Elevated Cardiac Troponin I in a Dog With an Intracranial Meningioma and Evidence of Myocardial Necrosis

Introduction

Cardiac troponin I (cTnI) is a sensitive and specific biomarker for myocardial injury in humans and animals.^1,2 The troponin complex is found within myofibers and is composed of three subunits: troponin I (TnI), troponin T (TnT), and troponin C (TnC). These regulate calcium-mediated interaction between actin and myosin.³ Troponin I exists in skeletal and cardiac muscle as distinct isoforms, which can be differentiated using enzyme-linked immunosorbent assays.^4,5 The protein structure of cTnI is highly conserved between species.^4,6–8 Consequently, evaluation of canine cTnI levels can be performed using commercially available kits for humans.⁹

Measurement of cardiac troponin levels was first developed in human medicine in the late 1980s, and it is currently considered a standard part of the diagnostic workup for people with suspected myocardial infarction.^10,11 In both humans and dogs, cTnI is the most cardiac specific of the troponins and has greater sensitivity and specificity for myocardial damage than other tests.^12–14 Blood cTnI levels are consistently low and often undetectable in normal humans and dogs, so even very slight elevations have been shown to be significant markers of myocyte injury.^13,15–17 At this time, normal ranges have been well established in the dog.¹⁵

In veterinary medicine, several canine studies have shown elevated cTnI levels with chronic cardiac diseases including mitral regurgitation, dilated cardiomyopathy, and multiple congenital cardiac diseases.^18,19 Consistent elevations in cardiac troponins have been found in dogs with other cardiac diseases (with the exception of congenital defects) and in disorders of other systems, including gastric dilatation and volvulus, blunt trauma, pericardial effusion, pyometra, snake envenomation, and infectious diseases.^20–29 To date, cTnI measurements have not been investigated in dogs with central nervous system (CNS) disorders. Although uncommon, an association between CNS disease and myocardial injury has been demonstrated in dogs.³⁰

Neoplasia is a common cause of intracranial disease in older dogs, and meningioma is the most common neoplasm. While definitive diagnosis of intracranial meningiomas requires histopathology, presumptive diagnosis can be made with magnetic resonance imaging (MRI).^31–33 The following report describes a dog with seizures resulting from an intracranial mass. At necropsy, an intracranial meningioma was identified along with associated changes to the hippocampus and myocardium. An elevated cTnI was documented postmortem using serum obtained at the time of referral and stored at 4°C until analysis.

Case Report

A 10-year-old, 35-kg, spayed female Weimaraner was referred to the University of Georgia Veterinary Teaching Hospital (UGA/VTH) for seizures and obtundation. Two days prior to admission, the dog had been evaluated by the referring veterinarian (rDVM) for an acute onset of generalized tremors and hypersalivation. At initial presentation to the rDVM, the dog was tachycardic (240 beats per minute [BPM]), panting, and hyperthermic (106.1°F). The rDVM had reported that the dog displayed generalized ataxia and may have had a hypermetric gait. Abnormal proprioceptive placing had been observed in the right thoracic limb. A corneal ulcer was detected in the right eye (OD). The day prior to the onset of clinical signs, the owner had applied a pyrethrin spray to the area where the dog was housed. No other exposure to toxins was reported.

Initial treatment by the rDVM had consisted of diazepam^a (0.4 mg/kg intravenously [IV]) and crystalloids^b as an IV constant-rate infusion at 2.8 mL/kg per hour; activated charcoal^c (11 mL/kg per os); and methocarbamol^d (34 mg/kg IV once). Results of the complete blood count and serum biochemical profile were normal. Previous medical history included surgical removal of multiple subcutaneous lipomas 6 months prior to presentation. The owner reported that the liver enzymes had been elevated at the time of removal of the lipomas. Further investigation of the elevated liver enzymes had not been pursued.

After initial treatment by the rDVM, the dog’s tremors had gradually resolved over several hours. Approximately 12 hours after presentation, tremors and hypersalivation had recurred. The dog was treated with diazepam^a at the previous dosage and methocarbamol^d (34 mg/kg IV, followed 2 hours later with 57 mg/kg IV q 2 hours for two doses). Approximately 24 hours after initial presentation, miosis was noted in the left eye (OS). Additionally, the dog had developed menace response deficits bilaterally. At 36 hours after presentation, the dog suffered a generalized seizure. She was treated with diazepam^a (0.4 mg/kg IV). Post-ictally, she had remained obtunded and was referred.

