109 show significant changes during the A Z T therapy. Abnormalities observed on the brain M R I in three of five patients were stable as were somatosensory and brainstem auditory EPs, which were and remained abnormal in four and three patients respectively. Moreover, the percentage of lymphoid cells with abnormal nuclei and of activated T-cell ( D R + ) , which are considered to be correlated with the viral load [1], remained stable. These findings suggest that zidovudine does not affect the encephalomyelopathic process associated with H T L V - 1 , in the dose range used. Further studies must assess the clinical outcome of a longer treatment to account for the possibility of a clinically stable state of a few years. Moreover, higher dosages in less disabled patients (i.e. at the onset of the disease) m a y help to control the chronic evolution of this disease. Acknowledgement. This study was supported by a grant from Assistance Publique-H6pitaux de Paris.
References 1. Gessain A, Saal F, Gout O, Daniel MT, Flandrin G, Th6 G de, P6ri6s J, Sigaux F (1990) High human T-cell lymphotropic virus type i proviral DNA load with polyclonal integration in peripheral blood mononuclear cells of French West Indian, Guianese and African patients with tropical spastic paraparesis. Blood 75 : 428-433 2. Gout O, Baulac M, Gessain A, Semah F, Saal F, P6ri~s J, Cabrol C, Foucault-Fretz C, Laplane D, Th6 G de (1990) Rapid development of myelopathy after HTLV-1 infection acquired by transfusion during cardiac transplantation. N Engl J Med 322: 383-388 3. Matsushita S, Mitsuya H, Reitz MS, Broder S (1987) Pharmacological inhibition of in vitro infectivity of human T lymphotropic virus type 1. J Clin Invest 80 : 393-400 4. Roman G, Vernant JC, Osame M (eds) (1989) HTLV-1 and the nervous system. (Neurology and neurobiology, vol 51) Liss, New York 5. Tendler CJ, Greenberg SJ, Blattner WA, Manns A, Murphy E, Fleisher T, Hanchard B, Morgan O, Burton JD, Nelson DL, Waldmann TA (1990) Transactivation of interleukin 2 and its receptor induces immune activation in human T-cell lymphotropic virus type 1-associated myelopathy: pathogenic implications and a rationale for immunotherapy. Proc Natl Acad Sci USA 87 : 5218-5222
Induction of seizures by transcranial magnetic stimulation in epileptic patients Andreas Hufnagel and ChristianE. Elger Universit~itsklinik ftir Epileptologie, Sigmund-Freud-Strasse 25, W-5300 Bonn, Federal Republic of Germany Received October 31, 1990/Accepted December 10, 1990
Sirs: Transcranial magnetic stimulation (TMS) is now available in m a n y neurophysiological laboratories and is on the brink of becoming a routine method. The induction of epileptic seizures has rarely b e e n described [3-7]. With regard to safety aspects it m a y be of interest to further elucidate the circumstances which p r o m o t e the induction of seizures by TMS in epileptic patients who theoretically bear the highest risk [1-9]. We have summarized our clinical experience accumulated during several studies which have b e e n published [5-7] or which are in press [4]. A total of 183 series of TMS was p e r f o r m e d in 140 epileptic patients either to evaluate m o t o r evoked potentials (n = 101; 135 series) [7] or to attempt activation of the epileptic focus in the process of presurgical evaluation of epilepsy (n = 39; 48 series) [4-6]. T h e great majority of patients had medically intractable complex focal seizures of temporal lobe origin. We used a Novametrix Magstim 