- Email: [email protected]
Neuroimaging findings in a case of fluoxetine overdose
Journal of Neuroradiology (2012) 39, 254—257
Available online at
www.sciencedirect.com
CASE REPORT
Neuroimaging findings in a case of fluoxetine overdose Résultats de l’imagerie dans un cas d’overdose à la fluoxétine Miklós Szólics a,f, Muhammad Chaudhry c,g, Milos Ljubisavljevic d,∗, Peter Corr e, Hashim A. Samir b, Klaus Neidl van Gorkom e a
Neurology Division, Department of Medicine, Tawam Hospital, Al Ain, United Arab Emirates Clinical Imaging Department, Tawam Hospital, Al Ain, United Arab Emirates c Tawam Molecular Imaging Center, Al Ain, United Arab Emirates d Physiology Department, Faculty of Medicine and Health Science, UAE University, PO Box 17666, Al Ain, United Arab Emirates e Radiology Department, Faculty of Medicine and Health Science, UAE University, Al Ain, United Arab Emirates f Medicine Department, Faculty of Medicine and Health Science, UAE University, Al Ain, United Arab Emirates g Department of Radiology and Radiological Health Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA b
KEYWORDS 18
F-FDG PET/CT; MRI; Pallidal necrosis; Serotonin toxicity; Fluoxetine overdose
Summary Brain MRI and 18 F-FDG PET/CT scans were performed in a patient who had survived a suicide attempt by fluoxetine overdose. The patient presented with the following clinical signs and symptoms, and neuroimaging findings: severe signs of serotonin toxicity, including comatose state, akinetic rigid syndrome and dysautonomia; bilateral globus pallidus changes consistent with extensive pallidal necrosis and subsequent reversible diffuse ischemic changes in white matter, with posterior predominance, involving the splenium of the corpus callosum on brain MRI; and marked hypometabolism in the frontal, parietal and temporal cortical regions as well as in both caudate nuclei on 18 F-FDG PET/CT performed 37 days later. These findings suggest that acute severe serotonin toxicity can induce structural and long-standing functional changes in multiple cortical and subcortical brain regions that are associated with cognitive and extrapyramidal syndromes. © 2011 Published by Elsevier Masson SAS.
Introduction Serotonin syndrome or serotonin toxicity is a potentially life-threatening adverse drug reaction that results from therapeutic drug use, intentional self-poisoning and inadver-
∗
Corresponding author. Fax: +971 37 67 19 66. E-mail address: [email protected] (M. Ljubisavljevic).
tent interactions between drugs [1]. Its signs and symptoms can include cognitive and behavioral changes, and signs of autonomic dysfunction, as well as a range of neurological symptoms. At the same time, no structural and/or changes in brain metabolism have been reported in serotonin toxicity syndrome. In this report of a case of attempted suicide by an overdose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine, the patient presented as serotonin toxicity
0150-9861/$ – see front matter © 2011 Published by Elsevier Masson SAS. doi:10.1016/j.neurad.2011.10.006
Neuroimaging of serotonin toxicity syndrome associated with structural and metabolic neuroimaging findings.
Case report A 28-year-old man, who had a past medical history of depression sporadically treated over the past 6 months with fluoxetine, was brought to the emergency room (ER) after being found unresponsive in his room early in the morning. On admission, his Glasgow Coma Scale was 3/15, temperature was 37.9 ◦ C, respiratory rate was 32 breaths/min, pulse was 112 beats/min, arterial blood pressure was 89/52 mmHg, oxygen saturation was 40% and he was acidotic. The patient also had mild leukocytosis and high serum creatinine. His blood glucose, electrolytes, cerebrospinal fluid analysis, chest X-ray and electrocardiography (ECG) were normal. A toxicology screen was also negative. The patient was admitted to the intensive care unit (ICU), where he remained comatose for the next 7 days. He had clinical signs of autonomic dysfunction (fever, profuse sweating, tachycardia), and signs of limb and axial rigidity. Careful examination of his medical history revealed that the patient had attempted suicide with 1.8 g of fluoxetine on the evening prior to admission. As the patient’s condition gradually improved, he regained consciousness, but still suffered from severe akinetic rigid syndrome, gait apraxia and cognitive disturbance, and remained socially dependent for the next 6 weeks.