On presentation to the UGA/VTH, the dog was recumbent and obtunded, displaying a minimal response to stimulation. Tachycardia (172 BPM), tachypnea (48 respirations per minute), and hyperthermia (102.4°F) were noted. Physical examination was essentially normal except for ocular discharge in both eyes (OU) and injected mucous membranes with a capillary refill time of <1 second. A complete neurological examination could not be performed given the severe obtundation. Gait and postural reactions were not evaluated. Spinal reflexes were normal. Cranial nerve examination revealed a decreased menace response OD with a normal menace response OS. Response to nasal stimulation was present bilaterally. No other cranial nerve abnormalities were detected. Tremors were not observed. Based on the findings of a limited neurological examination and the history of a seizure, neuroanatomical diagnosis was consistent with a left-sided prosencephalic lesion. The history of generalized tremors suggested diffuse CNS involvement. The initial ataxia observed by the rDVM was difficult to ascribe to a prosencephalic lesion. Although a definitive neuroanatomical diagnosis for the initial ataxia was not determined, peracute prosencephalic lesions may occasionally result in contralateral hemiparesis and ataxia.³⁴ The possible hypermetric quality of the gait may have been a result of diffuse CNS involvement.

On admission, the packed cell volume (PCV) and total solids (TS) were 58% and 8.0 g/dL, respectively (reference ranges 37% to 55% and 5.5 to 7.4 g/dL, respectively). Complete blood count revealed a leukocytosis (16 × 10³ cells/μL; reference range 5.1 to 13 × 10³ cells/μL), neutrophilia (12.8 × 10³ cells/μL; reference range 2.9 to 12 × 10³ cells/μL), and a left shift (band neutrophils 1.44 × 10³ cells/μL; reference range 0 to 0.45 × 10³ cells/μL). Moderate basophilic cytoplasm and slight toxic vacuolation of the white blood cells were observed. Serum biochemical profile showed decreased blood urea nitrogen (9 mg/dL; reference range 10 to 30 mg/dL), increased alkaline phosphatase (1397 U/L; reference range 13 to 122 U/L), increased alanine transferase (230 U/L; reference range 12 to 108 U/L), hypernatremia (163 mmol/L; reference range 146 to 154 mmol/L), hyperchloremia (134 mmol/L; reference range 107 to 125 mmol/L), and increased total bilirubin (0.3 mg/dL; reference range 0 to 0.2 mg/dL). Urinalysis was normal. Pre- and postprandial serum bile acid levels were normal. Serum ammonia was normal. Three view thoracic radiographs were normal. Abdominal radiographs showed an enlarged liver. Abdominal ultrasonography revealed multiple, small, hyperechoic nodules in the liver and spleen. Schirmer’s tear test was normal bilaterally. Large, superficial corneal ulcerations were noted OU with fluorescein stain. Intraocular pressure was decreased OU (OS 14 mm Hg, OD 9 mm Hg; reference range 15 to 24 mm Hg). No other ocular abnormalities were observed.

Initial treatment consisted of a 2-liter IV bolus of crystalloid fluids^b to correct for possible hypovolemia suggested by tachycardia and elevated PCV and TS. Approximately 2 hours after IV fluid administration, PCV (47%) and TS (6.6 g/dL) were normal (reference ranges 37% to 55% and 5.5 to 7.4 g/dL, respectively). Despite fluid resuscitation, the dog’s tachycardia continued. Continuous electrocardiogram monitoring disclosed sinus tachycardia with occasional premature ventricular complexes. Maintenance fluid therapy was continued with 0.45% sodium chloride supplemented with 2.5% dextrose and 16 mEq potassium chloride per liter to correct the hypernatremia and hyperchloremia. In the first 24 hours after admission, the dog had approximately 10 partial seizures, consisting of facial twitching and hypersalivation, and a single generalized seizure. The dog was administered phenobarbital^e (2 mg/kg IV q 12 hours) and a single IV bolus of mannitol^f (0.5 g/kg IV over 10 to 15 minutes).

Thirty-six hours after admission, MRI of the brain was performed with a 1.0 Tesla magnet.^g The following pulse sequences were obtained: T1-weighted (T1W), T2-weighted (T2W), T2-weighted fluid-attenuated inversion recovery (FLAIR), and postcontrast T1W images after IV administration of gadopentetate dimeglumine^h (0.1 mmol/kg body weight). Images were acquired in three planes. A mass affecting the left olfactory bulb, peduncle, tract, and frontal lobe of the cerebrum was identified. The mass was isointense in comparison to the normal gray matter on T1W images, and it was hyperintense on T2W and FLAIR images. On T1W images obtained after contrast administration, the mass displayed a well-circumscribed, homogenously strong, contrast enhancement pattern [Figures 1, 2, 3]. In addition, T2W and FLAIR images disclosed hyperintensity of the white matter of the left olfactory tract, internal capsule, and centrum semiovale; corona radiata of the dorsal parietal lobe of the cerebrum; rostral diencephalon; and head of the caudate nucleus. Rostrally, a midline shift of the falx cerebri to the right and compression of the left lateral ventricle were seen. The hippocampus, parahippocampal gyrus, and amygdala were hypointense on T1W images and hyperintense on T2W and FLAIR sequences bilaterally. The MRI findings were consistent with a meningioma affecting the olfactory bulb and tract, with secondary mass effect and vasogenic edema of the white matter and adjacent diencephalon. The changes in the hippocampi, parahippocampal gyri, and amygdala were also consistent with edema.

