844
Letters to the Editor / Clinical Neurophysiology 126 (2015) 843–849
Technology and Academic Research. Dr. Deng, Dr. Lisanby, and Dr. Peterchev are inventors on a patent application related to deep transcranial magnetic stimulation coils and on other TMS technology patents and patent applications. Dr. Lisanby has served as Principal Investigator on industry-sponsored research Grants to Columbia/RFMH or Duke (Neuronetics (past), Brainsway, ANS/St. Jude Medical, Cyberonics (past)); equipment loans to Columbia or Duke (Magstim, MagVenture); is supported by Grants from NIH (R01MH091083-01, 5U01MH084241-02, 5R01MH06088409), Stanley Medical Research Institute, National Alliance for Research on Schizophrenia and Depression, and the Wallace H. Coulter Foundation; and has no consultancies, speakers bureau memberships, board affiliations, or equity holdings in related industries. Dr. Peterchev has served as Principal Investigator on a research grant to Duke from Rogue Research and equipment donations to Columbia (Magstim, ANS/St. Jude Medical); has received patent royalties from Rogue Research through Columbia for technology unrelated to this manuscript; and is supported by Grants from NIH (R01MH091083) and the Wallace H. Coulter Foundation. References Deng ZD, Lisanby SH, Peterchev AV. Electric field strength and focality in electroconvulsive therapy and magnetic seizure therapy: a finite element simulation study. J Neural Eng 2011;8:016007. Deng ZD, Lisanby SH, Peterchev AV. Electric field depth–focality tradeoff in transcranial magnetic stimulation: simulation comparison of 50 coil designs. Brain Stimulation 2013;6:1–13. Deng ZD, Lisanby SH, Peterchev AV. Coil design considerations for deep transcranial magnetic stimulation. Clin Neurophysiol 2014;125:1202–12. Lontis ER, Voigt M, Struijk JJ. Focality assessment in transcranial magnetic stimulation with double and cone coils. J Clin Neurophysiol 2006;23:463–72. Roth Y, Padberg F, Zangen A. Transcranial magnetic stimulation of deep brain regions: principles and methods. In: Marcolin MA, Padberg F, editors. Transcranial brain stimulation for treatment of psychiatric disorders. Basel: Karger; 2007. p. 204–24. Roth Y, Zangen A. Basic principles and methodological aspects of transcranial magnetic stimulation. In: Miniussi C, Paulus W, Rossini PM, editors. Transcranial brain stimulation. Boca Raton, USA: CRC Press; 2013. p. 3–39. Roth Y, Pell GS, Chistyakov AV, Sinai A, Zangen A, Zaaroor M. Motor cortex activation by H-coil and figure-8 coil at different depths. Combined motor threshold and electric field distribution study. Clin Neurophysiol 2014;125:336–43.