255 splenium of the corpus callosum, with a reduction in the apparent diffusion coefficient (ADC) (Fig. 2). A follow-up MRI 22 days later revealed signs of pallidal necrosis together with the appearance of supratentorial white-matter ischemic changes, with resolution of the signal changes in the splenium of the corpus callosum. Single-voxel MR spectroscopy (MRS) placed in the pallidal region showed a decrease in the N-acetyl aspartate peak (NAA) at 2.04 ppm and an increase in the creatinine peak at 3.02 ppm due to neuronal injury and changes in energy metabolism. 18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography PET/CT was performed 37 days later, following the injection of 10 mCi of 18 F-FDG with an uptake phase of 40 min. PET/CT images were acquired from the skull vertex to the base of the skull, including the bilateral cerebellum. On visual analysis, brain PET images revealed gross hypometabolism primarily involving the bilateral frontal and parietal lobes (Fig. 3). Hypometabolism was also present bilaterally in the basal ganglia regions. However, metabolism was preserved bilaterally in the sensorimotor cortex.Further quantitative analysis was performed by calculating Z scores, compared with the pons as the reference region, using a 3D-SSP (stereotactic surface projection) imaging software program (Cortex ID, GE Healthcare, Waukesha, WI, USA). Mean Z scores revealed marked hypometabolism in the caudate nuclei (right: 3.87; left: 4.16) as well as additional involvement of the bilateral temporal association cortices (right: 3.77; left: 4.15), and frontal (right: 3.32; left: 3.44) and parietal (right: 3.77; left: 4.15) cortices. There was also significant bilateral hypometabolism in the cingulate regions (right: 1.77; left: 1.69) (Fig. 3).
Neuroimaging findings The patient’s brain computed tomography (CT), performed in the ER within 1 h of admission, was normal. Magnetic resonance imaging (MRI) performed 8 days later revealed a hyperintense signal on fluid-attenuated inversion recovery (FLAIR) and T2-weighted images (T2WI) in the globus pallidus bilaterally (Fig. 1). There was restricted diffusion in the posterior white matter tracts and signal changes in the
Figure 1
Discussion Overdosing with SSRIs is thought to be associated with low morbidity and mortality [2]. However, our patient took 1.8 g of fluoxetine, which is approximately 90 times higher than the usual daily dose. It is generally believed that fluoxetine overdose has no direct acute neurotoxic
Hyperintense signal changes are seen in both globi pallidi (A) and white matter (B) on FLAIR images.
256
M. Szólics et al.
Figure 2 Diffusion signal restriction (b = 1000 s/mm2 ) (A) and reduction in the apparent diffusion coefficient (B) in the splenium of the corpus callosum.