The dog recovered uneventfully from anesthesia. During recovery from anesthesia, another bolus of mannitol^f (0.5 g/kg IV over 10 minutes) and prednisolone sodium succinateⁱ (1.0 mg/kg IV) were administered. Despite continued anticonvulsant therapy with phenobarbital^e and treatment to reduce intracranial edema, the dog remained obtunded and continued to have partial seizures. Consequently, the owners elected euthanasia.

At necropsy, gross abnormalities were limited to the brain, heart, and liver. Grossly, enlargement of the left olfactory bulb and tract, with an irregular surface, was seen. In the ventral aspect of the olfactory tract, a 1 × 2-cm, dark gray and red mass was identified. On cut section, the mass was slightly gray, and the white matter of the internal capsule and rostral aspect of the corpus callosum were grossly enlarged on the left. A loss of distinction between the gray and white matter of the gyrus proreus was seen [Figures 4A, 4B]. In the heart, the cut surfaces of the myocardium, inter-ventricular septal, and inner third of the left ventricular walls had multiple, pale-gray foci. The liver had multiple, 5-to 10-mm diameter, pale-tan nodules that were widely scattered throughout the capsular and cut surfaces.

The histological examination of the liver was consistent with nodular hyperplasia. Histologically, the intracranial mass had microscopic features consistent with meningioma of the olfactory bulb and peduncle. The neoplasm was characterized by an expansile and highly infiltrative, densely cellular nodule of spindle cells arranged into sheets and whirling patterns about hyperemic vascular structures, with multiple foci of hemorrhage and necrosis. The neoplasm had obliterated the left olfactory bulb and peduncle and extended into the longitudinal fissure [Figure 5]. In the hippocampus, widespread neuronal degeneration and necrosis of neurons from the pyramidal cell layers of the CA1 to CA4 regions were seen. Neurons within the granular cell layer of the dentate gyrus were intact [Figure 6].

The heart showed acute multifocal myocardial degeneration and necrosis with perivascular edema and lymphangiectasia in the ventricles and septum [Figure 7]. Also seen were moderate, multifocal fibrosis within endomysial and perimysial spaces and multifocal myofiber atrophy and steatosis. Given the necropsy results, cTnI concentration was measured using serum obtained at initial presentation to UGA/VTH. The serum had been stored at 4°C for <48 hours prior to being analyzed. Measurement was performed using an automated chemiluminescence immunoanalyzer^j and reagents produced by the manufacturer that had been validated for use in dogs.³⁵ The cTnI concentration was severely elevated at 32.82 ng/mL (reference range 0 to 0.026 ng/mL).³⁵

Discussion

Although the mechanism through which intracranial lesions result in myocardial necrosis remains unclear, excitatory amino acids (EAAs) may play a role in the pathogenesis. Experimentally, microinjection of glutamate into the paraventricular nucleus of the hypothalamus results in increased blood pressure and heart rate, together with elevated circulating levels of epinephrine and norepinephrine.³⁶ Moreover, EAA injection into other various areas of the brain results in myocardial necrosis.^37,38

In the case reported here, the changes observed in the hippocampi on the MRI may suggest the presence of excessive EAAs. The MRI findings correlated with microscopic evidence of ischemic cell change in hippocampal neurons. Seizures can result in release of EAA neurotransmitters such as glutamate, which can precipitate neuronal injury.^39–41 Termed EAA neurotoxicity, this injury is characterized by a selective neuronal vulnerability leading to a distinctive pattern of neuronal loss.⁴² Specific vulnerability of CA3 pyramidal neurons of the hippocampus to N-methyl-D-aspartate receptor agonists has been documented.^43,44 Likewise, lesions in the hippocampus alone or in conjunction with the cingulated gyrus, dorsomedial thalamus, and amygdala have been occasionally observed in dogs with epilepsy.^45–47 Although speculative, EAA neurotoxicity may have been the underlying cause of the ischemic cell change in the hippocampi; this possibility lends support to a putative role in the development of myocardial necrosis in the dog reported here.

