Neither clinical nor electrophysiological long-term adverse effects were noted up to 4 months after the intoxication. O u r observations suggest that high dose intrathecal baclofen has substantially more effect on motor evoked than on somatosensory or acoustic evoked potentials. W h e t h e r a supraspinal site of action contributes to these findings is not yet clear.
Discussion
Mi~ller et al. (1987) reported no changes of multimodality evoked potentials in 3 cases after intrathecal bolus applications of 100-400
The authors are grateful to Dr. A. Beri6, Baylor College of Medicine, Houston, TX, U.S.A., for his advice and revision of the manuscript.
Cortical
A
B
c
lOrns
Fig. 2. Somatosensory evoked potentials (SSEPs) following right median nerve stimulation at the wrist. U p p e r traces: cortical responses, lower traces: cervical responses (two responses are superimposed). A: SSEPs 2 m o n t h s before intoxication. B: SSEPs on day 3 of intoxication. C: SSEPs 4 m o n t h s after intoxication.
86 References
Berid, A. and Prevec, T.S. Effects of valium on the tibial nerve SEP. Pain, 1984, Suppl. 2: S162. Davidoff, R.A. Antispasticity drugs: mechanisms of action. Ann. Neurol., 1985, 17: 107-116. Kochs, E. and Schulte am Esch, J. Neurophysiologisches Monitoring (Elektroenzephalogramm, evozierte Potentiale) und Benzodiazepinwirkung. An~isth. Intensivther. Notfallmed., 1988, 23: 145152. Kochs, E., Wust, P., Blanc, I. and Schulte am Esch, J. Acoustic and somatosensory evoked cortical potentials in sedation with midazolam and drug antagonism with flumazenil. Aniisth. Intensivther. Notfallmed., 1989, 24: 49-56. Koht, A., Schlitz, W., Schmidt, G., Schramm, J. and Watanabe, E. Effects of etomidate, midazolam, and thiopental on median nerve somatosensory evoked potentials and the additive effects of fentanyl and nitrous oxide. Anesth. Analg., 1988, 67: 435-441. Loughnan, B.L., Sebel, P.S., Thomas, D., Rutherfoord, C.F. and Rogers, H. Evoked potentials following diazepam or fentanyl. Anaesthesia, 1987, 42: 195-198. Miiller, H., Zierski, J., Dralle, D., B6rner, U. and Hoffmann, O. The effect of intrathecal baclofen on electrical muscle activity in spasticity. J. Neurol., 1987, 234: 348-352.
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