Arrhythmias and Elevated Troponin I in a Dog With Steroid-Responsive Meningitis-Arteritis

Introduction

Steroid-responsive meningitis-arteritis (SRMA) is an inflammatory meningitis usually diagnosed in young, medium- to large-breed dogs. The cause is thought to be immune-mediated in origin, and the condition most often results in paraspinal pain, fever, and possible paresis. The prognosis is usually good with appropriate corticosteroid therapy.^1–3 The dog in this report was presented with clinical signs and diagnostic findings suggestive of myocarditis. Many reported causes of meningitis have also been known to induce electrocardiogram (ECG) alterations.^4–7 Arrhythmias have not been previously reported to occur with SRMA. To our knowledge, this is the first report of a dog with SRMA and secondary cardiac rhythm disturbances.

Case Report

A 10-month-old, 12-kg, intact female border collie was referred for evaluation of a 2-week history of fever, lethargy, and inappetence that had progressed to 2 days of anorexia. The dog was previously healthy, primarily kept indoors, and properly vaccinated. She had started her estrous cycle shortly before showing clinical signs.

The dog was initially evaluated by the referring veterinarian; at that time, a fever (105.9°F) was present, and neutrophilia (25.0 cells/μL; reference range 2.8 to 10.5 × 10³ cells/μL) was seen on a complete blood count (CBC). A serum biochemical profile was unremarkable. The dog was treated with cephalexin (20 mg/kg per os [PO] q 12 hours), without improvement. Two days later, the dog remained febrile at 104.6°F, and dexamethasone sodium phosphate (1 mg/kg intravenously [IV]) was administered. Attitude improved slightly for the next 2 to 3 days, but the dog was returned to her veterinarian 8 days later because of worsening clinical signs. On physical examination, heart sounds were muffled, and radiographs were suggestive of an enlarged heart. The dog was sent home on furosemide (4.2 mg/kg PO q 24 hours) and was referred for further evaluation.

Upon presentation to the referral hospital, the dog was depressed but responsive. Body temperature was 105.1°F. Light brown and mucoid vulvar discharge, a slight increase in respiratory effort, and mild paraspinal hyperesthesia were noted. Ophthalmic and orthopedic examinations were within normal limits.

Abnormalities on venous blood gas analysis included mild hyponatremia (144.1 mmol/L; reference range 146.8 to 153.1 mmol/L), hypochloremia (107.2 mmol/L; reference range 110.6 to 115.5 mmol/L), and a mild increase in lactate (2.7 mmol/L; reference range 0.3 to 2.5 mmol/L) with a venous pH of 7.403. The CBC abnormalities included neutrophilia (28.9 cells/μL; reference range 3.0 to 11.5 × 10³ cells/μL) with a mild increase in bands (328 cells/μL; reference range 0 to 300 cells/μL) and monocytosis (1.9 cells/μL; reference range 0.15 to 1.3 × 10³ cells/μL). Abnormalities on the serum biochemical profile included mild hyperglobulinemia (3.9 g/dL; reference range 1.7 to 3.8 g/dL); mild increase in alkaline phosphatase (220 U/L; reference range 24 to 147 U/L); mild hypercholesterolemia (259 mg/dL; reference range 120 to 247 mg/dL); and mild decreases in ala-nine aminotransferase (8 U/L; reference range 10 to 130 U/L) and enzymatic carbon dioxide (20 mmol/L; reference range 21 to 28 mmol/L). Serum potassium concentration was normal (3.8 mmol/L; reference range 3.3 to 4.6 mmol/L). A urine sample had a specific gravity of 1.030 with inactive sediment.

Thoracic and abdominal radiographs were within normal limits. Abdominal ultrasonography revealed uterine changes consistent with estrus; hepatomegaly and hepatic venous congestion were suggestive of increased right heart pressures. Vaginal cytology was consistent with normal estrus. Echocardiography revealed mild right ventricular enlargement and a scant amount of pericardial effusion. Trivial mitral and tricuspid valve regurgitation and mild left atrial enlargement with preserved ventricular systolic function were also seen. Electrocardiographic findings included a heart rate of 75 beats per minute with narrow QRS complexes. No obvious P waves were in front of the QRS complexes; however, P waves may have been present following the QRS complex as occurs in a junctional rhythm with retrograde conduction of the atria [Figure 1]. These findings suggested either a junctional or sinoventricular rhythm. Serum cardiac troponin I was elevated (0.44 ng/mL; reference range 0 to 0.05 ng/mL). Serological tests for Trypanosoma cruzii, Ehrlichia canis, Rickettsia rickettsii, Borrelia burgdorferi, Bartonella vinsonii, Toxoplasma gondii, Neospora caninum, and Babesia canis were submitted. Urine and blood cultures (two samples obtained 2 hours apart) were obtained.

