Reversible Splenial Lesion Syndrome (RESLES) Following Glufosinate Ammonium Poisoning Tae Oh Jeong, Jae Chol Yoon, Jae Baek Lee, Young Ho Jin, Seung Bae Hwang From the Research Institute of Clinical Medicine of Chonbuk National University, Emergency Medicine, Jeonju-si, Republic of Korea (TOJ, JCY, JBL, YHJ); and Chonbuk National University Medical School and Hospital, Radiology, Jeonju-si, Republic of Korea (SBH).
ABSTRACT Isolated and reversible lesion restricted to the splenium of the corpus callosum, known as reversible splenial lesion syndrome, have been reported in patients with infection, high-altitude cerebral edema, seizures, antiepileptic drug withdrawal, or metabolic disturbances. Here, we report a 39-year-old female patient with glufosinate ammonium (GLA) poisoning who presented with confusion and amnesia. Diffusion-weighted magnetic resonance imaging of the brain revealed cytotoxic edema of the splenium of the corpus callosum. The lesion was not present on follow-up MR imaging performed 9 months later. We postulate that a GLA-induced excitotoxic mechanism was the cause of this reversible splenial lesion. Keywords: Corpus callosum, cytotoxic edema, glufosinate ammonium. Acceptance: Received September 1, 2014, and in revised form December 30, 2014. Accepted for publication January 2, 2015. Correspondence: Address correspondence to Jae Chol Yoon, Research Institute of Clinical Medicine of Chonbuk National University, Emergency Medicine, Jeonju-si, Republic of Korea. E-mail: [email protected] J Neuroimaging 2015;25:1050-1052. DOI: 10.1111/jon.12216
Introduction Reversible splenial lesion syndrome (RESLES) is characterized by the absence of lesion-related symptoms and reversible, nonenhancing, oval-shaped, and centrally located high signal intensity lesion in the splenium of the corpus callosum (SCC) on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images.1 In a review of RESLES, lesions were associated with various etiologies, including epilepsy, infection, metabolic disturbances, or other causes.2 The similar asymptomatic clinical features and imaging results of reversible focal lesions in the SCC suggest a common mechanism induced by different pathological events leading to the same outcome. Usually, diffusion-weighted images (DWI) show restricted diffusion with low apparent diffusion coefficient (ADC) values.2 Diffuse tensor images performed in epilepsy-related RESLES reveal symmetrical and intact fibers3 or decreased functional anisotropy4 during the acute phase. Coupled with reversible clinical course and lack of neuronal dysfunction, these imaging findings suggest that RESLES is due to glial cytotoxic edema and/or intramyelinic edema. Glufosinate ammonium (GLA), a phosphinic acid derivative of glutamate, is a nonselective herbicide.5 The clinical manifestations associated with GLA poisoning are classified as early gastrointestinal symptoms due to the irritant effect of surfactant on mucosa and delayed neurologic symptoms, such as mental status change, convulsions, or amnesia.6 Central nervous system lesions associated with GLA poisoning include ischemic white matter changes,6 cytotoxic edema of the hippocampus,7 and vasogenic edema of the basal ganglia.8 In this article, we describe a female patient who ingested GLA and developed RESLES.
