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.
846
Letters to the Editor / Clinical Neurophysiology 126 (2015) 843–849
Fig. 1. EEG showed diffuse 2 Hz triphasic sharp and slow waves. Calibration bar 100 lV and vertical bars delineate 1 s.
References Abdennour L, Sanchez-Peña P, Galanaud D, Navarro V, Weiss N, Puybasset L. Gabapentin-induced coma: a MR-spectrometry analysis. Neuropsychiatr Dis Treat 2007;3:695–702. Dolphin AC. Calcium channel a2d subunits in epilepsy and as targets for antiepileptic drugs. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s Basic Mechanisms of the Epilepsies. 4th ed. Bethesda (MD): National Center for Biotechnology Information (US); 2012. Ricard C, Martin K, Tournier M, Bégaud B, Verdoux H. A case of Parkinsonian syndrome, cognitive impairment and hyperammonemia induced by divalproate sodium prescribed for bipolar disorder. Encephale 2005;31:98–101. Sechi G, Murgia B, Sau G, Peddone L, Tirotto A, Barrocu M, Rosati G. Asterixis and toxic encephalopathy induced by gabapentin. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:195–9. Sutter R, Stevens RD, Kaplan PW. Significance of triphasic waves in patients with acute encephalopathy: a nine-year cohort study. Clin Neurophysiol 2013;124:1952–8.
⇑
K. Beauvais Department of Clinical Neurophysiology, CHU, Dijon 21000, France ⇑ Corresponding author. Address: Department of Clinical Neurophysiology, CHU Le Bocage, Dijon 21000, France. Tel.: +33 3 80 29 37 54; fax: +33 3 80 29 33 15. E-mail address: [email protected] A. Disson-Dautriche Burgundy Regional Pharmacovigilance Centre, CHU, Dijon 21000, France A. Jacquin Department of Clinical Neurophysiology, CHU, Dijon 21000, France C. Antoniol Department of Clinical Neurophysiology, CHU, Dijon 21000, France M. Lemesle Martin Department of Clinical Neurophysiology, CHU, Dijon 21000, France
Available online 18 August 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.2014.07.016
Recruitment responses do not localize electrodes to thalamus
In their reply to the letter ‘‘Recruitment responses have no localizing value’’ (Osorio, 2015), Kim et al. (2015) stress the value of said responses for localizing electrodes to the thalamus, deeming it superior to atlas-based targeting methods. Recruitment responses may be elicited from white matter and from callosal fibers in animal with extensive thalamic lesions (Morin and Steriade, 1981; Ferster and Lindstrom, 1985; Nunez et al., 1993; Steriade et al., 1993) as well as from the caudate nucleus (Weinberger et al., 1965). Hence, recruitment responses have no localizing value. Conflict of interest statement None. References Ferster D, Lindstrom S. Augmenting responses evoked in area 17 of the cat by intracortical axonal collaterals of cortico-geniculate cells. J Physiol (Lond) 1985;367:217–32.
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.
846
Letters to the Editor / Clinical Neurophysiology 126 (2015) 843–849
Fig. 1. EEG showed diffuse 2 Hz triphasic sharp and slow waves. Calibration bar 100 lV and vertical bars delineate 1 s.
References Abdennour L, Sanchez-Peña P, Galanaud D, Navarro V, Weiss N, Puybasset L. Gabapentin-induced coma: a MR-spectrometry analysis. Neuropsychiatr Dis Treat 2007;3:695–702. Dolphin AC. Calcium channel a2d subunits in epilepsy and as targets for antiepileptic drugs. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s Basic Mechanisms of the Epilepsies. 4th ed. Bethesda (MD): National Center for Biotechnology Information (US); 2012. Ricard C, Martin K, Tournier M, Bégaud B, Verdoux H. A case of Parkinsonian syndrome, cognitive impairment and hyperammonemia induced by divalproate sodium prescribed for bipolar disorder. Encephale 2005;31:98–101. Sechi G, Murgia B, Sau G, Peddone L, Tirotto A, Barrocu M, Rosati G. Asterixis and toxic encephalopathy induced by gabapentin. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:195–9. Sutter R, Stevens RD, Kaplan PW. Significance of triphasic waves in patients with acute encephalopathy: a nine-year cohort study. Clin Neurophysiol 2013;124:1952–8.
⇑
K. Beauvais Department of Clinical Neurophysiology, CHU, Dijon 21000, France ⇑ Corresponding author. Address: Department of Clinical Neurophysiology, CHU Le Bocage, Dijon 21000, France. Tel.: +33 3 80 29 37 54; fax: +33 3 80 29 33 15. E-mail address: [email protected] A. Disson-Dautriche Burgundy Regional Pharmacovigilance Centre, CHU, Dijon 21000, France A. Jacquin Department of Clinical Neurophysiology, CHU, Dijon 21000, France C. Antoniol Department of Clinical Neurophysiology, CHU, Dijon 21000, France M. Lemesle Martin Department of Clinical Neurophysiology, CHU, Dijon 21000, France
Available online 18 August 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.2014.07.016
Recruitment responses do not localize electrodes to thalamus
In their reply to the letter ‘‘Recruitment responses have no localizing value’’ (Osorio, 2015), Kim et al. (2015) stress the value of said responses for localizing electrodes to the thalamus, deeming it superior to atlas-based targeting methods. Recruitment responses may be elicited from white matter and from callosal fibers in animal with extensive thalamic lesions (Morin and Steriade, 1981; Ferster and Lindstrom, 1985; Nunez et al., 1993; Steriade et al., 1993) as well as from the caudate nucleus (Weinberger et al., 1965). Hence, recruitment responses have no localizing value. Conflict of interest statement None. References Ferster D, Lindstrom S. Augmenting responses evoked in area 17 of the cat by intracortical axonal collaterals of cortico-geniculate cells. J Physiol (Lond) 1985;367:217–32.