⇑
Zhi-De Deng Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA ⇑ Address: Division of Brain Stimulation and Neurophysiology, Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, 200 Trent Drive, Durham, NC 27710, USA. Tel.: +1 919 564 5282; fax: +1 919 681 8744. E-mail address: [email protected]
Reply to ‘‘On the stimulation depth of transcranial magnetic stimulation coils’’
We read with great interest the recent Letter by Deng et al. (2015) following our recent paper (Roth et al., 2014), and we thank them for the opportunity to clarify the issues. In their Letter the authors refer to the values of d½ as defined in their previous review (Deng et al., 2013) for the Magstim figure-8 coil (Magstim P/N 9925, 3190, d½ = 1.41) and for the double cone coil (Magstim P/N 9902, d½ = 1.98). That review considered some H-coils versions, such as the H2 coil (d½ = 2.32) and the HADD coil (d½ = 2.43). These values of d½ are significantly higher than the value found for the double cone coil, indicating that the rate of decay of electric field with distance from the double cone coil is significantly faster compared to various versions of H-coils. A more accurate method of field characterization than computer simulation using spherical head model (Deng et al., 2013, 2014) can be obtained using actual field measurements in a realistic shape head model. The electric field decay profile as a function of distance from the coil, normalized to its value 1.5 cm from coil, is shown in Fig. 1 for the Magstim figure-8 coil, the Magstim double cone coil, and the Brainsway. H-MCDEEP coil which was presented in Roth et al. (2014), based on measurements in a realistic shape model of the human head, filled with physiological saline solution. This head model treats the brain as a homogeneous volume conductor and does not account for the brain tissue heterogeneity. Yet it does reproduce the realistic shape of the head surface. It can be seen that the H-MCDEEP coil has a significant advantage over the double cone coil with respect to depth penetration, and that in most depth points the double cone coil values are closer to those of the figure-8 coil than to the H-MCDEEP coil. At depth of 5 cm, for instance, the H-MCDEEP coil has an advantage of 32% over the double cone coil and of 72% over the figure-8 coil, while the advantage of the double cone coil over the figure-8 coil is of only 30%. Acknowledgements Dr. Roth and Prof. Zangen are inventors of deep TMS coils and have financial interests in Brainsway Inc. Dr. Pell is an employee of Brainsway Inc. Drs. Chistyakov and Sinai and Prof. Zaaroor have no financial interests to report.
Sarah H. Lisanby Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA Department of Psychology and Neuroscience, Duke University, Durham, NC, USA Angel V. Peterchev Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA Department of Electrical and Computer Engineering, Duke University, Durham, NC, USA Available online 19 July 2014 1388-2457/ Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2014.06.048
Fig. 1. The electric field normalized to its value at 1.5 cm from coil as a function of distance from the coil is shown for the double cone coil, in addition to the figure-8 coil and the H-MCDEEP coil (Roth et al., 2014).
Letters to the Editor / Clinical Neurophysiology 126 (2015) 843–849
References Deng ZD, Lisanby SH, Peterchev AV. Electric field depth–focality tradeoff in transcranial magnetic stimulation: simulation comparison of 50 coil designs. Brain Stimul 2013;6:1–13. Deng Z-D, Lisanby SH, Peterchev AV. On the stimulation depth of transcranial magnetic stimulation coils. Clin Neurophysiol 2015;126:843–4. Roth Y, Pell GS, Chistyakov AV, Sinai A, Zangen A, Zaaroor M. Motor cortex activation by H-coil and figure-8 coil at different depths. Combined motor threshold and electric field distribution study. Clin Neurophysiol 2014;125:336–43.
⇑
Yiftach Roth Department of Life Sciences, Ben-Gurion University of the Negev, POB 653, Be’er Sheva 84105, Israel ⇑ Tel.: +972 52 5665875; fax: +972 2 5812517. E-mail address: [email protected] Gaby S. Pell Department of Life Sciences, Ben-Gurion University, Be’er Sheva, Israel Andrei V. Chistyakov Department of Neurosurgery, Rambam Health Care Campus and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel Alon Sinai Department of Neurosurgery, Rambam Health Care Campus, Haifa, Israel Department of Neurology, Rambam Health Care Campus, Haifa, Israel Abraham Zangen Department of Life Sciences, Ben-Gurion University, Be’er Sheva, Israel Menashe Zaaroor Department of Neurosurgery, Rambam Health Care Campus and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel Available online 18 July 2014 1388-2457/ Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2014.07.009
Gabapentin-induced encephalopathy