200 mL of BASTA (18% GLA) in attempted suicide. She had received gastric lavage followed by charcoal instillation at a local clinic very soon after ingestion. She was then transferred to our hospital. Her initial vital signs were stable and she was alert. Seven hours postadmission, she complained of memory disturbances regarding her ingestion. Twenty-two hours postadmission, she became drowsy and her oxygen saturation on pulse oximetry decreased to 65-70%. ABGA revealed respiratory acidosis with a pH of 7.234, PO2 of 40.8 mmHg, PCO2 of 59.7 mmHg, and HCO3 of 25.4 mmol/L. Chest X-ray revealed increased pulmonary vascular markings and parenchymal opacities in both lungs, compatible with pulmonary edema. Supportive care and endotracheal intubation with assisted ventilation were initiated. Following 17 hours of ventilator care, she was fully alert. Because she was responsive, extubation was performed. Her initial ammonia level was 52.2 umol/L (reference range 11.2-35.4 umol/L), which increased to 82.1 umol/L 2 days after admission and then declined. Followup clinical examination showed that the patient was unable to recall what happened during the 3 months preceding ingestion and what had occurred postingestion. We attributed this retrograde and anterograde amnesia to GLA poisoning. Brain magnetic resonance imaging (MRI) and MRA performed on day 5 showed a focal ovoid hyperintense lesion in the SCC on DWI, T2-weighted images, and FLAIR images. This lesion had a low ADC value and no contrast enhancement (Fig 1). The patient was discharged with persistent amnesia on day 6. Follow-up MRI performed at 9 months after discharge demonstrated that the lesion in the SCC had completely resolved (Fig 2).
Discussion Case Report A 39-year-old previously healthy woman presented to the emergency department 2 hours after ingestion of approximately 1050
Copyright
Cytotoxic edema of the SCC has a known excitotoxic mechanism.9 Excitotoxic brain edema results from increased extracellular glutamate,10 released from the presynaptic
◦ 2015 by the American Society of Neuroimaging C
Fig 1. Axial T2-weighted (A) and FLAIR (B) images reveal a focal, ovoid, and centrally located hyperintense lesion in the splenium of the corpus callosum (thin arrow). This lesion is hyperintense on DWI (C) and shows restricted diffusion on ADC map (D; black arrowhead). Postcontrast axial T1-weighted image after gadolinium administration (E) shows no contrast enhancement (thick arrow).
Fig 2. On follow-up MR imaging performed at 9 months later discharge, axial T2-weighted (A) and FLAIR (B) images show that the lesion seen on initial MR images is completely resolved (thin arrow). DWI (C) and ADC map (D) show complete reversal of diffusion restriction (black arrowhead).
terminals of neuronal axons into the synaptic cleft and removed by reuptake in the presynaptic terminal or adjacent glial cells.11 Because of their abundant high-affinity glutamate transporters, astrocytes are critically important for protection against neuronal injury due to glutamate. Astrocytes regulate the concentration of extracellular glutamate via reuptake by glutamate transporters and convert glutamate to nontoxic glutamine by glutamine synthetase (GS).12 In conditions associated with decreased glutamate reuptake via astrocytes or myelin, increased glutamate release due to leakage, or the presence of a structurally similar substance, extracellular glutamate can accumulate to cause excitotoxic injury.10 Excessive glutamate causes cell death or cytotoxic edema via binding to N-methyl-D-aspartate (NMDA) receptors and non-NMDA receptors, respectively.13 Sodium (Na+ ) and calcium (Ca2+ ) eventually enter glial cells and the myelin sheath to cause water diffusion. In addition, brief glutamate exposure causes astrocytes to swell by activating glutamate transporters.14 Because astrocytes and myelin have glutamate receptors and transporters, excitotoxicity and edema of these cells prevent acute-phase neuronal damage. This explains why this type of edema is reversible and asymptomatic in many cases.2 The edema is usually transitory, and MRI signal changes normalize with time or following removal of the causative pathologic factors.9 Our patient had none of the etiologic causes discussed in the Garcia et al review of RESLES, such as epilepsy-related, infection, metabolic, or miscellaneous. BASTA is composed of GLA as the active ingredient and sodium polyoxyethylene alkylether sulfate (AES) as a surfactant. Of theses, AES is a common anionic type surfactant with a moderate toxicity and is considered Jeong et al: Reversible Splenial Lesion Syndrome
