997
trinitrate to allow peripheral parenteral nutrition.’ Even the survival time cited for a feeding regimen of 720 mOsmol/kg (treatment 112 h vs control 67 h) is inaccurate. The correct medium infusion survival was 103 h (range 66-151) in the treatment group and 67 h (46-92) in the control group (log rank xz, p < 0’001).4 They used Mann Whitney U test for catheter survival comparison. We think that this test is not suitable and that life-table methods and log-rank test should have been used.s Furthermore, Cox proportional hazard important analysis would have adjusted for confounding effects of variables such as insertor, and age and sex of patients.6 Nonetheless, we recommend the use of peripheral parenteral nutrition as a holding regimen pending reappraisal of nutritional needs. This avoids complications of central venous cannulation, simplifies nursing care, reduces costs, and might prevent delay in initiating nutritional support. Furthermore, this route of delivery of nutrients is widely accepted by nursing staff and patients like 4 Firm III,
H. T. KHAWAJA M. MCCULLAGH
King’s College Hospital, London SE5 9RS, UK
1. Khawaja HT. Infusion phlebitis. Intens Ther Clin Monitoring 1988; 9: 190. 2 Archer DS, Fowler PD. Comparison of oxyphenbutazone and placebo in the treatment of superficial thrombophlebitis: an object lesson in clinical trial design. Practitioner 1977; 218: 3-5. 3. Khawaja HT, Campbell MJ, Weaver PC. Effect of transdermal glyceryl trinitrate on the survival of peripheral intravenous infusions: a double-blind prospective clinical study. Br J Surg 1988; 75: 1212-15. 4. Khawaja HT, Williams JD, Weaver PC. Transdermal glyceryl trinitrate to allow peripheral total parenteral nutrition: a double-blind placebo controlled feasibility study. J R Soc Med 1991; 84: 69-72. 5. Peto R, Pike MC, Armitage P. Design and analysis of randomized clinical trials requiring prolonged observation of each patient ii, analysis and examples. Br J Cancer 1977; 35: 1-39. 6. Cox DR. Regression models and life tables. J R Stat Soc B 1972; 34: 187-220.
Seizure induction and transcranial
magnetic
stimulation SiR,—Transcranial magnetic stimulation (TMS) may induce seizures in individuals with underlying brain lesions. TMS applied in single pulses at least 3 s apart has been reported to induce seizures in patients with recent stroke (l and Dr Fauth and colleagues’ letter, Feb 8, p 362) multiple sclerosisand epilepsy,3--s but not in healthy volunteers. A recently developed magnetic stimulator allows the delivery of TMS at a rapid rate (1-30 Hz).6 Dhuna et aF reported induction of after-discharges and a focal, secondarily generalised seizure in a patient with medically intractable partial epilepsy who received rapid-rate (16 Hz) TMS at 100% of the stimulator’s maximal output (about 2-5 T). We report here seizure induction with rapid-rate TMS in healthy people. During a safety study of rapid-rate TMS in ten healthy volunteers, a 35-year-old right-handed woman had a focal, secondarily generalised seizure after a 10 s train of TMS (10 Hz) delivered to the left motor cortex at 100% of maximum output. Two preceding identical trains of stimulation (5-10 min apart) had not caused difficulties. Her medical history was unremarkable and neurological examination was normal. A magnetic resonance scan and positron emission tomogram of her brain, obtained a month earlier as part of a different study, were normal. The seizure started as a simple partial motor seizure, characterised by arm abduction at the shoulder; it became secondarily generalised into a clonic-tonic-clonic convulsion that lasted for 57 s. Postictally, she was unresponsive for 3 min, and then confused for about 20 min. She had flaccid hemiparesis on the right side, which resolved over 35 min. The electroencephalogram retumed to normal within 45 min. At follow-up,1 and 5 weeks later, the neurological examination, neuropsychological testing, and electroencephalography revealed no abnormalities. When TMS is applied in pairs to the motor cortex, the response to the second stimulus may be inhibited or facilitated, depending on stimulus interval and intensity.8,9 When rapid-rate TMS is applied over the motor cortex, the movements evoked seem to increase in amplitude and complexity with each train (unpublished). For example, contralateral movements of the thumb progress, within a few pulses, to twitching of the entire hand with each stimulus,
rTMS
frequency (Hz)
Risk for spread of excitability induced bylostrainsof rapid-rate TMS (rTMS) applied to motor cortex of ten healthy volunteers as function of stimulus frequency and intensity.