An 85-year-old woman was admitted at hospital for sudden dysarthria and left brachio-facial palsy that disappeared within three hours. Two identical episodes had occurred in the past 4 months. She had a past medical history of hypertension, adult onset diabetes, hypercholesterolemia, cognitive impairment (MMSE: 23/30) and was treated with bisoprolol, irbesartan, atorvastatin, repaglinide, esomeprazole and lysine acetylsalicylate. Strokes or transient ischemic attacks in the middle cerebral artery territory were initially suspected. Magnetic resonance imaging showed neither stroke nor lacunar infarcts but diffuse cortical atrophy and small periventricular high-signal on T2-weighted images consistent with leukoaraiosis. MR angiography of the circle of Willis did not visualise stenosis. Electrocardiogram (ECG) was normal. Initial EEG showed slowing of the dominant rhythm in the theta range. Nevertheless Gabapentin (GBT) therapy for possible partial seizures was introduced to a daily dose of 300 mg on the first day then 900 mg per day. Five days later, the patient developed fluctuating confusion with deterioration of memory and time
845
disorientation. On the same day an EEG showed diffuse 2 Hz triphasic sharp and slow waves (Fig. 1). Serum electrolytes, glucose, erythrocyte sedimentation rate, liver, kidney, thyroid function tests, vitamin B 12 were normal. Creatinine clearance was 70 ml/ min. Ammonemia was 104 lmol/l (normal range, 11–32) the day following the beginning of the neurological symptoms. An adverse event of GBT was suspected and the drug was discontinued. Two days later, the patient had recovered her usual clinical state and the EEG returned to normal three days after the onset of the confusion. Ammonemia was still up to 189 lmol/l four days later then began to decrease one month later (112 lmol/l). In this case, the time course of clinical events argued for the diagnosis of GBT-induced encephalopathy. The patient developed cognitive deterioration and fluctuating confusional state which occurred few days after introduction of GBT and rapidly disappeared after it was discontinued. Even if we did not reintroduce the drug, the cause and effect relationship between the exposure to GBT and the onset of encephalopathy was probable. Indeed the recovery was complete and the EEG returned to normal within few days after GBT withdrawal. The time course was incompatible with the role of other concomitant drugs. Furthermore, other causes of metabolic encephalopathy were excluded as hepatic, uremic, hypo-glycemia encephalopathies, serum metabolites abnormalities or vitamin deficiencies. No overdose with GBT may be suspected with a normal creatinine clearance. Reversible encephalopathies were already described with numerous antiepileptic drugs, as valproate (Ricard et al., 2005). Rarely, it was also described after intake of vigabatrin, lamotrigine, topiramate, tiagabine or after overdose with levetiracetam and pregabalin. They could be triggered by a too fast introduction of high doses (Ricard et al., 2005). There are just 2 previous reports with gabapentin-induced encephalopathies. EEG with a metabolic pattern (triphasic waves) was described in only one case (Abdennour et al., 2007) and Sechi et al. (2004) described a patient who developed asterixis and encephalopathy after treatment by GBT at a dose of 900–3600 mg/day, with slowing of the dominant rhythm on EEG. The EEG during acute encephalopathy reveals slowing of background activity and sometimes triphasic waves (TW) but EEG pattern has little specificity. In our patient EEG was done before, then during confusion, and after gabapentin was discontinued (returned to normal). TW are also observed in hepatic and uremic encephalopathies or with medication as lithium, baclofen, and antiepileptic drugs. Sutter et al. (2013) suggested that TW are a marker of structural brain disease coupled with toxic-metabolic abnormalities. In our case, we did not find metabolic disorders which could explain TW. The pathogenesis of this GBT-induced encephalopathy remains elusive. Hyperammonemia could be involved. However, in the case of Abdennour et al. (2007), the symptoms occurred 5 days before increase of ammonemia. As in our patient, hyperammonemia is probably the consequence of GBT toxicity rather than the cause of the encephalopathy itself: first, we observed a peak of ammonium level while our patient had recovered her usual clinical state; second, this ammonium level was still elevated 3 weeks after withdrawal of GBT. Another explanation for mechanism of GBT-induced encephalopathy may be metabolic, which was in our case ruled out by normal hepatic, kidney, thyroid tests and serum metabolites. A third explanation could be an intrinsic effect on cerebral receptors. The mechanism of action of GBT is related to interactions with voltage-gated calcium channels (Dolphin, 2012). It enhances the activity of gamma aminobutyric acid (GABA), increasing inhibitory neurotransmission. In rare patients, this pro-GABAergic action could surpass its objective and trigger neuronal perturbations.