1051
to cause circulatory failure via cardiosuppressive and vasodilatory action in extremely severe intoxication.15 Koyama suggested that the central nervous system signs of acute human BASTA poisoning are essentially due to its main component, GLA.16 GLA was considered the causative agent of RESLES in this case. The mechanisms of GLA-induced RESLES are discussed here. First, GLA can increase extracellular glutamate through GS inhibition in the brain. GLA is a broad-spectrum herbicide that inhibits plant GS, leading to complete inhibition of glutamine synthesis from glutamate and ammonia.5 GLA also inhibits GS in laboratory animals and induces elevation of glutamate and ammonia.17 Ohtake et al showed a reduction in CSF glutamine concentration and suggested that GLA inhibits GS activity in the brain.18 In addition, GS inhibition by L-methionine-S-sulfoximine weakened glutamate clearance by astrocytes in an in vitro study.19 Second, GLA is a structural analogue of glutamate and can directly stimulate the glutamate receptor. The intraperitoneal administration of GLA at doses higher than 40 mg/kg caused convulsions in mice. An NMDA receptor antagonist significantly prolonged the onset of convulsions caused by GLA, suggesting that GLA stimulates NMDA receptors.20 Third, hyperammonemia associated with GLA poisoning can cause astrocyte swelling. Delayed hyperammonemia following massive GLA ingestion is associated with late-onset neurological manifestations that are considered to be induced by significant GS inhibition.21 Primary cultured astrocytes treated with ammonium chloride (NH4 Cl) swelled significantly in a vitro study,22 but ammonia-induced swelling can be attenuated by GS inhibition.23 It is not clear why reversible excitotoxic edema selectively involves the SCC. In epilepsy-related RESLES, the SCC has been postulated as a vulnerable structure because of its close functional relationship with limbic and temporal lobe structures that are critical to the spread of excitation of seizure.9 However, this concept cannot be generalized to other conditions. The predilection of the SCC to edema is partially explained by its large number of glutamate receptors and high enzymatic activity.24 Patients with RESLES are usually asymptomatic, and brain imaging studies incidentally detect lesions in the search for a cause of neuropsychiatric symptoms associated with underlying conditions. In summary, when brain imaging studies are performed in patients with GLA poisoning, one should consider that GLA can cause reversible cytotoxic edema in the SCC.
References 1. Garcia-Monco JC, Martinez A, Brochado AP, et al. Isolated and reversible lesions of the corpus callosum: a distinct entity. J Neuroimaging 2010;20:1-2. 2. Garcia-Monco JC, Cortina IE, Ferreira E, et al. Reversible splenial lesion syndrome (RESLES): what’s in a name? J Neuroimaging 2011;21:1-14. 3. Prilipko O, Delavelle J, Lazeyras F, et al. Reversible cytotoxic edema in the splenium of the corpus callosum related to
1052
4.
5.
6. 7.
8.
9. 10.
11.
12. 13.
14. 15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
antiepileptic treatment: report of two cases and literature review. Epilepsia 2005;46:1633-6. Anneken K, Evers S, Mohammadi S, et al. Transient lesion in the splenium related to antiepileptic drug: case report and new pathophysiological insights. Seizure 2008;17:654-7. Hoerlein G. Glufosinate (phosphinothricin), a natural amino acid with unexpected herbicidal properties. Rev Environ Contam Toxicol 1994;138:73-145. Watanabe T, Sano T. Neurological effects of glufosinate poisoning with a brief review. Hum Exp Toxicol 1998;17:35-9. Park HY, Lee PH, Shin DH, et al. Anterograde amnesia with hippocampal lesions following glufosinate intoxication. Neurology 2006;67:914-5. Lee HY, Song SY, Lee SH, et al. Vasogenic edema in striatum following ingestion of glufosinate-containing herbicide. J Clin Neurosci 2009;16:1372-3. Gallucci M, Limbucci N, Paonessa A, et al. Reversible focal splenial lesions. Neuroradiology 2007;49:541-4. Moritani T, Smoker WR, Sato Y, et al. Diffusion-weighted imaging of acute excitotoxic brain injury. Am J Neuroradiol 2005;26:21628. Bak LK, Schousboe A, Waagepetersen HS. The glutamate/GABAglutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem 2006;98:641-53. Coulter DA, Eid T. Astrocytic regulation of glutamate homeostasis in epilepsy. Glia 2012;60:1215-26. Mark LP, Prost RW, Ulmer JL, et al. Pictorial review of glutamate excitotoxicity: fundamental concepts for neuroimaging. Am J Neuroradiol 2001;22:1813-24. Chen CJ, Liao SL, Kuo JS. Gliotoxic