Speaker Bio
Kristin MacDonald, DVM, Ph.D., DACVIM (Cardiology)
Spring Seminar
March 8-10, 2024
Dr. Kristin MacDonald is the clinical cardiologist at VCA Animal Care Center of Sonoma, where she has a thriving cardiology practice including medical and interventional cardiology as well as participation in heart failure clinical trials. She is a national lecturer in cardiology for VCA and launched State of the Heart 2.0 for online cardiology education in VCA. Her veterinary education consists of earning a DVM degree from Auburn University, then completion of an internship in small animal medicine and surgery at Michigan State University. She finished a residency in veterinary cardiology at UC Davis and became a board-certified veterinary cardiologist in the American College of Veterinary Internal Medicine. She continued her education by earning a Ph.D. at UC Davis Comparative Pathology graduate group on hypertrophic cardiomyopathy in Maine Coon cats, and the effects of ACE inhibitors.
Dr. Kristin MacDonald
ECG Rescue: Diagnosis and Management of Arrhythmias
Kristin MacDonald, DVM, Ph.D., DACVIM (Cardiology)
1 CALIFORNIA ® VETERINARY MEDICAL ASSOCIATION
ECG Rescue: Diagnosis and Management of Arrhythmias
Kristin A. MacDonald, DVM, Ph.D., DACVIM (Cardiology) VCA Animal Care Center of Sonoma County
The primary indication for obtaining an electrocardiogram (ECG) is to evaluate an arrhythmia Patients with a history of syncope, episodic weakness, or collapse should be evaluated with an ECG. An ECG is an insensitive test for assessment of specif ic cardiac chamber enlargement, and interpretation of structural heart disease is best done using radiography and echocardiography. In order to simplify and standardize the process of ECG analysis, the interpreter should evaluate ECG’s in a specified order, which aids in interpretation of diff icult arrhythmias. The first step is to calculate the heart rate, either an average or an instantaneous rate. Average heart rate is the number of beats in 6 seconds x 10, or the number of beats in 3 seconds x 20. The instantaneous rate obtained by measuring the R-R interval (in seconds) of the particular beat (preceding beat is the first R to the beat of interest R), and dividing it into 60 s. The second step of ECG analysis is to assess whether the rhythm is regular or irregular, and if there is a pattern of the irregularity. Next, and most importantly, the rhythm is classified as either supraventricular or ventricular in origin. Supraventricular rhythms typically have narrow, upright QRS complexes in lead I, II, AVF, III, unless there is a bundle branch block. Ventricular arrhythmias have wide, tall or deep (negative) S waves, and have wide and bizarre T waves, and are not associated with a P wave. Assessment of the relationship of P waves to the QRS complexes is critical for determining many supraventricular and ventricular arrhythmias. At 50 mm/s and typically standard amplitude of 10 mm/mv, complex morphology (height and width of complexes, PR interval) should be measured. Lastly, the mean electrical axis is calculated, which can indicate whether there is a marked left or right axis deviation (normal MEA is 40-100 in dogs, 0-160 in cats). Right axis deviation is seen with right ventricular hypertrophy (normal QRS duration) or right bundle branch block (prolonged QRS duration).
Bradyarrhythmias are classified if the heart rate is < 80 bpm in small dogs, < 70 bpm in mediumlarge dogs, < 60 bpm in giant breed dogs, and < 120 bpm in cats. Sinus bradycardia is seen in animals with high vagal tone, sedation, hypothermia, sinus nodal disease, or increased intracranial disease (i.e., Cushings reflex). Sinus arrhythmia is a common normal variant, and often occurs in a pattern associated with respirations, where the heart rate increases during inspiration and decreases on exhalation. Often there is a wandering pacemaker, with changes in the P wave amplitude following the pattern of irregular rhythm (often there are taller P waves during inspiration when the heart rate increases) and is due to a shift in the location of sinus nodal depolarization associated with high vagal tone Sinus arrhythmia is often caused by high vagal tone, but some animals with early sick sinus
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syndrome may have what appears to be a pronounced sinus arrhythmia, which must be differentiated using an atropine challenge test. Sick sinus syndrome (SSS) is the most common arrhythmia in Schnauzers and Cocker Spaniels, and may also occur in other breeds SSS is composed of several arrhythmias, with sinus arrest (pause > 2 x RR interval) the sign ature of the disease. Other abnormalities include: sinus bradycardia, sinus arrhythmia, first and second-degree atrioventricular block (2DAVB). Supraventricular tachycardia (SVT) may precede sinus arrest (i.e., tachy-brady syndrome) Syncop e usually occurs when there is a pause of sinus arrest of > 6 seconds. An atropine challenge test is necessary to help differentiate sinus bradycardia or sinus arrhythmia due to high vagal tone f rom SSS. High dose atropine (0.04 mg/kg SC) is given and the ECG repeated 30 minutes later. Dogs with high vagal tone have regular sinus tachycardia, with HR > 140, and no pauses of sinus arrest or AV block. Dogs with SSS often have pauses of sinus arrest or suboptimal increase in rate (< 130 bpm). If there is a significant atropine response and the resting rate is slow (< 65), terbutaline, a nonselective beta agonist, can be given. If there is no clinical improvement, other anticholinergic agents such as propantheline could be given. Asymptomatic dogs with SSS have a signif icant risk of sudden death during general anesthesia, and require either a temporary pacemaker or isoproterenol constant rate infusion (CRI). A permanent pacemaker is the treatment of choice for symptomatic dogs with SSS Atrial standstill is a rare bradyarrhythmia, caused by severe hyperkalemia (reversible atrial standstill) or a serious atrial myopathy (permanent atrial standstill). ECG con sists of lack of P waves and a nodal or less commonly Purkinje escape. Electrolytes should be measured if this arrhythmia is seen, and atropine should be given. The prognosis for patients with atrial standstill and myopathy is very poor, and they are not ideal pacemaker candidates because they often quickly progress to develop severe right heart failure.