200 stimulator, which has a m a x i m u m magnetic field strength of 1.5T, connected to either a 7-cm or a 14-cm outer diameter circular coil. U p to 80 stimuli were applied to the vertex at 65-100% of the m a x i m u m output for evaluation of m o t o r evoked potentials. A m a x i m u m of 350 stimuli was applied at 70-100% stimulation intensity mainly to the central and temporal brain areas for "focal activation". Details of the techniques have been described elsewhere [1, 4-7]. Four clinical seizures and one aura occurred during the course of the investigation after application of 56, 61, 78,174 and 71 stimuli respectively. A n o t h e r two seizures and one aura were observed within 5 min after termination of the investigation and application of a total of 350 stimuli within approximately 40-60 min. No seizure was induced in a control group of 141 volunteers who received up to 80 stimuli. It can be argued that these seizures were spontaneous. However, electrocorticographic recordings via subdural electrodes (n = 6) p e r f o r m e d during the invasive phase of presurgical evaluation demonstrated that at least two of the seizures which occurred during the a t t e m p t e d "focal activation" were most likely to have been induced. In these 2 patients a progressive build-up of epileptiform afterdischarge was seen in the epileptogenic area prior to the induction of the seizure. The following circumstances a p p e a r e d to favour the occurrence of seizures during or shortly after TMS: Offprint requests to: A. Hufnagel
110
1. Anticonvulsants below therapeutical level. In 6 of the 8 patients the anticonvulsant medication had b e e n almost completely s t o p p e d during the invasive phase ot presurgical evaluation and only m i n i m u m serum levels of anticonvulsant medication were detectable. Conversely, only two seizures o c c u r r e d in 85 patients who had therapeutic serum levels of anticonvulsant medication. 2. Continuous epileptiforrn activity prior to TMS. Elect r o c o r t i c o g r a p h i c monitoring was available in 6 of the patients in w h o m a seizure was induced. T h e spontaneous f r e q u e n c y of spikes or sharp waves per minute immediately prior to T M S was m o r e than 30 in 4 of the patients and b e t w e e n 10 and 30 in the remaining 2 patients.
3. High frequency of spontaneous complex partial seizure of temporal lobe origin. T h e s p o n t a n e o u s seizure freq u e n c y in all 8 patients was high (minimum: 4 / m o n t h ; m a x i m u m : 2 8 / m o n t h ; average: 14.8/month). In all patients the s p o n t a n e o u s seizures could be classified as c o m p l e x partial and of t e m p o r a l lobe origin.
4. Proximity of spontaneous seizures. Seven of 8 patients had had 1 - 5 ( m e a n = 0 . 8 5 / d a y ) s p o n t a n e o u s seizures during the last 48 h preceding TMS.
5. TMS over the epileptic focus. O f the 5 patients in w h o m a seizure or aura was induced during serial TMS, 3 were stimulated o v e r the epileptic focus at the time the seizure occurred. T h e remaining 2 patients were stimulated at the vertex. In n o n e of the 8 patients was an increase of the spontan e o u s seizure f r e q u e n c y or any other deleterious effect n o t e d after cessation of the investigation.
In conclusion, the presented data indicate that the overall probability of inducing an epileptic seizure by T M S in epileptic patients is lower than 5%. Additional p r o v o k i n g circumstances a p p e a r to be necessary.
