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Fatal Caffeine Intoxication in a Dog M. Hensel1, M. Pashmakova2, and B.F. Porter*. 1 Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA 2 Department of Veterinary Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA. Correspondence to B. Porter ([email protected]) Phone number: (979) 847-8541 4467 TAMU College Station, TX. 77843 2 1 Abstract: An 8-month-old male Yorkshire terrier was presented for 2 ingestion of 800 mg of an over-the-counter caffeine supplement. 3 Clinical signs included extreme tachycardia, facial fasciculation, 4 coma/stupor and flailing. Due to the lack of response to medical 5 therapies, humane euthanasia was elected. Microscopically, 6 necrotic neurons were scattered throughout the hippocampus, 7 olfactory cortex, pyriform lobe, amygdala, and basal nuclei, with 8 relative sparing of the caudate nuclei. In addition, mild skeletal 9 myocyte necrosis and mural necrosis of cardiac arterioles in the 10 left and right ventricles were noted. This is the first report of the 11 microscopic lesions associated with caffeine intoxication in a dog. 12 Key words: Caffeine toxicity; neuron necrosis 13 Introduction 14 Caffeine is a natural plant alkaloid found in more than 60 15 plant species and many beverage and food products, over the 16 counter dietary supplements, and medications (9). Caffeine is the 17 common name for the chemical 1,3,7-trimethylxanthine, which is 18 absorbed through the gastrointestinal tract and metabolized by the 19 liver (5,9). Caffeine is generally considered a safe compound 20 because it has a high threshold of toxicity and is a gastric irritant 21 with emetic properties (20). Reports of toxicosis in the medical 22 literature have been attributed to both accidental and intentional 23 overdose (3,4,7,14,26,27). The few case reports in dogs have been 24 related to accidental ingestion or presumptive malicious poisoning 25 (6,12,16,24,25). To the best of our knowledge, this is the first 26 detailed description of the pathologic findings in canine caffeine 27 intoxication. 28 Case Report 29 An 8-month-old, male, 1.5 kg Yorkshire terrier presented to 30 an emergency hospital with an acute onset of extreme tachycardia 31 (HR= 220 bpm) after witnessed ingestion of 4 x 200 mg (800 mg) 32 caffeine tablets between 6 to 8 hours previously. The only active 33 ingredient in the over the counter caffeine supplement was 34 caffeine. Due to rapid absorption of the toxin and presentation with 35 clinical signs of cardiovascular and neurologic instability, gastric 36 decontamination was deemed unsafe and therefore not performed. 37 During hospitalization, the dog experienced 3 tonic seizures, which 38 progressed to alternating periods of stupor/coma and flailing with 39 facial fasciculation for the next 2 days. Tachycardia was 40 moderately controlled with beta-blockers; however, the patient was 41 refractory to pharmaceutical management of intracranial signs 42 including cluster seizures, inappropriate mentation, and eventual 43 display of intracranial hypertension as evidenced by a Cushing 44 reflex. Serial bloodwork from 24 hours after ingestion and at 48 45 hours revealed progressively increasing aspartate aminotransferase 46 (AST) 1126 U/L to 1768 U/L (10-34 U/L) and alanine 4 47 aminotransferase (ALT) 217 U/L to 490 U/L (10-130 U/L). 48 Creatine kinase (CK) remained >16,000 U/L (68-400 U/L), and 49 cardiac troponin was severely increased (3.306 ng/ml [0-0.06]). 50 Urinalysis revealed myoglobinuria. The dog developed ptyalism, 51 loss of gag reflex, possible aspiration pneumonia, and ultimately 52 humane euthanasia was elected 2 days after ingestion of caffeine. 53 A complete necropsy was performed, and no gross lesions 54 were observed. Sections of heart, kidney, liver, lung, pancreas, 55 spleen, urinary bladder, thyroid gland, parathyroid gland, skeletal 56 muscle, stomach, small intestine, colon, cerebrum, thalamus, 57 hippocampus, cerebellum, midbrain, and medulla oblongata were 58 fixed in 10% neutral buffered formalin, processed routinely, 59 embedded in paraffin, and stained by hematoxylin and eosin (HE) 60 for light microscopy. Due to the witnessed ingestion of caffeine 61 supplements and the lack of exposure to any other toxin, blood or 62 tissue were not assessed for caffeine levels in this case. 63 Microscopic brain lesions were largely limited to the 64 telencephalon and diencephalon. Scattered areas of neuronal 65 necrosis, varying from minimal to severe, were evident throughout 66 all cerebral lobes. Necrotic neurons were shrunken and angular 67 with hypereosinophilic cytoplasm and pyknotic nuclei. Necrosis 68 was severe in the hippocampus, olfactory cortex, pyriform lobe, 69 amygdala, and basal nuclei, with relative sparing of