Atrioventricular blocks are another group of bradyarrhythmias. First degree AV block is defined by a prolonged PR interval, and all P waves are conducted and associated with QRS complexes. It does not cause a clinical problem, and is often caused by high vagal tone or cardiac antiarrhythmic medications. Second degree atrioventricular block (2DAVB) is divided into Mobitz type I (i.e., W enckebach) where there are progressively prolonging PR intervals preceding the dropped P wave, Mobitz type II where the PR interval does not prolong prior to the dropped P wave, and high grade 2DAVB where there are never 2 consecutively conducted P waves (can describe the ratio of P’s to QRS, such as 2:1, 3:1). High vagal tone may cause Mobitz type I 2DAVB. AV nodal disease can cause Mobitz type I, II, and always causes high grade 2DAVB. An atropine challenge test should be done for any animal with 2DAVB to assess the role of high vagal tone in the arrhythmia.
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Third degree AV block (3DAVB) is evidenced by lack of any association of P waves with QRS complexes, and is caused by severe AV nodal disease. Nodal escape beats have a supraventricular morphology and typically a rate of 40-60 bpm in dogs, and 80-100 in cats. Purkinje escape beats are wide and bizarre, ventricular beats occurring at a slower rate of 20-40 bpm in dogs, and 60-80 bpm in cats. Patients with high grade 2DAVB and 3DAVB often present for lethargy, collapse, or syncope . Lidocaine or other ventricular antiarrhythmic therapy (beta blockers, Mexiletine sotalol) is contraindicated for treatment of 3DAVB, even if there are ventricular premature beats, as it will likely eliminate the life-saving Purkinje escape beats. Dogs with high grade 2DAVB have equal risk as dogs with 3DAVB for sudden death, and have a 30% risk of dying suddenly within 6 months of diagnosis regardless of whether clinical signs are present. Dogs with high grade 2DAVB and 3DAVB should be treated with a permanent pacemaker. (1) 3DAVB is much better tolerated in cats than in dogs, because their escape rates are often quite fast (often 80-140 bpm). In a recent study, median survival of cats with 3DAVB was 386 days, and most died of non-cardiac causes. Only 1 cat received a permanent pacemaker, and no cats died suddenly. (2)
Supraventricular tachyarrhythmias are a broad category of arrhythmias arising f rom the AV node or atria. Sinus tachycardia consists of heart rate >160 bpm, with narrow upright QRS complexes and associate d P waves. The tachycardia gradually increases and decreases without an abrupt onset or break. It is often an important physiologic compensation for hypovolemia, anemia, fever, hypoxia, sepsis, hyperthyroidism, and many other systemic abnormalities, and does not require antiarrhythmic treatment. On the contrary, supraventricular tachycardia (SVT) is caused by an ectopic atrial focus or a re-entrant pathway involving the AV node or an accessory pathway. SVT may be initiated by a P wave that appears different from the sinus nodal P wave, and may be negative or buried in the preceding T wave. PR interval may be different than the sinus derived PR interval. Often SVT has a rapid rate of 200-300 bpm, and typically has an abrupt onset and termination. SVT in cats is often 300-400 bpm. SVT often causes syncope, and requires emergency treatment with intravenous antiarrhythmics including IV diltiazem (0.125-0.25 mg/kg slow IV over 1-2 minutes, repeating dose if ineffective), esmolol (0.25-0.5 mg/kg IV over 1-2 minutes), or adenosine. Cardioversion may be another option for refractory SVT. Ideally, an echocardiogram is done to assess myocardial f unction, since beta blockers should not be given if there is severe myocardial failure. Choices, in order of preference, for chronic therapy include diltiazem (1-4 mg/kg PO TID, often high doses are needed) or sotalol (1-3 mg/kg PO BID) Chronic tachycardia > 180 bpm for longer than a couple of weeks may lead to pacing induced myocardial failure, which is indistinguishable f rom idiopathic dilated cardiomyopathy (DCM) on echocardiography. Tachycardiomyopathy, however, is rapidly reversible once rate control has been established.
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Atrial flutter is an irregularly irregular supraventricular arrhythmia with narrow upright QRS complexes and saw-toothed flutter (F) waves with rate of 250-350 bpm. The ventricular rate is variable and depends on amount of vagal tone at the AV node, but is often very fast if heart failure is present. Atrial fibrillation appears similar to atrial flutter, except there are less distinct fibrillatory waves or undulating baseline. Both atrial flutter and atrial fibrillation are often associated with severe underlyin g cardiac disease, and heart failure is often present Antiarrhythmic therapy is aimed at decreasing the AV nodal conduction by prolonging AV nodal conduction time and refractory period, which decreases the number of wavelets that depolarize the ventricles. Chronic oral therapy is used to maintain the heart rate < 140 bpm, and choices include: diltiazem (0.5- 3 mg/kg PO TID, starting at low dose), atenolol (0.5-2 mg/kg PO BID), or sotalol (1-3 mg/kg PO BID). Digoxin increases vagal tone and may aid in slowing the ventricular response rate, but is not usually adequate to maintain adequate rate control in severely tachycardic cases. Some cardiologist prefer electrical cardioversion to regain sinus rhythm, but there may be high recurrence rates in patients with signif icant cardiac disease and cardiomegaly. Giant breed dogs may develop “lone” atrial fibrillation in the absence of structural heart disease, and may not require antiarrhythmic therapy if heart rates are in the normal range. “Lone” atrial fibrillation often foreshadows development of DCM in Irish Wolfhounds, so serial echocardiograms are needed over time.
Ventricular arrhythmias may occur due to abnormal automaticity of non-excitatory ventricular myocardial cells, enhanced automaticity of purkinje cells, or most commonly re-entrant circuits involving diseased ventricular myocardium. Ventricular premature complexes (VPC’s) are premature beats, with wide and bizarre QRS and T waves and no P wave. VPC morphologies include tall and wide QRS complexes (left bundle branch block morphology) that likely arise f rom the right ventricle or basilar interventricular septum, or deep (negative) S waves that likely arise from the left ventricle. R on T phenomenon, couplets, and triplets are a higher grade of malignancy. Although VPC’s may not be hemodynamically deleterious, they may identif y patients with signif icant structural or functional heart disease that require an echocardiogram. Ventricular arrhythmias are also common with other systemic diseases, after trauma, in post-surgical splenectomy or gastric dilation volvulus patients, and often improve with treatment of the underlying problem and tincture of time. Greater than 3 VPC’s in a row (instantaneous ventricular rate > 160 bpm) is considered non-sustained ventricular tachycardia, and signifies a highly malignant arrhythmia grade and risk of sudden death. Sustained ventricular tachycardia lasts longer th an 30 seconds, and often requires emergency treatment. Accelerated idioventr icular rhythm consists of a ventricular derived rhythm with a rate of 80-160 bpm, and is most often seen in systemically ill dogs or post-operative splenectomy or GDV patients, and does not typically require therapy.