References 1. Barker AT, Freeston IL, Jalinous R, Jarrat JA (1987) Magnetic stimulation of the human brain and peripheral nervous system: an introduction and the results of an initial clinical evaluation. Neurosurgery 20:100-109 2. Bridgers SL, Delaney RC (1989) Assessment of short-term effects of magnetic cortical stimulation. Neurology 39 : 417-419 3. H6mberg V, Netz J (1989) Generalised seizure induced by transcranial magnetic stimulation of the motor cortex. Lancet II : 1223 4. Hufnagel A, Elger CE (1990) Responses of the epileptic focus to transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol (in press) 5. Hufnagel A, Elger CE, Durwen HF, B6ker DK, Entzian W (1990) Activation of the epileptic focus by transcranial magnetic stimulation of the human brain. Ann Neurol 27 : 49-60 6. Hufnagel A, Elger CE, Klingmtiller D, Zierz S, Kramer R (1990) Activation of epileptic loci by transcranial magnetic stimulation: effects on secretion of prolactin and luteinizing hormone. J Neurol 237 : 224-246 7. Hufnagel A, Elger CE, Marx W, Ising A (1990) Magnetic motor evoked potentials in epilepsy: effects of the disease and of anticonvulsant medication. Ann Neurol 28 : 680-686 8. Kandler R (1990) Safety of transcranial magnetic stimulation. Lancet I : 469-470 9. Michelucci R, Rubboli G, Plasmati R (1989) Transcranial magnetic stimulation of the cerebral cortex in epilepsy. Neurology 39 [Suppl 1] : 414
References 1. Gessain A, Saal F, Gout O, Daniel MT, Flandrin G, Th6 G de, P6ri6s J, Sigaux F (1990) High human T-cell lymphotropic virus type i proviral DNA load with polyclonal integration in peripheral blood mononuclear cells of French West Indian, Guianese and African patients with tropical spastic paraparesis. Blood 75 : 428-433 2. Gout O, Baulac M, Gessain A, Semah F, Saal F, P6ri~s J, Cabrol C, Foucault-Fretz C, Laplane D, Th6 G de (1990) Rapid development of myelopathy after HTLV-1 infection acquired by transfusion during cardiac transplantation. N Engl J Med 322: 383-388 3. Matsushita S, Mitsuya H, Reitz MS, Broder S (1987) Pharmacological inhibition of in vitro infectivity of human T lymphotropic virus type 1. J Clin Invest 80 : 393-400 4. Roman G, Vernant JC, Osame M (eds) (1989) HTLV-1 and the nervous system. (Neurology and neurobiology, vol 51) Liss, New York 5. Tendler CJ, Greenberg SJ, Blattner WA, Manns A, Murphy E, Fleisher T, Hanchard B, Morgan O, Burton JD, Nelson DL, Waldmann TA (1990) Transactivation of interleukin 2 and its receptor induces immune activation in human T-cell lymphotropic virus type 1-associated myelopathy: pathogenic implications and a rationale for immunotherapy. Proc Natl Acad Sci USA 87 : 5218-5222
Induction of seizures by transcranial magnetic stimulation in epileptic patients Andreas Hufnagel and ChristianE. Elger Universit~itsklinik ftir Epileptologie, Sigmund-Freud-Strasse 25, W-5300 Bonn, Federal Republic of Germany Received October 31, 1990/Accepted December 10, 1990
Sirs: Transcranial magnetic stimulation (TMS) is now available in m a n y neurophysiological laboratories and is on the brink of becoming a routine method. The induction of epileptic seizures has rarely b e e n described [3-7]. With regard to safety aspects it m a y be of interest to further elucidate the circumstances which p r o m o t e the induction of seizures by TMS in epileptic patients who theoretically bear the highest risk [1-9]. We have summarized our clinical experience accumulated during several studies which have b e e n published [5-7] or which are in press [4]. A total of 183 series of TMS was p e r f o r m e d in 140 epileptic patients either to evaluate m o t o r evoked potentials (n = 101; 135 series) [7] or to attempt activation of the epileptic focus in the process of presurgical evaluation of epilepsy (n = 39; 48 series) [4-6]. T h e great majority of patients had medically intractable complex focal seizures of temporal lobe origin. We used a Novametrix Magstim 200 stimulator, which has a m a x i m u m magnetic field strength of 1.5T, connected to either a 7-cm or a 14-cm outer diameter circular coil. U p to 80 stimuli were applied to the vertex at 65-100% of the m a x i m u m output for evaluation of m o t o r evoked potentials. A m a x i m u m of 350 stimuli was applied at 70-100% stimulation intensity mainly to the central and temporal brain areas for "focal activation". Details of the techniques have been described elsewhere [1, 4-7]. Four