the caudate 5 70 nuclei. Both the pyramidal layer (CA1-CA4) and dentate layer of 71 the hippocampus were severely and diffusely affected (Fig. A). In 72 the cerebral cortex, necrotic neurons were evident in superficial, 73 middle, and deep layers without a clear laminar pattern. Necrotic 74 neurons and occasional swollen axons (spheroids) were evident in 75 the thalamus, most notably in the lateral geniculate nucleus (Fig. 76 B). The dorsal thalamus was more affected than the ventral 77 thalamus. A few necrotic neurons had multiple basophilic 78 incrustations along their cell membrane (Fig. C, inset). Necrotic 79 neurons and adjacent blood vessels were often surrounded by clear 80 space interpreted as cytotoxic edema (Fig. C). Other vessel 81 changes in affected areas included hypertrophy of endothelial cells 82 and occasional mitotic figures. Rare Purkinje cell necrosis was 83 seen in the cerebellum. The midbrain and medulla oblongata were 84 within normal limits. Additional microscopic findings of this case 85 included scattered necrotic skeletal myocytes and mural necrosis of 86 arterioles in the left and right ventricles (Fig. D). 87 Discussion 88 The dog weighed 1.5 kg and ingested approximately 800 89 mg of pure caffeine (533 mg/kg). The toxic dose for dogs is 90 reported to be 140-150 mg/kg (20). The diagnosis of caffeine 91 intoxication is based on history of caffeine ingestion with 92 corresponding caffeine levels in blood or tissue samples 6 93 (4,7,14,27). Reported pathologic findings in human cases of 94 caffeine intoxication include pulmonary edema, visceral 95 congestion, myocardial infarction, rhabdomyolysis, and mild 96 gastric erosion with hemorrhage (4,7,26,27). Lesions in the central 97 nervous system are limited to cerebral edema, although most 98 reports do not include brain histology (27). The pathology of 99 caffeine toxicosis in dogs is poorly characterized. Necropsies were 100 not performed in most of the reported cases nor were caffeine 101 levels in the blood or tissues evaluated (12,16,19,25). Two cases 102 that received necropsies reported no gross findings, and 103 histopathology was not done in either case (6,24). 104 While caffeine intoxication is the most likely diagnosis, 105 similar microscopic lesions have been attributed to seizure activity 106 in epileptic dogs and are also seen in dogs with cardiac arrest, 107 cranial trauma, and hypoglycemia (11,13,17,18). The dog did not 108 have a previous history of epilepsy and lacked gross lesions or a 109 history of cranial trauma. In a study of epileptic beagles, the 110 distribution and nature of the lesions was similar to this case, 111 involving the cerebral cortex, basal nuclei, claustrum, amygdala, 112 septal nuclei, dorsal thalamic nuclei, isthmus of the pyriform lobe, 113 and hippocampus (13). The rostral cerebrum was most severely 114 affected, specifically the medial aspect of the frontal lobes and the 115 cingulate gyrus, a finding not appreciated in this case. The beagles 7 116 had infrequent cerebellar Purkinje cell necrosis, neuronal necrosis 117 in the thalamus, and frequent neuronal incrustation, all similar to 118 this case. Incrustations are a change that has been attributed to 119 dense pockets of neuronal cytoplasm caused by impingement of 120 swollen astrocyte processes on the neuronal cell membrane (21). 121 Hippocampal necrosis was seen in CA1-CA4 in the beagle study, 122 but did not involve the dentate gyrus, as it did in this case. Another 123 change not mentioned in the epileptic beagles but seen in this case 124 is the presence of spheroids within the thalamus, particularly the 125 lateral geniculate nucleus. 126 The prominent histologic findings of neuronal necrosis and 127 cytotoxic edema could be entirely due to seizure activity or 128 hypoxia resulting from cardiovascular collapse, rather than from 129 any direct toxic effects of caffeine. Caffeine increases the rate of 130 metabolism of structures within the extrapyramidal motor system, 131 thalamic nuclei, and hippocampus, resulting in relative 132 hypoperfusion of these areas (15). Caffeine also causes transient 133 vasoconstriction, which could contribute to relative hypoperfusion 134 (15). The lesions in this dog could be secondary to the inherent 135 vasoconstrictive properties of caffeine and increased glucose 136 utilization within the central nervous system. 