"Always safe" means that rTMS, at frequencies and intensities shown, did not cause spread of excitability in any volunteer; "uncertain risk" means that rTMS caused spread of excitability in some; "always unsafe" means that rTMS caused the spread of excitability in all volunteers. Frequencies and intensities at which rTMS induced seizures in two individuals are indicated: 6 =volunteer reported here and A =epileptic patient from Dhuna et alB Both lie in the "always unsafe" range. followed by extension or flexion of the wrist and then the elbow, and occasionally even shoulder abduction or adduction. This spread of excitability may represent the first step in the failure of intracortical inhibition, which usually prevents the development of selfsustained cortical discharges. Therefore, the frequency and intensity of rapid-rate TMS should be lower than those that cause the spread of excitability (figure). The after-discharge threshold of the cortex to direct electrical stimulation is lowest in the motor cortex and rapid-rate TMS that is safe over the motor cortex should be safe over any other cortical area. This woman had the lowest motor threshold intensity (48% of maximum output) of the volunteers we studied so stimulus intensity, relative to threshold intensity, was higher than in the others. Single-pulse TMS may cause seizures in predisposed individuals, but the risk is low. Rapid-rate TMS is more likely to induce seizures, even in healthy volunteers. The risk depends on the intensity and frequency of the stimulus, and careful planning of the study will help prevent complications. In general, patients with epilepsy are at highest risk for the spread of excitability induced by rapid-rate TMS, since studies with TMS have shown that intracortical inhibition is less prominent in the hemisphere with the epileptogenic focuslo and that the baseline level of cortical excitability is higher (Feb 8, p 363). Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA
ALVARO PASCUAL-LEONE JOSEP VALLS-SOLÉ JOAQUIM P. BRASIL-NETO LEONARDO G. COHEN MARK HALLETT
seizures induced by transcranial magnetic stimulation of the motor cortex. Lancet 1989; 334: 1223. 2. Kandler R. Safety of transcranial magnetic stimulation. Lancet 1990; 335: 469-70. 3. Tassinari CA, Michelucci R, Forti A, et al. Transcranial magnetic stimulation in epileptic patients: usefulness and safety. Neurology 1990; 40: 1132-33. 4. Hufnagel A, Elger CE, Durwen HF, et al. Activation of the epileptic focus by transcranial magnetic stimulation of the human brain. Ann Neurol 1990; 27: 49-60. 5. Hufnagel A, Elger CE Induction of seizures by transcranial magnetic stimulation in epileptic patients. J Neurol 1991, 238: 109-10. 6. Pascual-Leone A, Gates JR, Dhuna A. Induction of speech arrest and counting errors with rapid-rate transcranial magnetic stimulation Neurology 1991; 41: 697-702. 7. Dhuna A, Gates J, Pascual-Leone A. Transcranial magnetic stimulation in patients with epilepsy Neurology 1991; 41: 1067-71. 8. Rothwell JC, Ferbert A, Caramia MD, et al. Intracortical inhibitory circuits studied in humans. Neurology 1991; 41 (suppl 1): 192. 9. Valls-Solé J, Pascual-Leone A, Wassermann EM, et al. Motor evoked responses to paired transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol (in
1. Homberg V, Netz J Generalised
press). 10. Wroe S, Kujirai T, Rothwell JC, et al. Cortical inhibition m the motor area of with focal epilepsy. Epilepsia (m press).