Letters to the Editor / Clinical Neurophysiology 126 (2015) 843–849
Technology and Academic Research. Dr. Deng, Dr. Lisanby, and Dr. Peterchev are inventors on a patent application related to deep transcranial magnetic stimulation coils and on other TMS technology patents and patent applications. Dr. Lisanby has served as Principal Investigator on industry-sponsored research Grants to Columbia/RFMH or Duke (Neuronetics (past), Brainsway, ANS/St. Jude Medical, Cyberonics (past)); equipment loans to Columbia or Duke (Magstim, MagVenture); is supported by Grants from NIH (R01MH091083-01, 5U01MH084241-02, 5R01MH06088409), Stanley Medical Research Institute, National Alliance for Research on Schizophrenia and Depression, and the Wallace H. Coulter Foundation; and has no consultancies, speakers bureau memberships, board affiliations, or equity holdings in related industries. Dr. Peterchev has served as Principal Investigator on a research grant to Duke from Rogue Research and equipment donations to Columbia (Magstim, ANS/St. Jude Medical); has received patent royalties from Rogue Research through Columbia for technology unrelated to this manuscript; and is supported by Grants from NIH (R01MH091083) and the Wallace H. Coulter Foundation. References Deng ZD, Lisanby SH, Peterchev AV. Electric field strength and focality in electroconvulsive therapy and magnetic seizure therapy: a finite element simulation study. J Neural Eng 2011;8:016007. Deng ZD, Lisanby SH, Peterchev AV. Electric field depth–focality tradeoff in transcranial magnetic stimulation: simulation comparison of 50 coil designs. Brain Stimulation 2013;6:1–13. Deng ZD, Lisanby SH, Peterchev AV. Coil design considerations for deep transcranial magnetic stimulation. Clin Neurophysiol 2014;125:1202–12. Lontis ER, Voigt M, Struijk JJ. Focality assessment in transcranial magnetic stimulation with double and cone coils. J Clin Neurophysiol 2006;23:463–72. Roth Y, Padberg F, Zangen A. Transcranial magnetic stimulation of deep brain regions: principles and methods. In: Marcolin MA, Padberg F, editors. Transcranial brain stimulation for treatment of psychiatric disorders. Basel: Karger; 2007. p. 204–24. Roth Y, Zangen A. Basic principles and methodological aspects of transcranial magnetic stimulation. In: Miniussi C, Paulus W, Rossini PM, editors. Transcranial brain stimulation. Boca Raton, USA: CRC Press; 2013. p. 3–39. Roth Y, Pell GS, Chistyakov AV, Sinai A, Zangen A, Zaaroor M. Motor cortex activation by H-coil and figure-8 coil at different depths. Combined motor threshold and electric field distribution study. Clin Neurophysiol 2014;125:336–43.