action of glutamate on cultured astrocytes. J Neurochem 2000;75:1557-65. Koyama K, Koyama K, Goto K. Cardiovascular effects of a herbicide containing glufosinate and a surfactant: in vitro and in vivo analyses in rats. Toxicol Appl Pharmacol 1997;145:409-14. Koyama K. Glufosinate and a surfactant: which component produces effects on the central nervous system in acute oral BASTA poisoning? Vet Hum Toxicol 1999;41:341. Hack R, Ebert E, Ehling G, et al. Glufosinate ammonium—some aspects of its mode of action in mammals. Food Chem Toxicol 1994;32:461-70. Ohtake T, Yasuda H, Takahashi H, et al. Decreased plasma and cerebrospinal fluid glutamine concentrations in a patient with bialaphos poisoning. Hum Exp Toxicol 2001;20:429-34. Zou J, Wang YX, Dou FF, et al. Glutamine synthetase downregulation reduces astrocyte protection against glutamate excitotoxicity to neurons. Neurochem Int 2010;56:577-84. Matsumura N, Takeuchi C, Hishikawa K, et al. Glufosinate ammonium induces convulsion through N-methyl-D-aspartate receptors in mice. Neurosci Lett 2001;304:123-5. Mao YC, Wang JD, Hung DZ, et al. Hyperammonemia following glufosinate-containing herbicide poisoning: a potential marker of severe neurotoxicity. Clin Toxicol 2011;49:48-52. Norenberg MD, Baker L, Norenberg LO, et al. Ammonia-induced astrocyte swelling in primary culture. Neurochem Res 1991;16:8336. Willard-Mack CL, Koehler RC, Hirata T, et al. Inhibition of glutamine synthetase reduces ammonia-induced astrocyte swelling in rat. Neuroscience 1996;71:589-99. Domercq M, Matute C. Expression of glutamate transporters in the adult bovine corpus callosum. Brain Res Mol Brain Res 1999;67:296-302.
Journal of Neuroimaging Vol 25 No 6 November/December 2015
ABSTRACT Isolated and reversible lesion restricted to the splenium of the corpus callosum, known as reversible splenial lesion syndrome, have been reported in patients with infection, high-altitude cerebral edema, seizures, antiepileptic drug withdrawal, or metabolic disturbances. Here, we report a 39-year-old female patient with glufosinate ammonium (GLA) poisoning who presented with confusion and amnesia. Diffusion-weighted magnetic resonance imaging of the brain revealed cytotoxic edema of the splenium of the corpus callosum. The lesion was not present on follow-up MR imaging performed 9 months later. We postulate that a GLA-induced excitotoxic mechanism was the cause of this reversible splenial lesion. Keywords: Corpus callosum, cytotoxic edema, glufosinate ammonium. Acceptance: Received September 1, 2014, and in revised form December 30, 2014. Accepted for publication January 2, 2015. Correspondence: Address correspondence to Jae Chol Yoon, Research Institute of Clinical Medicine of Chonbuk National University, Emergency Medicine, Jeonju-si, Republic of Korea. E-mail: [email protected] J Neuroimaging 2015;25:1050-1052. DOI: 10.1111/jon.12216
Introduction Reversible splenial lesion syndrome (RESLES) is characterized by the absence of lesion-related symptoms and reversible, nonenhancing, oval-shaped, and centrally located high signal intensity lesion in the splenium of the corpus callosum (SCC) on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images.1 In a review of RESLES, lesions were associated with various etiologies, including epilepsy, infection, metabolic disturbances, or other causes.2 The similar asymptomatic clinical features and imaging results of reversible focal lesions in the SCC suggest a common mechanism induced by different pathological events leading to the same outcome. Usually, diffusion-weighted images (DWI) show restricted diffusion with low apparent diffusion coefficient (ADC) values.2 Diffuse tensor images performed in epilepsy-related RESLES reveal symmetrical and intact fibers3 or decreased functional anisotropy4 during the acute phase. Coupled with reversible clinical course and lack of neuronal dysfunction, these imaging findings suggest that RESLES is due to glial cytotoxic edema and/or intramyelinic edema. Glufosinate ammonium (GLA), a phosphinic acid derivative of glutamate, is a nonselective herbicide.5 The clinical manifestations associated with GLA poisoning are classified as early gastrointestinal symptoms due to the irritant effect of surfactant on mucosa and delayed neurologic symptoms, such as mental status change, convulsions, or amnesia.6 Central nervous system lesions associated with GLA poisoning include ischemic white matter changes,6 cytotoxic edema of the hippocampus,7 and vasogenic edema of the basal ganglia.8 In this article, we describe a female patient who ingested GLA and developed RESLES.