clinical seizures and one aura occurred during the course of the investigation after application of 56, 61, 78,174 and 71 stimuli respectively. A n o t h e r two seizures and one aura were observed within 5 min after termination of the investigation and application of a total of 350 stimuli within approximately 40-60 min. No seizure was induced in a control group of 141 volunteers who received up to 80 stimuli. It can be argued that these seizures were spontaneous. However, electrocorticographic recordings via subdural electrodes (n = 6) p e r f o r m e d during the invasive phase of presurgical evaluation demonstrated that at least two of the seizures which occurred during the a t t e m p t e d "focal activation" were most likely to have been induced. In these 2 patients a progressive build-up of epileptiform afterdischarge was seen in the epileptogenic area prior to the induction of the seizure. The following circumstances a p p e a r e d to favour the occurrence of seizures during or shortly after TMS: Offprint requests to: A. Hufnagel
110
1. Anticonvulsants below therapeutical level. In 6 of the 8 patients the anticonvulsant medication had b e e n almost completely s t o p p e d during the invasive phase ot presurgical evaluation and only m i n i m u m serum levels of anticonvulsant medication were detectable. Conversely, only two seizures o c c u r r e d in 85 patients who had therapeutic serum levels of anticonvulsant medication. 2. Continuous epileptiforrn activity prior to TMS. Elect r o c o r t i c o g r a p h i c monitoring was available in 6 of the patients in w h o m a seizure was induced. T h e spontaneous f r e q u e n c y of spikes or sharp waves per minute immediately prior to T M S was m o r e than 30 in 4 of the patients and b e t w e e n 10 and 30 in the remaining 2 patients.
3. High frequency of spontaneous complex partial seizure of temporal lobe origin. T h e s p o n t a n e o u s seizure freq u e n c y in all 8 patients was high (minimum: 4 / m o n t h ; m a x i m u m : 2 8 / m o n t h ; average: 14.8/month). In all patients the s p o n t a n e o u s seizures could be classified as c o m p l e x partial and of t e m p o r a l lobe origin.
4. Proximity of spontaneous seizures. Seven of 8 patients had had 1 - 5 ( m e a n = 0 . 8 5 / d a y ) s p o n t a n e o u s seizures during the last 48 h preceding TMS.
5. TMS over the epileptic focus. O f the 5 patients in w h o m a seizure or aura was induced during serial TMS, 3 were stimulated o v e r the epileptic focus at the time the seizure occurred. T h e remaining 2 patients were stimulated at the vertex. In n o n e of the 8 patients was an increase of the spontan e o u s seizure f r e q u e n c y or any other deleterious effect n o t e d after cessation of the investigation.
In conclusion, the presented data indicate that the overall probability of inducing an epileptic seizure by T M S in epileptic patients is lower than 5%. Additional p r o v o k i n g circumstances a p p e a r to be necessary.
References 1. Barker AT, Freeston IL, Jalinous R, Jarrat JA (1987) Magnetic stimulation of the human brain and peripheral nervous system: an introduction and the results of an initial clinical evaluation. Neurosurgery 20:100-109 2. Bridgers SL, Delaney RC (1989) Assessment of short-term effects of magnetic cortical stimulation. Neurology 39 : 417-419 3. H6mberg V, Netz J (1989) Generalised seizure induced by transcranial magnetic stimulation of the motor cortex. Lancet II : 1223 4. Hufnagel A, Elger CE (1990) Responses of the epileptic focus to transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol (in press) 5. Hufnagel A, Elger CE, Durwen HF, B6ker DK, Entzian W (1990) Activation of the epileptic focus by transcranial magnetic stimulation of the human brain. Ann Neurol 27 : 49-60 6. Hufnagel A, Elger CE, Klingmtiller D, Zierz S, Kramer R (1990) Activation of epileptic loci by transcranial magnetic stimulation: effects on secretion of prolactin and luteinizing hormone. J Neurol 237 : 224-246 7. Hufnagel A, Elger CE, Marx W, Ising A (1990) Magnetic motor evoked potentials in epilepsy: effects of the disease and of anticonvulsant medication. Ann Neurol 28 : 680-686 8. Kandler R (1990) Safety of transcranial magnetic stimulation. Lancet I : 469-470 9. Michelucci R, Rubboli G, Plasmati R (1989) Transcranial magnetic stimulation of the cerebral cortex in epilepsy. Neurology 39 [Suppl 1] : 414