The dog initially was started on IV fluid therapy, doxycycline^a (8 mg/kg PO q 12 hours), enrofloxacin^b (10 mg/kg IV q 24 hours), ketoconazole^c (8 mg/kg PO q 12 hours) for possible Trypanosoma cruzii infection, and dolasetron^d (0.6 mg/kg IV q 24 hours). After 36 hours, the dog’s body temperature remained elevated, and meloxicam^e (0.2 mg/kg PO) was administered. Appetite improved, but the dog remained febrile. On day 3, meloxicam was discontinued and carprofen^f (2 mg/kg PO q 12 hours) was administered. Body temperature normalized within 6 hours, and the dog’s attitude and appetite returned to normal over the next 24 hours. On day 4, an ECG was repeated and demonstrated a sinus rhythm and variable P-R intervals. The longer P-R intervals were consistent with first-degree atrioventricular (AV) block or another possible AV node conduction disturbance [Figure 2]. The dog was maintained on doxycycline, ketoconazole, carprofen, and enrofloxacin (11.5 mg/kg PO q 24 hours) and continued to be clinically normal for the next 48 hours. The dog was discharged to the care of the owner, pending culture and serology results. All serology results were negative, and cultures revealed no growth.

Eleven days after discharge, the dog had a body temperature of 102.6°F and became lethargic. The next morning, the dog was also hyporexic, and body temperature was elevated to 104.0°F. Upon return to the referral hospital for further evaluation, the dog’s temperature was 103.7°F. Neurological examination showed normal mental alertness, gait, postural reactions, segmental spinal cord reflexes, and cranial nerve function. Reactivity to palpation of the cervical musculature and vertebral column was excessive, which suggested a degree of hyperesthesia. Based on this assessment, pathology within the cervical musculature, vertebrae, ligamentous structures, intervertebral disks, or meninges was suspected. Referred hyperesthesia arising from the dura of the caudal fossa was also considered.

A CBC was repeated and demonstrated neutrophilia (24.5 cells/μL; reference range 3.0 to 11.5 × 10³ cells/μL) and monocytosis (1.4 cells/μL; reference range 0.15 to 1.3 × 10³ cells/μL). A repeat serum biochemical profile showed no significant changes from previous values. An ECG demonstrated sinus arrhythmia with variable P wave height and P-R intervals [Figure 3]. An echocardiogram revealed resolution of the pericardial effusion, persistent trivial mitral regurgitation, and no left atrial enlargement. Mild right ventricular enlargement was still present, but it had improved when compared to the previous examination. Abdominal ultrasound revealed smaller hepatic veins compared to the previous examination. A convalescent Trypanosoma cruzii titer was performed and was negative.

The following day, the dog’s body temperature normalized, and appetite and energy returned to normal. Computed tomography (CT) scan of the brain and cervical spinal cord, cerebrospinal fluid (CSF) collection, and arthrocentesis were performed. To elucidate the cause of the arrhythmias, right ventricular endomyocardial biopsy was also performed under anesthesia as previously described.⁸ Endomyocardial biopsy showed evidence of mild, reversible myocyte changes. These alterations included slight focal perinuclear clearing, attenuation, and stretching of the myocytes. No microscopic evidence of inflammation or infectious organisms were seen [Figure 4]. These findings may indicate stress and could contribute to the echocardiographic appearance of mild dilatation. The CT scan showed multiple, ill-defined, noncontrast-enhancing, hypodense regions throughout the prosencephalon. These findings were considered to be most suggestive of encephalitis. Analysis of CSF revealed a marked increase in white blood cells (1400 cells/μL) with a moderate increase in red blood cells (120 cells/μL). The CSF microprotein concentration was also markedly increased (202 mg/dL) with 2+ Pandy. On cytological examination, a 100-cell differential consisted of 73% neutrophils, 1% small lymphocytes and small mononuclear cells, and 26% macrophages and large mononuclear cells. No infectious agents or neoplastic cells were observed. These findings were consistent with a neutrophilic pleocytosis. Subsequent CSF culture was negative for growth. Cytological examination of joint fluid was within normal limits.