200 mL of BASTA (18% GLA) in attempted suicide. She had received gastric lavage followed by charcoal instillation at a local clinic very soon after ingestion. She was then transferred to our hospital. Her initial vital signs were stable and she was alert. Seven hours postadmission, she complained of memory disturbances regarding her ingestion. Twenty-two hours postadmission, she became drowsy and her oxygen saturation on pulse oximetry decreased to 65-70%. ABGA revealed respiratory acidosis with a pH of 7.234, PO2 of 40.8 mmHg, PCO2 of 59.7 mmHg, and HCO3 of 25.4 mmol/L. Chest X-ray revealed increased pulmonary vascular markings and parenchymal opacities in both lungs, compatible with pulmonary edema. Supportive care and endotracheal intubation with assisted ventilation were initiated. Following 17 hours of ventilator care, she was fully alert. Because she was responsive, extubation was performed. Her initial ammonia level was 52.2 umol/L (reference range 11.2-35.4 umol/L), which increased to 82.1 umol/L 2 days after admission and then declined. Followup clinical examination showed that the patient was unable to recall what happened during the 3 months preceding ingestion and what had occurred postingestion. We attributed this retrograde and anterograde amnesia to GLA poisoning. Brain magnetic resonance imaging (MRI) and MRA performed on day 5 showed a focal ovoid hyperintense lesion in the SCC on DWI, T2-weighted images, and FLAIR images. This lesion had a low ADC value and no contrast enhancement (Fig 1). The patient was discharged with persistent amnesia on day 6. Follow-up MRI performed at 9 months after discharge demonstrated that the lesion in the SCC had completely resolved (Fig 2).
Discussion Case Report A 39-year-old previously healthy woman presented to the emergency department 2 hours after ingestion of approximately 1050
Copyright
Cytotoxic edema of the SCC has a known excitotoxic mechanism.9 Excitotoxic brain edema results from increased extracellular glutamate,10 released from the presynaptic
◦ 2015 by the American Society of Neuroimaging C
Fig 1. Axial T2-weighted (A) and FLAIR (B) images reveal a focal, ovoid, and centrally located hyperintense lesion in the splenium of the corpus callosum (thin arrow). This lesion is hyperintense on DWI (C) and shows restricted diffusion on ADC map (D; black arrowhead). Postcontrast axial T1-weighted image after gadolinium administration (E) shows no contrast enhancement (thick arrow).
Fig 2. On follow-up MR imaging performed at 9 months later discharge, axial T2-weighted (A) and FLAIR (B) images show that the lesion seen on initial MR images is completely resolved (thin arrow). DWI (C) and ADC map (D) show complete reversal of diffusion restriction (black arrowhead).