⇑
Zhi-De Deng Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA ⇑ Address: Division of Brain Stimulation and Neurophysiology, Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, 200 Trent Drive, Durham, NC 27710, USA. Tel.: +1 919 564 5282; fax: +1 919 681 8744. E-mail address: [email protected]
Reply to ‘‘On the stimulation depth of transcranial magnetic stimulation coils’’
We read with great interest the recent Letter by Deng et al. (2015) following our recent paper (Roth et al., 2014), and we thank them for the opportunity to clarify the issues. In their Letter the authors refer to the values of d½ as defined in their previous review (Deng et al., 2013) for the Magstim figure-8 coil (Magstim P/N 9925, 3190, d½ = 1.41) and for the double cone coil (Magstim P/N 9902, d½ = 1.98). That review considered some H-coils versions, such as the H2 coil (d½ = 2.32) and the HADD coil (d½ = 2.43). These values of d½ are significantly higher than the value found for the double cone coil, indicating that the rate of decay of electric field with distance from the double cone coil is significantly faster compared to various versions of H-coils. A more accurate method of field characterization than computer simulation using spherical head model (Deng et al., 2013, 2014) can be obtained using actual field measurements in a realistic shape head model. The electric field decay profile as a function of distance from the coil, normalized to its value 1.5 cm from coil, is shown in Fig. 1 for the Magstim figure-8 coil, the Magstim double cone coil, and the Brainsway. H-MCDEEP coil which was presented in Roth et al. (2014), based on measurements in a realistic shape model of the human head, filled with physiological saline solution. This head model treats the brain as a homogeneous volume conductor and does not account for the brain tissue heterogeneity. Yet it does reproduce the realistic shape of the head surface. It can be seen that the H-MCDEEP coil has a significant advantage over the double cone coil with respect to depth penetration, and that in most depth points the double cone coil values are closer to those of the figure-8 coil than to the H-MCDEEP coil. At depth of 5 cm, for instance, the H-MCDEEP coil has an advantage of 32% over the double cone coil and of 72% over the figure-8 coil, while the advantage of the double cone coil over the figure-8 coil is of only 30%. Acknowledgements Dr. Roth and Prof. Zangen are inventors of deep TMS coils and have financial interests in Brainsway Inc. Dr. Pell is an employee of Brainsway Inc. Drs. Chistyakov and Sinai and Prof. Zaaroor have no financial interests to report.
Sarah H. Lisanby Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA Department of Psychology and Neuroscience, Duke University, Durham, NC, USA Angel V. Peterchev Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA Department of Electrical and Computer Engineering, Duke University, Durham, NC, USA Available online 19 July 2014 1388-2457/ Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2014.06.048
Fig. 1. The electric field normalized to its value at 1.5 cm from coil as a function of distance from the coil is shown for the double cone coil, in addition to the figure-8 coil and the H-MCDEEP coil (Roth et al., 2014).
Letters to the Editor / Clinical Neurophysiology 126 (2015) 843–849
References Deng ZD, Lisanby SH, Peterchev AV. Electric field depth–focality tradeoff in transcranial magnetic stimulation: simulation comparison of 50 coil designs. Brain Stimul 2013;6:1–13. Deng Z-D, Lisanby SH, Peterchev AV. On the stimulation depth of transcranial magnetic stimulation coils. Clin Neurophysiol 2015;126:843–4. Roth Y, Pell GS, Chistyakov AV, Sinai A, Zangen A, Zaaroor M. Motor cortex activation by H-coil and figure-8 coil at different depths. Combined motor threshold and electric field distribution study. Clin Neurophysiol 2014;125:336–43.
⇑
Yiftach Roth Department of Life Sciences, Ben-Gurion University of the Negev, POB 653, Be’er Sheva 84105, Israel ⇑ Tel.: +972 52 5665875; fax: +972 2 5812517. E-mail address: [email protected] Gaby S. Pell Department of Life Sciences, Ben-Gurion University, Be’er Sheva, Israel Andrei V. Chistyakov Department of Neurosurgery, Rambam Health Care Campus and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel Alon Sinai Department of Neurosurgery, Rambam Health Care Campus, Haifa, Israel Department of Neurology, Rambam Health Care Campus, Haifa, Israel Abraham Zangen Department of Life Sciences, Ben-Gurion University, Be’er Sheva, Israel Menashe Zaaroor Department of Neurosurgery, Rambam Health Care Campus and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel Available online 18 July 2014 1388-2457/ Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2014.07.009
Gabapentin-induced encephalopathy