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Holter monitors are necessary to help quantify the severity of ventricular arrhythmias, and are especially useful in Doberman Pinschers and Boxer dogs.
Normal dogs have < 50 VPC’s in 24 hours and there is a grey zone of 100-500 VPC’s/24 hours (for Boxers). (3) > 50 VPC’s in 24 hrs., 1 couplet or triplet in overtly normal Doberman Pinschers with normal echocardiographic studies was highly predictive of development of DCM. (4) Couplets, triplets, and non-sustained ventricular tachycardia are abnormal and require antiarrhythmic treatment Sustained ventricular tachycardia requires acute antiarrhythmic therapy and hospitalization. Lidocaine is the drug of choice (2-4 mg/kg IV, repeated to 6 mg/kg total cumulative dose followed by CRI 30-90 mcg/kg/min). Intravenous procainamide, esmolol, or amiodarone are other choices for refractory ventricular arrhythmias. Chronic antiarrhythmic treatment choices include sotalol (1- 3 mg/kg PO BID, mexiletine (5-7 mg/kg PO TID), and amiodarone (10-15 mg/kg PO BID x 7 days then 5-7 mg/kg PO q24 hr.). If there is severe decompensated DCM, atenolol and possibly sotalol should be avoided as they will further decrease contractility. Sotalol effectively decreases the severity of arrhythmia and reduces syncopal episodes in Boxers with arrhythmogenic right ventricular cardiomyopathy, and mexiletine may be added if there is inadequate control with solely sotalol.(5) Follow-up ECG and ideally holter monitoring is important after starting antiarrhythmic medication. Amiodarone is typically reserved for refractory ventricular arrhythmias or for treatment of severe ventricular arrhythmias in dogs with severe DCM.
Terminal arrhythmias include asystole, where there is lack of any electrical cardiac activity, and ventricular fibrillation. Both should be treated aggressively with immediate cardiac defibrillation (5-10 joules/kg extra thoracic), as well as emergency drugs including atropine and epinephrine. Asystole has very little chance of cardioversion, given the lack of electrical activity.
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Reference List:
1. Schrope, D. P. and Kelch, W. J. Signalment, Clinical Signs, and Prognostic Indicators Associated W ith HighGrade Second- or Third-Degree Atrioventricular Block in Do gs: 124 Cases (January 1, 1997-December 31, 1997). J Am Vet Med Assoc.2006.J un.1;228.(11):1710.-7. 6-1-2006;228:1710-7.
2 Kellum, H B. and Stepien, R. L. Third-Degree Atrioventricular Block in 21 Cats (1997-2004). J Vet Intern Med.2006.Jan.-Feb.;20.(1):97.-103. 2006;20:97-103.
3 Ulloa, H. M , Houston, B. J., and Altrogge, D. M. Arrhythmia Prevalence During Ambulat ory Electrocardiographic Monitoring of B eagles. Am.J.Vet.Res. 1995;56:275-81.
4 Calvert, C. A., Jacobs, G. J., Smith, D. D., Rathb un, S. L., and Pickus, C. W. Association Between Results of Ambulatory Electrocardiography and Development of Cardiomyopathy During Long-T erm Follow-Up o f Doberman Pinschers. J Am Vet Med Assoc.2000.Jan.1;216.(1):34.-9 1-1-2000;216:34-9.
5. Meurs, K. M., Spier, A. W., Wright, N. A., Atkins, C. E., DeFrancesco, T. C., Gordon, S. G., Hamlin, R. L., Keene, B. W., Miller, M. W., and Moise, N. S. Comparison of the E ffects of Four Antiarrhythmic Treatments for Fami lial Ventricular Arrhythmias in Boxers. J Am Vet Med Assoc.2002.Aug.15.;221. (4):522.-7 8-15-2002;221:522-7.
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Is It Heart or Not?
Kristin MacDonald, DVM, Ph.D., DACVIM (Cardiology)
9
VETERINARY
CALIFORNIA ®
MEDICAL ASSOCIATION
Is It Heart or Not?
Kristin MacD onald, DV M, Ph.D., DACVIM (Cardiology)
VCA Anim al Care Center of Sonom a County
Coughing dogs comprise a substantial part of clinical caseload, yet often are viewed with frustration or trepidation. Dyspneic animals are also viewed with dread as they may have lif e threatening problems that require time-sensitive assessment and treatment. The clinician is faced with challenging diagnostic pathways to determine the cause of the cough or dyspnea and thereby formulate an appropriate treatment plan. This is complicated by the high f requency of concurrent cardiac and re spiratory disease in dogs. Many small breed dogs have he art murmurs and concurrent cough, and clinical signs of heart failure and pulmonary disease greatly overlap. What can be done to better define causes of respiratory signs in dogs?
Small breed dogs most commonly su ffer from cough of various etiologies: collapsing trachea, chronic bronchitis, pulmonary disease, or cardiac causes including congestive heart failure or left mainstem bronchial compression from left atrial dilation. When obtaining a clinical history, the characteristics of the cough, precipitating events causing cough, and pulmonary abnormalities may be ascertained. Review of a movie of the cough may be helpful to assess if it is a typical honking, high pitched cou gh often heard with collapsing trachea. If cough mostly o ccurs with excitement or drinking, this may also be more likely to be large airwa y related. A h acking cou gh with terminal retch is n on-specific and is common in both lower airway disease, pulmonary disease, or heart failure. In addition to cough, it is important to inquire whether the dog is having effortful, labored, fast breathing even when sleeping, or restless nature and unable to sleep at night due to breathing problems. These respirator y abnormalities are more likely to be caused by pulmonary parenchymal disease or h eart failure. Owners can be trained to obtain resting respiratory effort while the dog is sleeping and undisturbed to quantify whether resting tachypnea is present. Resting respiratory rates greater than 30 breaths/min may suggest congestive heart failure or pulmonary parenchymal disease.
Physical examination
Older, small breed dogs are often af fected with mitral valve degeneration and chronic airway disease, making it likely there may be a left apical holosystolic murmur present on examination. A soft I-II/VI mitral murmur in a small breed dog makes it less likely that the do g has left heart failure and more likely that there is a respiratory cause of the cough.