effects on its own. Nevertheless, our patient had significant bilateral pallidal and reversible, predominantly posterior, diffuse white-matter ischemic changes involving the splenium of the corpus callosum. This has not been previously reported in the literature in cases of serotonin syndrome or toxicity. Basal ganglia lesions have previously been reported in various acute metabolic conditions, including metabolic acidosis and hypoglycemia, and with toxic exposures to carbon monoxide, ethylene glycol, MDMA (3,4methylenedioxymethamphetamine), cocaine and heroin [3—5]. Most of the reported neuroimaging changes in the basal ganglia were symmetrical lesions that usually involved the corpus striatum (putamen and caudate nuclei). Parenchymal injuries topographically restricted to the
globus pallidus have been reported less frequently, and were mostly associated with the acute phase of carbon monoxide toxicity and hypotensive conditions. Pallidal lesions have also been observed among intravenous heroin addicts and MDMA users, resulting in the akinetic rigid syndrome. Most reports suggest that the basal ganglia lesions in these conditions were probably due to hypoxia, causing metabolic mismatch, that was probably due to a high neuronal rate of oxygen and glucose consumption [1,5]. Studies examining the effects of MDMA have suggested that local release of serotonin induced by ecstasy can result in prolonged vasospasm with subsequent ischemic changes [5—7]. Thus, in our patient, the neuroimaging findings consistent with pallidal necrosis and white-matter changes may potentially be explained by ischemic—hypoxic
Figure 3 18 F-FDG PET images on 3D-SSP [bar on the left represents the standard deviation (SD) from reference regions] show hypometabolism in the frontal and temporoparietal lobes (thick arrows in the right and left hemispheres, respectively), striatum (dashed arrow) and posterior part of the cingulate gyri (thin arrows bilaterally).
Neuroimaging of serotonin toxicity challenge, most likely secondary to serotonin-induced reversible vasoconstriction. The 18 F-FDG PET findings in our patient showed significant frontal, parietal and striatal glucose hypometabolism. However, we could find no data in the literature describing such brain metabolism changes in patients with serotonin syndrome or toxicity, although similar FDG PET brainmetabolism changes have been described in chronic users of MDMA [5,6]. Indeed, it has been shown that MDMA causes significant serotonin toxicity in a variety of animal species [7], although the exact mechanism(s) of its actions remain unclear [1,5—7]. It is thought that MDMA induces the release of serotonin and, to a lesser extent, dopamine, and decreases reuptake of these neurotransmitters, which is then followed by their acute depletion [6]. At certain doses, MDMA can also cause the destruction of serotonin terminals [1,6,7]. Fluoxetine treatment inhibits the nigrostriatal dopaminergic neurons through an increase of serotonin activity in the raphe nuclei. SSRIs potentiate the inhibitory action of serotonin in both the metabolic production and release of dopamine by basal ganglia neurons, as demonstrated by the fact that the synthesis of catecholamines is acutely inhibited by fluoxetine in regions rich in dopamine [7]. Our patient presented with pronounced akinetic rigid syndrome, which could be secondary to pallidal necrosis, associated with acute dysfunction of the metabolic production and release of dopamine.
Conclusion Fluoxetine overdose in our patient led to long-standing functional and partially reversible structural neuroimaging changes in multiple cortical and subcortical brain regions. These findings suggest complex interactions of serotonin, dopamine and norepinephrine neurotransmission between
257 cortical structures and the basal ganglia, together with significant vasomotor effects, in cases of serotonin toxicity.
Disclosure of Interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements The authors would like to thank Dr Richard L. Wahl, Professor of Radiology at Johns Hopkins University School of Medicine, for his help and statistical analysis of the brain PET images using Cortex ID software (GE Healthcare).
References [1] Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112—20. [2] Barbey JT, Roose SP. SSRI safety in overdose. J Clin Psychiatry 1998;59(Suppl: 15):42—8. [3] Rahmani M, Bennani M, Benabdeljlil M. [Neuropsychological and magnetic resonance imaging findings in five patients after carbon monoxide poisoning]. Rev Neurol (Paris) 2006;162:1240—7. [4] De Roock S, Hantson P, Laterre PF, Duprez T. Extensive pallidal and white matter injury following cocaine overdose. Intensive Care Med 2007;33:2030—1. [5] Parrott AC. Recreational ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity. Pharmacol Biochem Behav 2002;71:837—44. GA, Yuan J, McCann UD. (+/-) 3,4[6] Ricaurte Methylenedioxymethamphetamine (’Ecstasy’)-induced serotonin neurotoxicity: studies in animals. Neuropsychobiology 2000;42:5—10. [7] [7]Isbister GK, Buckley NA. The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment. Clin Neuropharmacol 2005;28:205—14.