An 85-year-old woman was admitted at hospital for sudden dysarthria and left brachio-facial palsy that disappeared within three hours. Two identical episodes had occurred in the past 4 months. She had a past medical history of hypertension, adult onset diabetes, hypercholesterolemia, cognitive impairment (MMSE: 23/30) and was treated with bisoprolol, irbesartan, atorvastatin, repaglinide, esomeprazole and lysine acetylsalicylate. Strokes or transient ischemic attacks in the middle cerebral artery territory were initially suspected. Magnetic resonance imaging showed neither stroke nor lacunar infarcts but diffuse cortical atrophy and small periventricular high-signal on T2-weighted images consistent with leukoaraiosis. MR angiography of the circle of Willis did not visualise stenosis. Electrocardiogram (ECG) was normal. Initial EEG showed slowing of the dominant rhythm in the theta range. Nevertheless Gabapentin (GBT) therapy for possible partial seizures was introduced to a daily dose of 300 mg on the first day then 900 mg per day. Five days later, the patient developed fluctuating confusion with deterioration of memory and time
845
disorientation. On the same day an EEG showed diffuse 2 Hz triphasic sharp and slow waves (Fig. 1). Serum electrolytes, glucose, erythrocyte sedimentation rate, liver, kidney, thyroid function tests, vitamin B 12 were normal. Creatinine clearance was 70 ml/ min. Ammonemia was 104 lmol/l (normal range, 11–32) the day following the beginning of the neurological symptoms. An adverse event of GBT was suspected and the drug was discontinued. Two days later, the patient had recovered her usual clinical state and the EEG returned to normal three days after the onset of the confusion. Ammonemia was still up to 189 lmol/l four days later then began to decrease one month later (112 lmol/l). In this case, the time course of clinical events argued for the diagnosis of GBT-induced encephalopathy. The patient developed cognitive deterioration and fluctuating confusional state which occurred few days after introduction of GBT and rapidly disappeared after it was discontinued. Even if we did not reintroduce the drug, the cause and effect relationship between the exposure to GBT and the onset of encephalopathy was probable. Indeed the recovery was complete and the EEG returned to normal within few days after GBT withdrawal. The time course was incompatible with the role of other concomitant drugs. Furthermore, other causes of metabolic encephalopathy were excluded as hepatic, uremic, hypo-glycemia encephalopathies, serum metabolites abnormalities or vitamin deficiencies. No overdose with GBT may be suspected with a normal creatinine clearance. Reversible encephalopathies were already described with numerous antiepileptic drugs, as valproate (Ricard et al., 2005). Rarely, it was also described after intake of vigabatrin, lamotrigine, topiramate, tiagabine or after overdose with levetiracetam and pregabalin. They could be triggered by a too fast introduction of high doses (Ricard et al., 2005). There are just 2 previous reports with gabapentin-induced encephalopathies. EEG with a metabolic pattern (triphasic waves) was described in only one case (Abdennour et al., 2007) and Sechi et al. (2004) described a patient who developed asterixis and encephalopathy after treatment by GBT at a dose of 900–3600 mg/day, with slowing of the dominant rhythm on EEG. The EEG during acute encephalopathy reveals slowing of background activity and sometimes triphasic waves (TW) but EEG pattern has little specificity. In our patient EEG was done before, then during confusion, and after gabapentin was discontinued (returned to normal). TW are also observed in hepatic and uremic encephalopathies or with medication as lithium, baclofen, and antiepileptic drugs. Sutter et al. (2013) suggested that TW are a marker of structural brain disease coupled with toxic-metabolic abnormalities. In our case, we did not find metabolic disorders which could explain TW. The pathogenesis of this GBT-induced encephalopathy remains elusive. Hyperammonemia could be involved. However, in the case of Abdennour et al. (2007), the symptoms occurred 5 days before increase of ammonemia. As in our patient, hyperammonemia is probably the consequence of GBT toxicity rather than the cause of the encephalopathy itself: first, we observed a peak of ammonium level while our patient had recovered her usual clinical state; second, this ammonium level was still elevated 3 weeks after withdrawal of GBT. Another explanation for mechanism of GBT-induced encephalopathy may be metabolic, which was in our case ruled out by normal hepatic, kidney, thyroid tests and serum metabolites. A third explanation could be an intrinsic effect on cerebral receptors. The mechanism of action of GBT is related to interactions with voltage-gated calcium channels (Dolphin, 2012). It enhances the activity of gamma aminobutyric acid (GABA), increasing inhibitory neurotransmission. In rare patients, this pro-GABAergic action could surpass its objective and trigger neuronal perturbations.