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However, there is tremendous overlap in murmur severity and severity of mitral regurgitation in dogs with moderate grade murmurs (III-IV)/VI.
Murmur intensity in medium to large breed do gs is not useful to predict severity of heart disease since there may be a soft left apical systolic murmur in the face of severe dilated cardiomyopathy and heart failure. Presence of a soft S3 gallop heart sound (soft low intensity thud after S2), or arrhythmias may increase suspicion for dilated cardiomyopathy in medium to large breed dogs. Respiratory sinus arrhyth mia or mildly slow heart rates are common in small breed dogs with chronic lower airway disease causing high vagal tone. Sinus tachycardia increases suspicion of heart failure and activation of sympathetic tone.
Thorough assessment of the respiratory characteristics of breathing in the examination room may help provide initial clues to the location of the pulmonary abnormality. Before touching the dog, observe the dog breathing. Increased abdominal component to breathing, exaggerated thoracic wall motion, and tachypnea may be present in dogs with heart failure or pulmonary parenchymal disease. Pulmonary auscultation in dogs with lower airway disease or pulmonary parenchymal disease often reveals course crackles, expiratory wheezes, or increased adventitious lung sounds. Congestive he art failure may cause increased adventitious lung sounds or soft crackles, but there are often normal bronch ovesicular lung sounds unless severe h eart failure is present. Auscu ltation of “clear lungs” is impossible, as there may be pulmonary edema present despite normal pulmonary auscultation. High pitched wheezing on inspiration may be present with extra thoracic tracheal collapse. Loud, harsh high pitched inspiratory laryngeal noise may be present in dogs with laryngeal disease. Tachypnea with restrictive breathin g motion (fast and shallow b reaths) and muffled lung sounds is suggestive of pleu ral effusion, and warrants triage thoracic u ltrasound or thoracic radiographs if ultrasound is unavailable.
Thoracic radiography
Thoracic radiographs are the highest priority for diagnostic testing in dogs with respiratory abnormalities. Collimation should include the neck to visualize the extra thoracic trachea. Assessment of the heart size subjectively and objectively with vertebral he art siz e measurement is helpful to assess the likelihood of heart failure. Left atrial size should be carefully assessed, since left atrial dilation should be present in patients with left heart failure unless it is peracute, such as in cases of in fective e ndocarditis. Left atrial dilation can be visualized as: straightening of the caudal waist on the lateral vie w, left auricular dilation on the DV or VD view at 3:00 p osition, and double opacity sign of left atrial enlargement between the mainstem bronchi on DV or VD view. The carina and mainstem bronchi sh ould be carefull y evaluated for collapse if there is bronchomalacia, or compression if there is left atrial dilation.
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Pulmonary vasculature should be assessed for pulmonary venodilation in dogs with left he art failure or pulmonary arterial dilation in patients with pulmonary hypertension. Thoracic radiographs are an essential tool to diagnose congestive heart failure. Presence of left atrial dilation and cardiomegaly, as well as perihilar to caudodorsal interstitial to alveolar pulmonary infiltrates, with or without pulmonary venous distension is pathognomic for left he art failure in dogs. Thoracic radiographic abnormalities of left he art failure in cats is much more variable, but classic abnormalities include cardiomegaly and left atrial dilation, pulmonar y venous distension, diffuse interstitial to alveolar pulmonary infiltrates or pleural e ffusion.
Pulmonary parenchymal abnormalities often overlap in dogs with cardiac or respirator y disease. In particular, the interstitial or bronchointerstitial pulmonary patterns is commonly present in dogs with either pulmonary disease or heart failure. A perihilar to caudodorsal pulmonary pattern of infiltrates occurs with left he art failure, but can also be present in primar y pulmonary disease. Bronchial thickening (i.e., donuts) is common in dogs with lower airwa y disease such as chronic bronchitis. Cranial or cranioventral pulmonary inf iltrates rarely are caused by he art failure unless there is diffuse flooding of all lung lobes with an alveolar pulmonary pattern. Pulmonary masses (i.e., primary pulmonary neoplasia) and pneumonia can be impossible to differentiate on 3 view thoracic radiographs, and either requires serial radiographs during antibiotic therapy to assess change in infiltrates, or may require a thoracic CT scan +/- thoracic ultrasound. Ultrasound guided fine needle aspirates of pulmonary masses may be considered for cytologic evaluation. Pleural e ffusion can be caused by either intrathoracic non-cardiac disease or he art failure from right heart or biventricular heart disease. Pleural effusion should be removed for therapeutic and diagnostic reasons, and fluid analysis and cytology pe rformed at a laboratory. It is often helpful to repeat radiographs after thoracocentesis to visualize the intrathoracic structures and assess heart size.
NT-proBNP Biomarker
In some cases, physical examination and thoracic radiographs do not conclusively differentiate pulmonary disease vs. congestive heart failure as a cause of the cough or dyspnea. Nt-proBNP is a cardiac biomarker test (Cardiocare®, IDEXX laboratory) that may help differentiate between respiratory disease and heart failure in dyspneic dogs: a cutoff of >1725 pmol/L is highly sensitive (88%) and specific (77 %) for diagnosis of CHF.1 Other causes of elevated NT-proBNP include precapillary pulmonary hypertension or cardiomegal y without heart failure, which may complicate interp retation of the results in dogs with respirator y signs.
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NT-ProBNP was higher in dogs with precap illary pulmonary hyperte nsion (n=12; 2011 pmol/l) compared to control dogs with respiratory disease and no pulmonary hypertension (n=8;744 pmol/l). Renal failure may be associated with increased Nt-proBNP in dogs and people, but a recent study documented that Nt-ProBNP was not independently associated with mean glomerular filtration rate in dogs. A negative Nt-proBNP in a symptomatic dog makes heart failure unlikely. However, dogs may have concurrent heart disease leading to elevated NtproBNP as well as underlyin g respiratory disease. Therefore, like any diagnostic test, it must be combined with other clinical parameters for appropriate interpretation.