Based on lack of evidence for infectious etiology, appropriate signalment and clinical signs, and neutrophilic CSF pleocytosis, the diagnosis of SRMA was made. The dog was initially placed on antiinflammatory prednisone^g (0.4 mg/kg PO q 12 hours) until all pending cultures and serological tests were complete. The prednisone dosage was then increased to an immunosuppressive level (2 mg/kg PO q 24 hours) to be given in a tapering schedule over the next 6 months. As of the time of publication, the owner reports the dog is doing well and has had no relapse of clinical signs.

Discussion

Steroid-responsive meningitis-arteritis is a noninfectious disorder that most commonly occurs in medium- to large-breed dogs <2 years of age.^1–3 Although the etiology is unknown, the positive response to corticosteroid therapy in most dogs suggests immunopathological mechanisms. A mild vasculitis, T cell activation, and excessive production of immunoglobulin A (IgA) have also been indicated in the pathogenesis of this disease.^2,9–11

Clinical signs may be acute, chronic, or waxing and waning in nature. Acute cases are usually presented with cervical and/or thoracolumbar pain, reluctance to move, muscle rigidity, and fever. In more severe or chronic cases, ataxia, tetra- or paraparesis, and postural reaction deficits may be observed.^2,12 Peripheral neutrophilia is also commonly seen. This condition usually results in significantly elevated CSF white blood cell counts (15 out of 32 dogs having counts >1000 cells/μL in one report), with neutrophils being the predominant cell type.¹³ Increased protein in the CSF is also commonly observed. Characteristic CSF findings without evidence of an infectious etiology, followed by clinical response to corticosteroid therapy, lead to diagnosis.

Beyond histopathological analysis, no specific test is available to definitively diagnose SRMA; however, some investigators have utilized CSF IgA levels as supportive evidence.^9,11 The mainstay of treatment consists of immunosuppressive corticosteroid therapy on a tapering schedule over several months. Corticosteroids may need to be continued for 4 to 6 months and should be based on response to therapy and clinical signs. Recurrence of clinical signs may necessitate an increased dose of corticosteroids, followed by prolongation of therapy. Prognosis for survival and resolution of clinical signs is good.^3,9,12

The cardiac changes observed in this dog are thought to be a result of myocarditis secondary to the neurological inflammatory disease. Myocarditis is inflammation of the cardiac myocytes that can lead to asymptomatic or symptomatic ECG alterations as well as cardiac failure. Myocarditis can also result in direct cardiac myocyte damage and cell lysis.^14,15 Myocarditis is caused by primary cardiac disease or a variety of secondary disorders involving traumatic, toxic, and infectious causes. Some of the more common infectious possibilities include Trypanosoma cruzi, Toxoplasmosis gondii, Neospora caninum, Parvovirus, Borrelia burgdorferi, West Nile virus, Bartonella spp., rickettsial diseases, and other bacteria.^{5–7,14–16} Electrocardiographic abnormalities may include atrial or ventricular arrhythmias and conduction abnormalities including AV block.^14,17

Endomyocardial biopsy demonstrating infiltration of inflammatory cells and/or myocytolysis is a useful tool for diagnosis in human medicine, but this procedure is not commonly performed at this time in the veterinary profession.¹⁴ Cardiac troponin I has been validated in the dog as a specific marker for cardiac myocyte damage, and it can also be used to aid in the diagnosis of myocarditis.¹⁸ If no primary cardiac disease is diagnosed, systemic disorders that result in myocarditis should be evaluated through serological or other appropriate testing. Therapy for myocarditis is aimed at specifically treating any underlying disease and administering antiarrhythmic agents when deemed necessary for cardiovascular stability.^14,19 Most myocarditis arrhythmias caused by systemic disease will resolve over several days of treatment for the underlying disorder.