patients
trinitrate to allow peripheral parenteral nutrition.’ Even the survival time cited for a feeding regimen of 720 mOsmol/kg (treatment 112 h vs control 67 h) is inaccurate. The correct medium infusion survival was 103 h (range 66-151) in the treatment group and 67 h (46-92) in the control group (log rank xz, p < 0’001).4 They used Mann Whitney U test for catheter survival comparison. We think that this test is not suitable and that life-table methods and log-rank test should have been used.s Furthermore, Cox proportional hazard important analysis would have adjusted for confounding effects of variables such as insertor, and age and sex of patients.6 Nonetheless, we recommend the use of peripheral parenteral nutrition as a holding regimen pending reappraisal of nutritional needs. This avoids complications of central venous cannulation, simplifies nursing care, reduces costs, and might prevent delay in initiating nutritional support. Furthermore, this route of delivery of nutrients is widely accepted by nursing staff and patients like 4 Firm III,
H. T. KHAWAJA M. MCCULLAGH
King’s College Hospital, London SE5 9RS, UK
1. Khawaja HT. Infusion phlebitis. Intens Ther Clin Monitoring 1988; 9: 190. 2 Archer DS, Fowler PD. Comparison of oxyphenbutazone and placebo in the treatment of superficial thrombophlebitis: an object lesson in clinical trial design. Practitioner 1977; 218: 3-5. 3. Khawaja HT, Campbell MJ, Weaver PC. Effect of transdermal glyceryl trinitrate on the survival of peripheral intravenous infusions: a double-blind prospective clinical study. Br J Surg 1988; 75: 1212-15. 4. Khawaja HT, Williams JD, Weaver PC. Transdermal glyceryl trinitrate to allow peripheral total parenteral nutrition: a double-blind placebo controlled feasibility study. J R Soc Med 1991; 84: 69-72. 5. Peto R, Pike MC, Armitage P. Design and analysis of randomized clinical trials requiring prolonged observation of each patient ii, analysis and examples. Br J Cancer 1977; 35: 1-39. 6. Cox DR. Regression models and life tables. J R Stat Soc B 1972; 34: 187-220.
Seizure induction and transcranial
magnetic
stimulation SiR,—Transcranial magnetic stimulation (TMS) may induce seizures in individuals with underlying brain lesions. TMS applied in single pulses at least 3 s apart has been reported to induce seizures in patients with recent stroke (l and Dr Fauth and colleagues’ letter, Feb 8, p 362) multiple sclerosisand epilepsy,3--s but not in healthy volunteers. A recently developed magnetic stimulator allows the delivery of TMS at a rapid rate (1-30 Hz).6 Dhuna et aF reported induction of after-discharges and a focal, secondarily generalised seizure in a patient with medically intractable partial epilepsy who received rapid-rate (16 Hz) TMS at 100% of the stimulator’s maximal output (about 2-5 T). We report here seizure induction with rapid-rate TMS in healthy people. During a safety study of rapid-rate TMS in ten healthy volunteers, a 35-year-old right-handed woman had a focal, secondarily generalised seizure after a 10 s train of TMS (10 Hz) delivered to the left motor cortex at 100% of maximum output. Two preceding identical trains of stimulation (5-10 min apart) had not caused difficulties. Her medical history was unremarkable and neurological examination was normal. A magnetic resonance scan and positron emission tomogram of her brain, obtained a month earlier as part of a different study, were normal. The seizure started as a simple partial motor seizure, characterised by arm abduction at the shoulder; it became secondarily generalised into a clonic-tonic-clonic convulsion that lasted for 57 s. Postictally, she was unresponsive for 3 min, and then confused for about 20 min. She had flaccid hemiparesis on the right side, which resolved over 35 min. The electroencephalogram retumed to normal within 45 min. At follow-up,1 and 5 weeks later, the neurological examination, neuropsychological testing, and electroencephalography revealed no abnormalities. When TMS is applied in pairs to the motor cortex, the response to the second stimulus may be inhibited or facilitated, depending on stimulus interval and intensity.8,9 When rapid-rate TMS is applied over the motor cortex, the movements evoked seem to increase in amplitude and complexity with each train (unpublished). For example, contralateral movements of the thumb progress, within a few pulses, to twitching of the entire hand with each stimulus,
rTMS
frequency (Hz)
Risk for spread of excitability induced bylostrainsof rapid-rate TMS (rTMS) applied to motor cortex of ten healthy volunteers as function of stimulus frequency and intensity.