Energy Exercise
Body Condition N or N or Sleeping breathing N or Heart rate N or +/-
arrhythmia
Cardiac Pulmonary
May be normal Cough may limit activity
Sinus
Pulmonary auscultation N or lung sounds Crackles, Wheezes Adventitious sounds
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Cough Soft, hacking Honking or wheeze if LMSB Dry, honking, harsh NtProBNP
N or mild
Echocardiography
Echocardiography is indicated in dogs with evidence of cardiomegaly on radiographs, dogs with suspicion of congestive h eart failure on radiographs, or in dogs with a murmur and uncertainty of cause of re spiratory signs. It also is an important test to evaluate for pulmonar y hypertension in dogs with chronic pulmonary disease, especially if there is a history of syncope or a right sided murmur on physical examination.
Triage echocardiogram
Evaluation of left atrial size is the most critical echocardiographic measurement when assessing if respiratory signs are caused by heart disease. Presence of left atrial dilation makes heart failure a possible or likely differential, and should be combined with thoracic radiographs to evaluate for pulmonary edema. Left atrial dilation may be present witho ut heart failure, and could cause cough due to compression of the left mainstem bronchus. This would be ascertained by thoracic radiography. Left atrial dilation is usually moderate or severe (LA:Ao >1.8-2) in dogs with left heart failure due to mitral valve degeneration or dilated cardiomyopathy, except for peracute heart failure which may occur with infective endocarditis or primary chordae tendineae rupture. Left ventricular size and systolic function is also important in diagnosing specific cardiac disease as well as treatment decisions for medications that are indicated or contraindicated. For example, dogs with acute heart failure from dilated cardiomyopathy should not be given negative inotropes such as beta blockers and may not tolerate sotalol for treatment of tachyarrhythmias.
Evaluation of pulmonary hypertension requires a higher level, detailed echocardiogram better suited for a cardiologist to perform. Right ventricular concentric and eccentric hypertrophy, right atrial dilation, and pulmonary artery dilation are hallmarks of cor pulmonale secondary to p recapillary pulmonary hyp ertension. Some dogs with severe left heart disease have less obvious right sided cardiac changes despite severe pulmonary hypertension. Measurement of the tricu spid regurgitation velocity and calculated right ventricular to right atrial pressure gradient confirms presence of pulmonary hypertension and helps determine severit y (50-75 mmHg mod erate; >75 mmHg severe). Do gs with pulmonary signs attributed to precapillary pulmonary hypertension typically have moderate to severe pulmonary hypertension. Often dogs with chronic left heart failure from severe mitral valve disease also have pulmonar y hypertension which may contribute to dyspnea and hypoxemia. This can also be diagnosed with a detailed echocardiogram.
Additional testing
Additional respiratory diagnostic tests may be indicated in patients with suspected primary respiratory disease, and may include a respiratory PCR panel for common respirator y pathogens, bronchoscopy, or thoracic CT scan.
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Comprehensive minimum data based would include complete blood count, blood chemistry, thyroid level, heartworm antigen, and urinalysis. Pulmonary thromboembolism, heartworm disease, chronic pulmonary disease, or idiopathic pulmonary arteriopathy are common causes of pre capillary PH, and require further systemic workup. While not commonly done, arterial blood gas can be obtained, and is often abnormal in dogs with PTE, including: hypoxemia, hypo capnia, and increased alveolar-to-arterial gradient However, normal arterial oxygenation does not exclude the diagnosis of PTE. If there is proteinuria, urine protein creatinine (UPC) ratio should be measured, and if abnormal then plasma anti-thrombin III should be measured. Hyperadrenocorticism should be evaluated if there are corresponding clinical signs.
Plasma D-dimer is a useful screening test in people and animals for PTE. D-dimer is a breakdown product of cross-linked fibrin (from a stabilized clot), which is produced when fibrin is degraded by plasmin. Plasma D-dimer is used in the diagnosis of PTE in humans, with 96% sensitivity and 52% specificity. D-dimer appears to be highly sensitive (10 0%) for diagnosis of pulmonary thromboembolism in dogs, since all 20 dogs had elevated D-dimer > 500 ng/dl in one study. Larger studies need to be conducted to verify these early findings. The author has had two cases wh ere th ere was an abnormal pe rfusion scan indicative of PTE in the face of normal D-dimer con centration. Elevated D-dimer is not specific for PTE, and may be increased with DIC, hepatic disease, or other fibrinolytic conditions.
Treatment
All treatment decisions for dogs with respiratory abnormalities hinges on differentiatin g whether the cause is cardiac vs. primary pulmonary disease. The treatment of primar y pulmonary disease often involves broad spectrum pulmonary therapies including assessment for infectious etiologies and appropriate selection of broad-spectrum antibiotics for common pulmonary pathogens, bronchodilators, cough suppressants (i.e., hydrocodone), and often corticosteroids. Inhalant therapy can be consid ered for delivery of steroids to the lungs with less systemic e ffects. Specific respiratory therapies are beyond the scope of this lecture. Oxyge n therapy is also a mainstay for treatment of dyspnea and hypoxemia of either respiratory or cardiac cause.
Precapillary pulmonary hypertension may be secondary to chronic respiratory disease, so broad sp ectru m respiratory therapy is often instituted in addition to pulmonary arterial vasodilation with sildenafil (1-3 mg/kg PO BID-TID up-titrating based on clinical signs and echocardiographic parameters). Patients with suspected PTE should be treated with either anticoagulant therapy in hospital (heparin or low molecular weight hep arin) +/- antiplatelet therapy with clopidogrel (10 mg/kg PO once then 3- 5 mg/kg PO q24 hr) in hospital and chronic at home therapy if often continued with clopidogrel Treatment should also be focused on th e underlying systemic disease (if identified) that may have been responsible f or PTE. Steroids are contraindicated in treatment of PTE unless they are necessary for specific
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u nderlying disease, since they have been sho wn to increase clot strength and decrease clot lysis in healthy dogs after 1 week of therapy.
Treatment of left heart failure will be discussed in the following lectures. M oderate to severe but compensated mitral regurgitation (Stage B2) may cause cough due to left mainstem bronchial compression, and is often treated with p imobendan (0.25 mg/kg PO BID), a cough suppressant (hydrocodone 0.25 mg/kg PO BID-TID), and often an ACE inhibitor (enalapril, benazepril 0.5 mg/kg PO BID).
Reference List
1.Oyama MA, Fox PR, Rush JE, et al. Clinical utility of serum N-terminal pro-B-type natriuretic peptide concentration for identifying cardiac disease in dogs and assessing disease severity. J Am Vet Med Assoc 2008 May 15 ;232 (10):1496 -503 2008;232:1496-1503.