Available online at
www.sciencedirect.com
CASE REPORT
Neuroimaging findings in a case of fluoxetine overdose Résultats de l’imagerie dans un cas d’overdose à la fluoxétine Miklós Szólics a,f, Muhammad Chaudhry c,g, Milos Ljubisavljevic d,∗, Peter Corr e, Hashim A. Samir b, Klaus Neidl van Gorkom e a
Neurology Division, Department of Medicine, Tawam Hospital, Al Ain, United Arab Emirates Clinical Imaging Department, Tawam Hospital, Al Ain, United Arab Emirates c Tawam Molecular Imaging Center, Al Ain, United Arab Emirates d Physiology Department, Faculty of Medicine and Health Science, UAE University, PO Box 17666, Al Ain, United Arab Emirates e Radiology Department, Faculty of Medicine and Health Science, UAE University, Al Ain, United Arab Emirates f Medicine Department, Faculty of Medicine and Health Science, UAE University, Al Ain, United Arab Emirates g Department of Radiology and Radiological Health Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA b
KEYWORDS 18
F-FDG PET/CT; MRI; Pallidal necrosis; Serotonin toxicity; Fluoxetine overdose
Summary Brain MRI and 18 F-FDG PET/CT scans were performed in a patient who had survived a suicide attempt by fluoxetine overdose. The patient presented with the following clinical signs and symptoms, and neuroimaging findings: severe signs of serotonin toxicity, including comatose state, akinetic rigid syndrome and dysautonomia; bilateral globus pallidus changes consistent with extensive pallidal necrosis and subsequent reversible diffuse ischemic changes in white matter, with posterior predominance, involving the splenium of the corpus callosum on brain MRI; and marked hypometabolism in the frontal, parietal and temporal cortical regions as well as in both caudate nuclei on 18 F-FDG PET/CT performed 37 days later. These findings suggest that acute severe serotonin toxicity can induce structural and long-standing functional changes in multiple cortical and subcortical brain regions that are associated with cognitive and extrapyramidal syndromes. © 2011 Published by Elsevier Masson SAS.
Introduction Serotonin syndrome or serotonin toxicity is a potentially life-threatening adverse drug reaction that results from therapeutic drug use, intentional self-poisoning and inadver-
∗
Corresponding author. Fax: +971 37 67 19 66. E-mail address: [email protected] (M. Ljubisavljevic).
tent interactions between drugs [1]. Its signs and symptoms can include cognitive and behavioral changes, and signs of autonomic dysfunction, as well as a range of neurological symptoms. At the same time, no structural and/or changes in brain metabolism have been reported in serotonin toxicity syndrome. In this report of a case of attempted suicide by an overdose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine, the patient presented as serotonin toxicity
0150-9861/$ – see front matter © 2011 Published by Elsevier Masson SAS. doi:10.1016/j.neurad.2011.10.006
Neuroimaging of serotonin toxicity syndrome associated with structural and metabolic neuroimaging findings.
Case report A 28-year-old man, who had a past medical history of depression sporadically treated over the past 6 months with fluoxetine, was brought to the emergency room (ER) after being found unresponsive in his room early in the morning. On admission, his Glasgow Coma Scale was 3/15, temperature was 37.9 ◦ C, respiratory rate was 32 breaths/min, pulse was 112 beats/min, arterial blood pressure was 89/52 mmHg, oxygen saturation was 40% and he was acidotic. The patient also had mild leukocytosis and high serum creatinine. His blood glucose, electrolytes, cerebrospinal fluid analysis, chest X-ray and electrocardiography (ECG) were normal. A toxicology screen was also negative. The patient was admitted to the intensive care unit (ICU), where he remained comatose for the next 7 days. He had clinical signs of autonomic dysfunction (fever, profuse sweating, tachycardia), and signs of limb and axial rigidity. Careful examination of his medical history revealed that the patient had attempted suicide with 1.8 g of fluoxetine on the evening prior to admission. As the patient’s condition gradually improved, he regained consciousness, but still suffered from severe akinetic rigid syndrome, gait apraxia and cognitive disturbance, and remained socially dependent for the next 6 weeks.