Alternatively, both acute and gradual increases in intracranial pressure (ICP) can result in catecholamine releases through sympathoadrenal response in experimental models.^48,49 Through activation of the sympathetic nervous system, acute rises of ICP can result in acute myocardial necrosis.⁴⁸ Dogs with intracranial space-occupying lesions can have elevations in ICP.⁵⁰ Intracranial pressure was not measured in the dog of this case; however, the magnitude of the mass effect created by the intracranial mass and accompanying edema, along with the severe alteration in the dog’s mentation, suggests that ICP may have been elevated.

Seizures can also result in myocardial injury through several mechanisms. Seizures can result in elevated plasma catecholamines.⁵¹ Elevated plasma catecholamines increase heart rate, blood pressure, contractility, and myocardial oxygen demand. Catecholamines may also have a direct toxic effect on the myocardium, which can lead to myocardial necrosis.⁵²

Another potential cause of myocardial injury in this dog was hyperthermia.^53,54 Severe hyperthermia was documented by the rDVM, and its magnitude may have caused myocardial injury.⁵⁵ The underlying cause of hyperthermia was not determined. Hyperthermia may have been secondary to seizures.⁵⁶ Alternatively, hyperthermia may have been secondary to muscle tremors. Common signs of pyrethrin toxicity include hypersalivation and muscle tremors, while hyperthermia and seizures are less commonly observed.^57,58 Although pyrethrin toxicity may have contributed to the initial observation of generalized tremors and hypersalivation, pyrethrin intoxication was considered an unlikely cause of seizures based upon the asymmetry in the menace response and subsequent diagnostic findings. Although the underlying cause of myocardial necrosis in this case was not determined, multiple factors likely played a role.

In humans, cTnI concentration has been utilized to investigate the existence of myocardial injury with intracranial disease, such as subarachnoid hemorrhage.^59–63 Using cTnI concentration, myocardial injury has been demonstrated in up to 20% of humans with subarachnoid hemorrhage.^60,63 Although myocardial injury has been reported with intracranial disease in veterinary medicine, the incidence is unknown.^30,64 Traditionally, electrocardiography, echocardiography, and serum creatinine kinase levels have been used to assess animals for myocardial injury.⁶⁵ In humans, electrocardiographic abnormalities do occur with myocardial injury secondary to subarachnoid hemorrhage; however, cTnI is a more sensitive and reliable indicator of myocardial injury.⁶⁰ In the dog of this report, electrocardiographic abnormalities were detected. Unfortunately, an echocardiogram was not performed to identify preexisting myocardial disease.

Importantly, neurological outcomes in humans with intracranial subarachnoid hemorrhage have been correlated with the existence of myocardial injury.^66,67 Elevated cTnI has been reliably established as a negative prognostic indicator in cardiovascular disease in humans.⁴ Also, in a limited number of veterinary studies, cTnI levels have been correlated with morbidity and mortality in such diseases as acquired cardiac disease, gastric dilatation-volvulus, and babesiosis.^4,18,68,69 Given this, a prospective study of cTnI levels in dogs with intracranial disease may reveal valuable prognostic information.

In this case, causes of myocardial disease other than the intracranial pathology were not identified postmortem. The serum troponin value corresponds to the magnitude of elevations documented in acute myocyte damage and death in other studies.^15–17,69 Despite evidence of some chronic myocardial changes on histopathology, the cTnI level confirms that acute damage was also present. While unlikely without gross evidence of a primary myocardial disease, an undetected primary myocardial disease perhaps led to increased susceptibility to acute myocardial necrosis as a consequence to the intracranial neoplasm and seizures.

The mechanism causing myocyte damage and subsequent troponin elevation in noncardiac diseases is unknown. Hypotheses include myocardial hypoxia, systemic inflammatory response syndrome, septic microemboli, endotoxins, ischemia and reperfusion injury, or an elevation in troponin level as a result of reduced clearance from serum.^4,24

Conclusion

This is the first case report to document an elevation in cTnI in a dog with myocardial injury that is believed to be secondary to CNS disease. In addition to myocardial injury, the dog of this report had extensive lesions in the hippocampus that were likely the result of EAA neurotoxicity secondary to seizures. In this case, the most likely inciting cause of seizures was the meningioma in the olfactory lobe of the cerebrum. Although myocardial injury as a result of CNS disease has been described, the incidence in dogs is unknown. In the future, measuring cTnI concentrations in dogs with suspected intracranial disease may help to identify animals with myocardial damage and possibly lead to earlier therapeutic interventions.