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A Dog’s Journey with Mitral Valve Disease
Kristin MacDonald, DVM, Ph.D., DACVIM (Cardiology)
19 CALIFORNIA ® VETERINARY MEDICAL ASSOCIATION
A Dog’s Journey with Mitral Valve Disease
Kristin MacDonald, DVM, PhD, DACVIM Cardiology
VCA Animal Care Center of Sonoma, Rohnert Park, CA
Mitral valve disease (MVD), i.e. myxomatous valve disease or mitral valve degenera�on, is the most prevalent and important heart disease in veterinary cardiology, and comprises 75% of our cardiology cases. General prac��oners are at the front lines for iden�fica�on of a new murmur, which then opens the door to staging of heart disease with diagnos�c tes�ng. With the support of evidenced base medicine, there are medical management recommenda�ons based on the stage of heart disease, with the ul�mate goal of improvement in quality of life and clinical outcomes.
Breed predilec�on
MVD is most common in older (>7 yrs. of age), male, small breed dogs (<20 kg). Cavalier King Charles o�en develop a murmur at an earlier age (mean age 6 yrs) than other breeds, and have the highest prevalence of MVD of all dog breeds (Odds ra�o 47).1 Other highly predilected breeds include: chihuahua, Whippet, Poodle, Dachshund, Yorkshire Terrier, and Schnauzer.1 Many other small breed dogs are affected with MVD as well as some medium to large breed dogs such as the German Shepherd dog and Border Collie.
E�ology of MV disease
Mitral valve degenera�on is a disorder of the extracellular matrix of the valve characterized by mitral valve thickening and weakening of the valve apparatus, leading to valvular prolapse, possible rupture of the chordae tendineae, and resul�ng in mitral regurgita�on. There is expansion of the inters��al valve layer with glycosaminoglycan and proteoglycan, fragmenta�on of elas�n, and disrup�on and loss of collagen. Valvular inters��al cells become transformed to myofibroblasts. There is a complex system of interac�ve pathways involved in the process of valvular degenera�on including mechanical and shear stress, neurohormonal ac�va�on, serotonin pathways, TGFB1 and related pathways, and changes in regulatory cellular developmental pathways, which lead to the phenotype of the thickened, prolapsing degenera�ve mitral valve.
ABCD Heart Disease Staging
Staging canine heart disease using the ACVIM ABCD system helps define appropriate workup and treatment depending on the severity of the disease, which can be helpful to adopt into general clinical prac�ce.3 Dogs with no cardiovascular abnormali�es that are gene�cally predisposed to develop cardiac disease may be considered Stage A (i.e. Cavalier King Charles Spaniels). Asymptoma�c dogs with a cardiovascular abnormality (i.e. murmur) are a Stage B, which is subdivided into B1- no cardiac enlargement, and B2- cardiac enlargement but no
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conges�ve heart failure. A Stage C dog has either current conges�ve heart failure or history of heart failure and receives heart failure medica�ons. Dogs with refractory heart failure that have symptoms despite high furosemide doses of > 8 mg/kg/day, RAAS antagonists, and pimobendan are Stage D.
Stage A MV disease
Ausculta�on for a le� apical systolic heart murmur is the main monitoring tool for predisposed breeds or any middle aged to older dog in clinical prac�ce. Ausculta�on of a le� sided systolic murmur is not specific for MV disease, but indicate the need for further evalua�on with an echocardiogram. The combina�on of echocardiography and ausculta�on in a Danish breeding program for Cavalier King Charles spaniels reduced the prevalence of MVD by 73% over an 8-10year period in one study.2
Stage B MV disease diagnos�c tes�ng
The day has come where you first iden�fy a le� apical systolic murmur, likely on a rou�ne health appointment or for evalua�on of another problem. Based on pa�ent signalment, i.e. <20 kg adult to geriatric dog and murmur characteris�cs, the most likely cause of the le� apical systolic murmur is mitral valve disease. Other ddx that are less common would include func�onal mitral regurgita�on secondary to dilated cardiomyopathy or diet associated cardiomyopathy, infec�ve endocardi�s, or innocent/func�onal murmur. An echocardiogram is necessary to determine the specific e�ology of the murmur, as well as most accurately stage the disease. However, an echocardiogram may not be available or feasible, so the GP must reach for other tools to evaluate the new murmur pa�ent.
Thoracic radiographs are priori�zed for the first step to assess a new murmur in a small breed older dog. Determina�on of whether there is cardiomegaly and le� atrial dila�on is necessary to differen�ate between stage B1 and stage B2, which has treatment and prognos�c implica�ons. Subjec�ve assessment of cardiac size can some�mes be misleading on radiographs, and may falsely diagnose cardiomegaly when not present, or conversely miss cardiomegaly when present on an echocardiogram. An objec�ve measurement of heart size may be done using a vertebral heart size (VHS) measurement. The purpose for indexing the heart size to vertebrae lengths is to lessen the effect of chest conforma�on (deep vs.broad shaped chest conforma�ons) on subjec�ve assessment of heart size, and provide a measurement that can be chronologically compared over �me. VHS of 10.7 vertebrae or larger accurately (78% accuracy) discriminates dogs with cardiomegaly and heart disease from normal dogs.2 A helpful resource is the James Buchanan Cardiology Library Vertebral Heart size, available on Vin.com, with a link posted at the following URL: htp://research.vet.upenn.edu/smallanimalcardiology/JamesBuchananCardioLibrary.
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A VHS of 11.5 units or greater was the most accurate VHS value predic�ng echocardiographic classifica�on of Stage B2 mitral valve disease dogs who fit the criteria for early use of pimobendan. 3 There is a grey zone of 10.7- 11.5 in which dogs may or may not have stage B2 MV disease. If the pa�ent is not going to be referred for an echocardiogram, or if there is a delay in �me to referral, iden�fica�on pa�ents who should be started on pimobendan based on EPIC clinical trial results is appropriate, and in absence of an echocardiogram would include radiographic abnormali�es of cardiomegaly, le� atrial dila�on, VHS >11.5, and > III/VI le� apical holosystolic murmur in an older small breed dog. Measurement of vertebral le� atrial size (VLAS) is another radiographic parameter that can be used to predict echocardiographic criteria for MV stage B2, with measurements of >2.8- 3 highly predic�ve for le� atrial dila�on.3,4 Serial radiographs are helpful to assess for progressive cardiomegaly, either subjec�vely or objec�vely by measuring VHS, which may predict high risk for decompensa�ng with heart failure within 6 months.5 Dogs with stage B1 MV disease can be evaluated annually, but dogs with stage B2 MV disease should be evaluated more frequently every 6 months.