255 splenium of the corpus callosum, with a reduction in the apparent diffusion coefficient (ADC) (Fig. 2). A follow-up MRI 22 days later revealed signs of pallidal necrosis together with the appearance of supratentorial white-matter ischemic changes, with resolution of the signal changes in the splenium of the corpus callosum. Single-voxel MR spectroscopy (MRS) placed in the pallidal region showed a decrease in the N-acetyl aspartate peak (NAA) at 2.04 ppm and an increase in the creatinine peak at 3.02 ppm due to neuronal injury and changes in energy metabolism. 18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography PET/CT was performed 37 days later, following the injection of 10 mCi of 18 F-FDG with an uptake phase of 40 min. PET/CT images were acquired from the skull vertex to the base of the skull, including the bilateral cerebellum. On visual analysis, brain PET images revealed gross hypometabolism primarily involving the bilateral frontal and parietal lobes (Fig. 3). Hypometabolism was also present bilaterally in the basal ganglia regions. However, metabolism was preserved bilaterally in the sensorimotor cortex.Further quantitative analysis was performed by calculating Z scores, compared with the pons as the reference region, using a 3D-SSP (stereotactic surface projection) imaging software program (Cortex ID, GE Healthcare, Waukesha, WI, USA). Mean Z scores revealed marked hypometabolism in the caudate nuclei (right: 3.87; left: 4.16) as well as additional involvement of the bilateral temporal association cortices (right: 3.77; left: 4.15), and frontal (right: 3.32; left: 3.44) and parietal (right: 3.77; left: 4.15) cortices. There was also significant bilateral hypometabolism in the cingulate regions (right: 1.77; left: 1.69) (Fig. 3).
Neuroimaging findings The patient’s brain computed tomography (CT), performed in the ER within 1 h of admission, was normal. Magnetic resonance imaging (MRI) performed 8 days later revealed a hyperintense signal on fluid-attenuated inversion recovery (FLAIR) and T2-weighted images (T2WI) in the globus pallidus bilaterally (Fig. 1). There was restricted diffusion in the posterior white matter tracts and signal changes in the
Figure 1
Discussion Overdosing with SSRIs is thought to be associated with low morbidity and mortality [2]. However, our patient took 1.8 g of fluoxetine, which is approximately 90 times higher than the usual daily dose. It is generally believed that fluoxetine overdose has no direct acute neurotoxic
Hyperintense signal changes are seen in both globi pallidi (A) and white matter (B) on FLAIR images.
256
M. Szólics et al.
Figure 2 Diffusion signal restriction (b = 1000 s/mm2 ) (A) and reduction in the apparent diffusion coefficient (B) in the splenium of the corpus callosum.