137 138 Diffuse brain hypoxia from cardiopulmonary dysfunction is another possible explanation for the brain lesions. Myocardial 8 139 infarction and cardiac arrest have been reported after massive 140 ingestion of caffeine, resulting in abnormal electrocardiograph 141 (ECG) findings and elevated cardiac troponin levels (3,7). Cardiac 142 arrest with resulting global ischemia is a well-known cause of 143 neurologic deficits. In a research model utilizing pigs, cardiac 144 arrest of 7 or 10 minutes duration resulted in varying degrees of 145 neuronal necrosis and cerebral edema within the cerebral cortex, 146 caudate nucleus, putamen, hippocampus, thalamus, and cerebellar 147 median fissure (10). Necrotic neurons were found in layers III and 148 V of the 7 minute group and progressed to diffuse involvement by 149 10 minutes. The lesions reported in these pigs are similar to those 150 described in this case. The dog did not experience cardiac arrest, 151 but elevated cardiac troponin and mural necrosis of epicardial 152 arterioles of the left and right ventricles suggests compromised 153 myocardial function. Vascular necrosis has apparently not been 154 observed in previous cases of canine or human caffeine toxicity. 155 Caffeine is quickly absorbed after ingestion and reaches 156 peak serum levels within 1 hour (2,20). Clinical signs include 157 gastrointestinal derangements (vomiting, diarrhea), cardiovascular 158 instability (hypertension or hypotension, tachycardia), and 159 neurologic effects (delusions, hallucinations, and seizures) (14,20). 160 Caffeine’s effects are mediated through competitive antagonism of 161 adenosine receptors, which are found in the cardiovascular, 9 162 respiratory, renal, gastrointestinal, and central nervous systems 163 (1,2). 164 Caffeine is structurally similar to the methylxanthines 165 theobromine and theophylline. Due to its presence in chocolate 166 products, theobromine toxicosis is well recognized in dogs. In an 167 experimental study of canine theobromine intoxication, clinical 168 signs included restlessness, panting, and muscle tremors (8). 169 Lesions were limited to necrosis of cardiac muscle in the right 170 auricle with thickening of adjacent arterioles, presumably due to 171 smooth muscle hyperplasia and perivascular fibrosis. The brain 172 was apparently not examined in this study. With the exception of 173 renal tubular necrosis in one case, histopathologic lesions have not 174 been reported in natural cases of canine theobromine toxicosis 175 (22,23). The clinical signs in an experimental study of canine 176 theophylline intoxication included vomiting, erythema, a 177 staggering gait, hyperpnea, spasms, salivation, excitement, and 178 convulsions (22). The brain was not examined in the study, and 179 myocardial necrosis was the only lesion described. 180 Caffeine is a potent stimulant. Although toxicity is rare in 181 dogs, the drug can induce severe pathologic changes in the species. 182 The extent to which the lesions reported herein are due to seizure 183 activity, cardiopulmonary dysfunction, or some other mechanism 184 remains to be determined. 10 185 No conflicts of interest have been declared. 186 Acknowledgements 187 188 The authors wish to thank Dr. Brian Summers for consulting on this case. 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 Literature Cited 1 ABBOTT PJ. Caffeine: a toxicological overview. Med. J. Aust., 1986, 145, 10, 518-521. 2 BENOWITZ NL. Clinical pharmacology of caffeine. Annu. Rev. Med., 1990, 41, 277-288. 3 BERGER AJ, ALFORD K. Cardiac arrest in a young man following excess consumption of caffeinated "energy drinks". Med. J. 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Acute and subacute toxicities of theophylline are directly reflected by its plasma concentration in dogs. Methods Find. Exp. Clin. Pharmacol., 2000, 22, 3, 173-178. 23 SUTTON RH. Cocoa poisoning in a dog. Vet. Rec., 1981, 109, 25-26, 563-564. 24 TAWDE SN, PUSCHNER B, ALBIN T, STUMP S, POPPENGA RH. Death by caffeine: presumptive malicious poisoning of a dog by incorporation in ground meat. J. Med. Toxicol., 2012, 8, 4, 436-440. 25 WIDGERSON F. Accidental caffeine poisoning in a dog. J. Am. Vet. Med. Assoc., 1956, 134. 26 WRENN KD, OSCHNER I. Rhabdomyolysis induced by a caffeine overdose. Ann. Emerg. Med., 1989, 18, 94-97. 27 YAMAMOTO T, YOSHIZAWA K, KUBO S, EMOTO Y, HARA K, WATERS B. Autopsy report for a caffeine 12 271 272 intoxication case and review of the current literature. J. Toxicol. Pathol., 2015, 28, 1, 33-36. 273 274 275 276 277 278 279 280 Fig. 1. Hippocampus. Hypereosinophilic and shrunken neurons in the dentate layer (*) and within the pyramidal layer (arrows). HE. Bar, 70 m. 281 282 Fig. 2. Thalamus. Multifocal swollen axons (arrows) in the lateral geniculate nucleus. HE. Bar, 35 m. 283 284 285 286 287 Fig. 3. Cerebrum. The perivascular space is expanded by cytotoxic edema (*). Multifocally, neurons are necrotic (solid arrow). HE. Bar, 70 m. Upper inset. Some neurons have basophilic incrustations along the cell membrane (open arrow). HE. Bar, 20 m. 288 289 Fig. 4. Heart. Mural fibrinoid necrosis (*) in an epicardial arteriole. HE. Bar, 20 m. 13