ProBNP levels in Stage B Mitral valve disease
ProBNP is most accurate in differen�a�ng symptoma�c dogs with heart failure from primary respiratory disease. Diagnosis of stage B2 MV disease using ProBNP is less accurate. A Pro-BNP >1100 was insensi�ve (53% and moderately specific (specificity 85%, PPV 57%) for differen�a�on of stage B2 from B1 MV disease.1 An elevated ProBNP was predic�ve of development of heart failure within the next 12 months in dogs with MV degenera�on with moderate sensi�vity of 80% and specificity of 76%.6 Similarly, pa�ents with a ProBNP >1500 had a 6 fold increase in risk for developing heart failure within 3-6 months in another study. 7
Treatment of Stage B2 MV disease
The EPIC clinical trial is a landmark clinical trial evalua�ng effects of pimobendan versus placebo in 360 small breed dogs (<15 kg) evenly divided between treatment groups with Stage B2 MV disease. It was terminated early due to beneficial effects of pimobendan extending �me to a composite of conges�ve heart failure or cardiovascular death by approximately 15 months (pimobendan 1228 days vs. placebo 766 days).8 Risk of development of heart failure was reduced by 1/3 in the pimobendan group. All- cause mortality was the secondary endpoint, which was prolonged in dogs treated with pimobendan by approximately 5 months (pimobendan 1059 days versus placebo 902 days). Longitudinal analysis of heart size and clinical variables demonstrated that dogs treated with pimobendan had reduc�on in le� atrial size, le� ventricular eccentric hypertrophy, increased systolic func�on at day 35, and overall heart size assessed by VHS was smaller than placebo over the dura�on of the 5-year study.9 Reduc�on in le� atrial and le� ventricular size was associated with prolonged �me to heart failure or cardiac death.
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Once dogs developed heart failure, echocardiographic measurements of heart size were not different between pimobendan and placebo groups. Extrapola�on of these data to larger dogs with Stage B2 MV disease seems clinically acceptable. There is a lack of evidence showing beneficial effects of early ACE inhibitor treatment in Stage B2 dogs with mitral valve disease. Two large-scale, blinded, randomized, placebo controlled clinical studies (SVEP and VETPROOF) failed to show an improvement in survival or increased �me un�l development of CHF when treated prior to heart failure with enalapril.10,11 ACE inhibitors may be considered in dogs with marked progression in cardiomegaly who may be deemed on the cusp of heart failure, but the author does not prescribe them in typical B2 MVD dogs. Likewise, the combina�on of benazepril and spironolactone (Cardalis) failed to prolong �me to heart failure in dogs with stage B2 MV disease, but did reduce NT-ProBNP biomarker for cardiac enlargement and wall stress compared to placebo.
GP monitoring of Stage B2 MV disease pa�ents
General prac��oners are well suited for chronic monitoring of mitral valve disease pa�ents to assess risk for decompensa�ng or evidence of early heart failure. Once a dog is placed on pimobendan, recheck radiographs and blood pressure should be done every 6 months. Progressive increase in radiographically assessed cardiomegaly (ideally with VHS measurement) over a 6-month period of �me may predict high risk for developing heart failure in the near future. Owners should be trained on how to monitor sleeping respiratory rates and know the normal baseline RR for their pet. Progressive, persistent tachypnea should trigger the client to contact the doctor, and o�en pa�ents will need to be seen to obtain thoracic radiographs to assess if heart failure has developed. An annual evalua�on by the cardiologist including an echocardiogram can be considered to assess for evidence of advanced MV disease or development of pulmonary hypertension.
ProBNP levels may aid in assessment of risk of heart failure in preclinical MV disease. An elevated Nt-ProBNP predicted onset of CHF in 12 months with a moderate sensi�vity and specificity (80% and 76% respec�vely).3 Likewise, dogs with a proBNP >1500 had 6-fold higher risk for CHF within 3- 6 months than dogs with normal proBNP levels.2 This may impact treatment decisions and require closer and more frequent monitoring. Not all stage B2 mitral valve disease dogs are guaranteed to develop heart failure in their lives, and the �me un�l heart failure can vary widely but may be quite prolonged. For example, in the EPIC trial, 43% of dogs treated in the pimobendan group developed heart failure over a mean �me of 3.5 years, compared to 50% of dogs receiving placebo developed heart failure over a mean of 2 years. This extension in symptom free �me is meaningful, with less medica�ons required and less impact of disease on the dog in the preclinical phase.
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Stage C heart failure
The day has finally come… You receive a call from your client that her dog with mitral valve disease is restless, lethargic, and has respiratory signs of dyspnea and tachypnea. Clinical signs of coughing, dyspnea, or tachypnea are present. A moderate or loud le� apical systolic murmur is present in small breed dogs with MV disease. Thoracic radiographs are priori�zed, and criteria for heart failure are met, including: le� atrial dila�on, cardiomegaly with increased VHS >10.7 (typically >11.5 with CHF), inters��al to alveolar perihilar to caudodorsal pulmonary infiltrates, and o�en pulmonary venous distension. Blood pressure is measured to assess for evidence of low output heart failure with hypotension, or systemic hypertension which would drama�cally worsen severity of mitral regurgita�on due to increased a�erload. Your pa�ent has graduated from stage B2 to stage C heart failure!