effects on its own. Nevertheless, our patient had significant bilateral pallidal and reversible, predominantly posterior, diffuse white-matter ischemic changes involving the splenium of the corpus callosum. This has not been previously reported in the literature in cases of serotonin syndrome or toxicity. Basal ganglia lesions have previously been reported in various acute metabolic conditions, including metabolic acidosis and hypoglycemia, and with toxic exposures to carbon monoxide, ethylene glycol, MDMA (3,4methylenedioxymethamphetamine), cocaine and heroin [3—5]. Most of the reported neuroimaging changes in the basal ganglia were symmetrical lesions that usually involved the corpus striatum (putamen and caudate nuclei). Parenchymal injuries topographically restricted to the
globus pallidus have been reported less frequently, and were mostly associated with the acute phase of carbon monoxide toxicity and hypotensive conditions. Pallidal lesions have also been observed among intravenous heroin addicts and MDMA users, resulting in the akinetic rigid syndrome. Most reports suggest that the basal ganglia lesions in these conditions were probably due to hypoxia, causing metabolic mismatch, that was probably due to a high neuronal rate of oxygen and glucose consumption [1,5]. Studies examining the effects of MDMA have suggested that local release of serotonin induced by ecstasy can result in prolonged vasospasm with subsequent ischemic changes [5—7]. Thus, in our patient, the neuroimaging findings consistent with pallidal necrosis and white-matter changes may potentially be explained by ischemic—hypoxic
Figure 3 18 F-FDG PET images on 3D-SSP [bar on the left represents the standard deviation (SD) from reference regions] show hypometabolism in the frontal and temporoparietal lobes (thick arrows in the right and left hemispheres, respectively), striatum (dashed arrow) and posterior part of the cingulate gyri (thin arrows bilaterally).
Neuroimaging of serotonin toxicity challenge, most likely secondary to serotonin-induced reversible vasoconstriction. The 18 F-FDG PET findings in our patient showed significant frontal, parietal and striatal glucose hypometabolism. However, we could find no data in the literature describing such brain metabolism changes in patients with serotonin syndrome or toxicity, although similar FDG PET brainmetabolism changes have been described in chronic users of MDMA [5,6]. Indeed, it has been shown that MDMA causes significant serotonin toxicity in a variety of animal species [7], although the exact mechanism(s) of its actions remain unclear [1,5—7]. It is thought that MDMA induces the release of serotonin and, to a lesser extent, dopamine, and decreases reuptake of these neurotransmitters, which is then followed by their acute depletion [6]. At certain doses, MDMA can also cause the destruction of serotonin terminals [1,6,7]. Fluoxetine treatment inhibits the nigrostriatal dopaminergic neurons through an increase of serotonin activity in the raphe nuclei. SSRIs potentiate the inhibitory action of serotonin in both the metabolic production and release of dopamine by basal ganglia neurons, as demonstrated by the fact that the synthesis of catecholamines is acutely inhibited by fluoxetine in regions rich in dopamine [7]. Our patient presented with pronounced akinetic rigid syndrome, which could be secondary to pallidal necrosis, associated with acute dysfunction of the metabolic production and release of dopamine.
Conclusion Fluoxetine overdose in our patient led to long-standing functional and partially reversible structural neuroimaging changes in multiple cortical and subcortical brain regions. These findings suggest complex interactions of serotonin, dopamine and norepinephrine neurotransmission between
257 cortical structures and the basal ganglia, together with significant vasomotor effects, in cases of serotonin toxicity.
Disclosure of Interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements The authors would like to thank Dr Richard L. Wahl, Professor of Radiology at Johns Hopkins University School of Medicine, for his help and statistical analysis of the brain PET images using Cortex ID software (GE Healthcare).
References [1] Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112—20. [2] Barbey JT, Roose SP. SSRI safety in overdose. J Clin Psychiatry 1998;59(Suppl: 15):42—8. [3] Rahmani M, Bennani M, Benabdeljlil M. [Neuropsychological and magnetic resonance imaging findings in five patients after carbon monoxide poisoning]. Rev Neurol (Paris) 2006;162:1240—7. [4] De Roock S, Hantson P, Laterre PF, Duprez T. Extensive pallidal and white matter injury following cocaine overdose. Intensive Care Med 2007;33:2030—1. [5] Parrott AC. Recreational ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity. Pharmacol Biochem Behav 2002;71:837—44. GA, Yuan J, McCann UD. (+/-) 3,4[6] Ricaurte Methylenedioxymethamphetamine (’Ecstasy’)-induced serotonin neurotoxicity: studies in animals. Neuropsychobiology 2000;42:5—10. [7] [7]Isbister GK, Buckley NA. The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment. Clin Neuropharmacol 2005;28:205—14.