terminals of neuronal axons into the synaptic cleft and removed by reuptake in the presynaptic terminal or adjacent glial cells.11 Because of their abundant high-affinity glutamate transporters, astrocytes are critically important for protection against neuronal injury due to glutamate. Astrocytes regulate the concentration of extracellular glutamate via reuptake by glutamate transporters and convert glutamate to nontoxic glutamine by glutamine synthetase (GS).12 In conditions associated with decreased glutamate reuptake via astrocytes or myelin, increased glutamate release due to leakage, or the presence of a structurally similar substance, extracellular glutamate can accumulate to cause excitotoxic injury.10 Excessive glutamate causes cell death or cytotoxic edema via binding to N-methyl-D-aspartate (NMDA) receptors and non-NMDA receptors, respectively.13 Sodium (Na+ ) and calcium (Ca2+ ) eventually enter glial cells and the myelin sheath to cause water diffusion. In addition, brief glutamate exposure causes astrocytes to swell by activating glutamate transporters.14 Because astrocytes and myelin have glutamate receptors and transporters, excitotoxicity and edema of these cells prevent acute-phase neuronal damage. This explains why this type of edema is reversible and asymptomatic in many cases.2 The edema is usually transitory, and MRI signal changes normalize with time or following removal of the causative pathologic factors.9 Our patient had none of the etiologic causes discussed in the Garcia et al review of RESLES, such as epilepsy-related, infection, metabolic, or miscellaneous. BASTA is composed of GLA as the active ingredient and sodium polyoxyethylene alkylether sulfate (AES) as a surfactant. Of theses, AES is a common anionic type surfactant with a moderate toxicity and is considered Jeong et al: Reversible Splenial Lesion Syndrome
1051
to cause circulatory failure via cardiosuppressive and vasodilatory action in extremely severe intoxication.15 Koyama suggested that the central nervous system signs of acute human BASTA poisoning are essentially due to its main component, GLA.16 GLA was considered the causative agent of RESLES in this case. The mechanisms of GLA-induced RESLES are discussed here. First, GLA can increase extracellular glutamate through GS inhibition in the brain. GLA is a broad-spectrum herbicide that inhibits plant GS, leading to complete inhibition of glutamine synthesis from glutamate and ammonia.5 GLA also inhibits GS in laboratory animals and induces elevation of glutamate and ammonia.17 Ohtake et al showed a reduction in CSF glutamine concentration and suggested that GLA inhibits GS activity in the brain.18 In addition, GS inhibition by L-methionine-S-sulfoximine weakened glutamate clearance by astrocytes in an in vitro study.19 Second, GLA is a structural analogue of glutamate and can directly stimulate the glutamate receptor. The intraperitoneal administration of GLA at doses higher than 40 mg/kg caused convulsions in mice. An NMDA receptor antagonist significantly prolonged the onset of convulsions caused by GLA, suggesting that GLA stimulates NMDA receptors.20 Third, hyperammonemia associated with GLA poisoning can cause astrocyte swelling. Delayed hyperammonemia following massive GLA ingestion is associated with late-onset neurological manifestations that are considered to be induced by significant GS inhibition.21 Primary cultured astrocytes treated with ammonium chloride (NH4 Cl) swelled significantly in a vitro study,22 but ammonia-induced swelling can be attenuated by GS inhibition.23 It is not clear why reversible excitotoxic edema selectively involves the SCC. In epilepsy-related RESLES, the SCC has been postulated as a vulnerable structure because of its close functional relationship with limbic and temporal lobe structures that are critical to the spread of excitation of seizure.9 However, this concept cannot be generalized to other conditions. The predilection of the SCC to edema is partially explained by its large number of glutamate receptors and high enzymatic activity.24 Patients with RESLES are usually asymptomatic, and brain imaging studies incidentally detect lesions in the search for a cause of neuropsychiatric symptoms associated with underlying conditions. In summary, when brain imaging studies are performed in patients with GLA poisoning, one should consider that GLA can cause reversible cytotoxic edema in the SCC.
References 1. Garcia-Monco JC, Martinez A, Brochado AP, et al. Isolated and reversible lesions of the corpus callosum: a distinct entity. J Neuroimaging 2010;20:1-2. 2. Garcia-Monco JC, Cortina IE, Ferreira E, et al. Reversible splenial lesion syndrome (RESLES): what’s in a name? J Neuroimaging 2011;21:1-14. 3. Prilipko O, Delavelle J, Lazeyras F, et al. Reversible cytotoxic edema in the splenium of the corpus callosum related to
1052
4.