"Always safe" means that rTMS, at frequencies and intensities shown, did not cause spread of excitability in any volunteer; "uncertain risk" means that rTMS caused spread of excitability in some; "always unsafe" means that rTMS caused the spread of excitability in all volunteers. Frequencies and intensities at which rTMS induced seizures in two individuals are indicated: 6 =volunteer reported here and A =epileptic patient from Dhuna et alB Both lie in the "always unsafe" range. followed by extension or flexion of the wrist and then the elbow, and occasionally even shoulder abduction or adduction. This spread of excitability may represent the first step in the failure of intracortical inhibition, which usually prevents the development of selfsustained cortical discharges. Therefore, the frequency and intensity of rapid-rate TMS should be lower than those that cause the spread of excitability (figure). The after-discharge threshold of the cortex to direct electrical stimulation is lowest in the motor cortex and rapid-rate TMS that is safe over the motor cortex should be safe over any other cortical area. This woman had the lowest motor threshold intensity (48% of maximum output) of the volunteers we studied so stimulus intensity, relative to threshold intensity, was higher than in the others. Single-pulse TMS may cause seizures in predisposed individuals, but the risk is low. Rapid-rate TMS is more likely to induce seizures, even in healthy volunteers. The risk depends on the intensity and frequency of the stimulus, and careful planning of the study will help prevent complications. In general, patients with epilepsy are at highest risk for the spread of excitability induced by rapid-rate TMS, since studies with TMS have shown that intracortical inhibition is less prominent in the hemisphere with the epileptogenic focuslo and that the baseline level of cortical excitability is higher (Feb 8, p 363). Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA
ALVARO PASCUAL-LEONE JOSEP VALLS-SOLÉ JOAQUIM P. BRASIL-NETO LEONARDO G. COHEN MARK HALLETT
seizures induced by transcranial magnetic stimulation of the motor cortex. Lancet 1989; 334: 1223. 2. Kandler R. Safety of transcranial magnetic stimulation. Lancet 1990; 335: 469-70. 3. Tassinari CA, Michelucci R, Forti A, et al. Transcranial magnetic stimulation in epileptic patients: usefulness and safety. Neurology 1990; 40: 1132-33. 4. Hufnagel A, Elger CE, Durwen HF, et al. Activation of the epileptic focus by transcranial magnetic stimulation of the human brain. Ann Neurol 1990; 27: 49-60. 5. Hufnagel A, Elger CE Induction of seizures by transcranial magnetic stimulation in epileptic patients. J Neurol 1991, 238: 109-10. 6. Pascual-Leone A, Gates JR, Dhuna A. Induction of speech arrest and counting errors with rapid-rate transcranial magnetic stimulation Neurology 1991; 41: 697-702. 7. Dhuna A, Gates J, Pascual-Leone A. Transcranial magnetic stimulation in patients with epilepsy Neurology 1991; 41: 1067-71. 8. Rothwell JC, Ferbert A, Caramia MD, et al. Intracortical inhibitory circuits studied in humans. Neurology 1991; 41 (suppl 1): 192. 9. Valls-Solé J, Pascual-Leone A, Wassermann EM, et al. Motor evoked responses to paired transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol (in
1. Homberg V, Netz J Generalised
press). 10. Wroe S, Kujirai T, Rothwell JC, et al. Cortical inhibition m the motor area of with focal epilepsy. Epilepsia (m press).
patients