Myocarditis was diagnosed as the cause for the observed arrhythmias and cardiac alterations based on the ECG and echocardiographic changes observed in this dog, as well as the significant elevation in troponin I. The final diagnosis for the neurological disease was SRMA. Based on the diagnostic testing performed, a second, distinct disorder to explain the myocarditis was not found. The cardiac abnormalities improved in conjunction with clinical improvement of the neurological disease. Therefore, the myocarditis observed in this dog was likely secondary to inflammation caused by SRMA. To our knowledge, no previous cases of cardiac conduction disturbances in conjunction with SRMA in dogs have been reported.

Meningitis-induced ECG alterations have been reported in both human and veterinary medicine literature.^5–6,17 The pathogenesis of meningitis-induced arrhythmias is not well understood, but the disorder may occur from a variety of factors. The nervous system maintains a primary role in the control and modulation of heart rate, vasomotor tone, and cardiac output via nervous conduction and neurotransmitter release.¹⁹ Irritation of the meninges may have resulted in increased parasympathetic discharge, resulting in the conduction disturbances seen in this case.¹⁷

During neurological injury in humans, an excessive release of catecholamines has been shown.^17,19,20 These catecholamines may affect cardiac action potentials and increase intracellular calcium, predisposing patients to changes in myocardial repolarization and arrhythmias.¹⁹ The increased catecholamine concentration may also result in coronary vasospasm, direct myocyte damage by catecholamine metabolites, or free radical damage to myocyte cell membranes, resulting in myocardial necrosis.^17,19,20 These myocardial changes have been reported in human medicine to cause sinus bradycardia, as well as other supraventricular and ventricular arrhythmias.^17,19 Additionally, increased norepinephrine has been shown to induce cardiac myocyte hypertrophy, which may have contributed to the changes seen on endomyocardial biopsy.²¹ Some of these theories have not been evaluated in veterinary medicine and are largely based on subarachnoid hemorrhage and traumatic head injuries in human medicine; therefore, they warrant further investigation. Furthermore, recent reports have shown increased C-reactive protein and oxidative stress in dogs with SRMA.^h,i These findings suggest that SRMA is a systemic disease, which may result in the potential for multi-organ involvement with this disorder.

No specific tests are available to definitively diagnose SRMA; therefore, a possible infectious etiology that remains undiagnosed might have contributed to this dog’s clinical signs. Suppurative meningoencephalitis is most commonly attributed to bacterial and immunological diseases, but less-common viral or other infectious etiologies cannot be excluded.^13,22 The etiology of SRMA remains unclear, and previous studies have not been able to isolate a consistent infectious cause. Likewise, premortem testing for inflammatory central nervous system disorders does not always yield accurate results when compared with postmortem analysis.²³

Although troponin I elevation and echocardiographic and ECG alterations were suggestive of myocarditis, this diagnosis was not supported by the endomyocardial biopsy results. The biopsy results demonstrated no visible inflammation but did show mild myocardial hypertrophy and acute reversible changes, which could represent an early stage of cardiomyopathy. This discrepancy of results may be attributed to several factors.

In human medicine, focal patterns of myocardial inflammation have resulted in up to 55% false negatives on histopathological analysis.^15,24 Biopsies obtained in this case (three 0.8- to 1-mm subendocardial fragments) were from the right ventricle using fluoroscopic guidance. Therefore, focal areas of disease may have been present that were not sampled due to limited sample access and small sample size. Also, several studies in human medicine have demonstrated low sensitivity and specificity for endomyocardial histopathology when used as the sole source of assessment for myocarditis.¹⁵ Additionally, reports in human medicine indicate that inflammatory cells are more commonly found in patients in whom biopsies are obtained early in the disease process.²⁴ In this case, a 3-week delay came between the initial and most severe cardiac alterations and the time when the endomyocardial biopsies were actually obtained. A repeat troponin may have provided additional information, but unfortunately it was not obtained.

Conclusion

The dog of this report had signalment, clinical signs, CSF results, and response to therapy that were most consistent with SRMA and a secondary myocarditis. The presence of myocarditis has not been previously reported to be associated with this disease. This case suggests that SRMA may be an additional cause of myocarditis that must be considered in the dog. Additional investigation into this association is warranted.