5.
6. 7.
8.
9. 10.
11.
12. 13.
14. 15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
antiepileptic treatment: report of two cases and literature review. Epilepsia 2005;46:1633-6. Anneken K, Evers S, Mohammadi S, et al. Transient lesion in the splenium related to antiepileptic drug: case report and new pathophysiological insights. Seizure 2008;17:654-7. Hoerlein G. Glufosinate (phosphinothricin), a natural amino acid with unexpected herbicidal properties. Rev Environ Contam Toxicol 1994;138:73-145. Watanabe T, Sano T. Neurological effects of glufosinate poisoning with a brief review. Hum Exp Toxicol 1998;17:35-9. Park HY, Lee PH, Shin DH, et al. Anterograde amnesia with hippocampal lesions following glufosinate intoxication. Neurology 2006;67:914-5. Lee HY, Song SY, Lee SH, et al. Vasogenic edema in striatum following ingestion of glufosinate-containing herbicide. J Clin Neurosci 2009;16:1372-3. Gallucci M, Limbucci N, Paonessa A, et al. Reversible focal splenial lesions. Neuroradiology 2007;49:541-4. Moritani T, Smoker WR, Sato Y, et al. Diffusion-weighted imaging of acute excitotoxic brain injury. Am J Neuroradiol 2005;26:21628. Bak LK, Schousboe A, Waagepetersen HS. The glutamate/GABAglutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem 2006;98:641-53. Coulter DA, Eid T. Astrocytic regulation of glutamate homeostasis in epilepsy. Glia 2012;60:1215-26. Mark LP, Prost RW, Ulmer JL, et al. Pictorial review of glutamate excitotoxicity: fundamental concepts for neuroimaging. Am J Neuroradiol 2001;22:1813-24. Chen CJ, Liao SL, Kuo JS. Gliotoxic action of glutamate on cultured astrocytes. J Neurochem 2000;75:1557-65. Koyama K, Koyama K, Goto K. Cardiovascular effects of a herbicide containing glufosinate and a surfactant: in vitro and in vivo analyses in rats. Toxicol Appl Pharmacol 1997;145:409-14. Koyama K. Glufosinate and a surfactant: which component produces effects on the central nervous system in acute oral BASTA poisoning? Vet Hum Toxicol 1999;41:341. Hack R, Ebert E, Ehling G, et al. Glufosinate ammonium—some aspects of its mode of action in mammals. Food Chem Toxicol 1994;32:461-70. Ohtake T, Yasuda H, Takahashi H, et al. Decreased plasma and cerebrospinal fluid glutamine concentrations in a patient with bialaphos poisoning. Hum Exp Toxicol 2001;20:429-34. Zou J, Wang YX, Dou FF, et al. Glutamine synthetase downregulation reduces astrocyte protection against glutamate excitotoxicity to neurons. Neurochem Int 2010;56:577-84. Matsumura N, Takeuchi C, Hishikawa K, et al. Glufosinate ammonium induces convulsion through N-methyl-D-aspartate receptors in mice. Neurosci Lett 2001;304:123-5. Mao YC, Wang JD, Hung DZ, et al. Hyperammonemia following glufosinate-containing herbicide poisoning: a potential marker of severe neurotoxicity. Clin Toxicol 2011;49:48-52. Norenberg MD, Baker L, Norenberg LO, et al. Ammonia-induced astrocyte swelling in primary culture. Neurochem Res 1991;16:8336. Willard-Mack CL, Koehler RC, Hirata T, et al. Inhibition of glutamine synthetase reduces ammonia-induced astrocyte swelling in rat. Neuroscience 1996;71:589-99. Domercq M, Matute C. Expression of glutamate transporters in the adult bovine corpus callosum. Brain Res Mol Brain Res 1999;67:296-302.
Journal of Neuroimaging Vol 25 No 6 November/December 2015