Measurement of circula�ng biomarkers, especially ProBNP, is useful to help differen�ate whether dyspnea is due to CHF or primary respiratory disease in dogs and cats. ProBNP levels (Cardiocare®, IDEXX laboratory) have been evaluated for differen�a�on of CHF from primary respiratory disease in dyspneic dogs, and a cutoff of >1725 pmol/L is highly sensi�ve (88%) and specific (77%) for diagnosis of CHF.12 There is a point of care, quan�ta�ve assay newly available for dogs, which is being evaluated clinically (Vcheck by Bionote).b
In the stable outpa�ent, the standard therapy for CHF includes “quad therapy” of: furosemide, an angiotensin conver�ng enzyme (ACE) inhibitor, spironolactone, and pimobendan. The dose and route of administra�on of furosemide varies depending on the severity of the CHF and the stability of the pa�ent. Dogs with mild heart failure may be managed with lower furosemide doses (typically 1-2 mg/kg PO BID, usually star�ng higher then decreasing based on recheck results and clinical signs). Oral bioavailability is only ~50% with marked individual variability. When administered intravenously, the diure�c effect is seen 5 minutes post-IV injec�on, with a peak diure�c effect 30 minutes post IV injec�on, and dura�on of diuresis 2- 3 hrs. When given orally, the diure�c effect is seen by 1 hr, with a peak effect at 1-2 hrs., and dura�on of diuresis 6 hrs. Emergency use of furosemide includes doses of 2- 4 mg/kg IV q2 -8 hrs., tapering to lower dose and longer frequency interval as dyspnea improves. In dogs not responding to high dose (4 mg/kg IV) boluses of furosemide, dobutamine may be necessary to improve renal blood flow and delivery of the furosemide to the kidney, as well as considering switching to a furosemide CRI of 1 mg/kg/hr for 6-8 hrs., which is tapered to 0.66 mg/kg/hr as dyspnea resolves and RRs decrease to <40- 50 breaths per minute.
Pimobendan (0.25 mg/kg PO BID) has drama�cally improved outcomes in chronic heart in dogs with CHF secondary to DCM or mitral regurgita�on. Pimobendan is a phosphodiesterase III (PDE III) inhibitor and a calcium sensi�zer, which exerts powerful posi�ve inotropic and vasodilatory effects.
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Benefits of pimobendan in dogs with stage C heart failure from MV disease have been documented in several clinical trials, including prolonged survival �me, reduc�on in clinical signs and heart failure class when compared to benazepril (QUEST study; pimobendane MST 267 days benazepril 140 days).13 14
ACE inhibitors have been the standard choice for RAAS antagonism, and are indicated for treatment of CHF in dogs and cats. Dogs benefit from improved quality of life as well as survival, and one study demonstrated a 55% reduc�on in risk of worsened heart failure.15 The IMPROVE trial showed that enalapril resulted in very modest acute reduc�ons of pulmonary capillary wedge pressure and arterial blood pressure in dogs, but greater long term clinical improvement was seen only in the DCM group and not the mitral regurgita�on group.16 Other clinical trials found improved symptoms and survival in both DCM and mitral regurgita�on groups.
Aldosterone breakthrough occurs in approximately 40-50% of dogs, cats, and humans receiving an ACE inhibitor. It is characterized by an increase in blood or urine aldosterone concentra�on despite adequate ACE inhibi�on. Aldosterone has many deleterious effects on the cardiovascular system in heart failure pa�ents, including sodium and water reten�on, adverse cardiac remodeling including myocardial fibrosis, adverse vascular remodeling and endothelial dysfunc�on, and baroreceptor dysfunc�on. Addi�on of an aldosterone receptor blockers (spironolactone) to ACE inhibitors can provide a more comprehensive RAAS blockade. Timing of when to add an aldosterone receptor blocker to standard triple therapy has been specula�ve and o�en based on clinical preference. O�en, spironolactone is added with progressive heart failure. However, a shi� to earlier aldosterone blockade in heart failure pa�ents may be supported by data from the BESST trial.17 The BESST clinical trial demonstrated superiority of the combina�on spironolactone and benazepril over benazepril alone in dogs with stage C MVD (heart failure). Fewer dogs on spironolactone- benazepril combina�on reached end point of worsened heart failure or cardiac death at day 360 than benazepril alone. Secondary endpoints were also met including less dogs achieving cardiac endpoint at all �me points except day 30, with prolonga�on to worsened heart failure or death in the spironolactone benazepril group.
Low salt diets can be considered in dogs with Stage C heart failure, especially in those with progressive heart failure or stage D heart failure. Low salt diets (0.15- 0.2 g sodium/1000 kcal, 50-80 mg sodium/ 100 kcal) will help limit sodium and water reten�on. A comprehensive and frequently updated list of low salt diets and treats is available at Tu�s Veterinary Medical School Heartsmart nutri�on website (htps://heartsmart.vet.tu�s.edu).
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Can I start heart failure medica�ons without an echocardiogram?
Most heart failure dogs require medical interven�on before an echocardiogram can be arranged. Star�ng “Quad” therapy (furosemide, pimobendan, ACE inhibitor, spironolactone) is jus�fiable and recommended in dogs with high likelihood of heart failure based on radiographic and clinical abnormali�es. ProBNP blood levels can also be measured to provide further informa�on on likelihood of heart failure causing the clinical signs. A proBNP of >1725 pmol/L is highly sensi�ve (88%) and moderately specific (77%) for diagnosis of CHF in symptoma�c dogs.3 If uncertain of heart failure diagnosis, a furosemide trial can be done with 2 mg/kg PO BID of furosemide, while the owner monitors res�ng RR and assesses response to therapy including respiratory effort and cough severity. Baseline and repeat radiographs can be compared to assess if pulmonary infiltrates improve on furosemide. If a posi�ve response clinically and radiographically is seen, quad therapy can be ins�tuted.
For chronic heart failure pa�ents, the mantra of proac�ve, prospec�ve rechecks is encouraged. A recheck in 3-4 months a�er the first post-acute recheck is recommended, including blood pressure, radiographs, and blood work. Some stable chronic heart failure pa�ents are able to minimize appointments to every 6 months, but clients should be highly discouraged from cancelling recheck appointments since their pet is doing so well, as o�en there is a boomerang effect when the dog severity decompensates which may have been iden�fied earlier during a rou�ne recheck appointment.
Cardiologist involvement
Ideally an echocardiogram should be obtained to establish diagnosis of cause of murmur, severity of heart disease (i.e. HF staging), and whether heart failure is present. An echocardiogram is also highly priori�zed in dogs with right sided murmurs, syncope, or dogs not responding to heart failure therapy that had clinical suspicion of heart failure. Any young dog with a murmur, (especially > 2/6 systolic, or other murmur characteris�cs such as con�nuous or right sided) would be a high priority referral to a cardiologist to evaluate for congenital heart disease with a detailed echocardiogram. Cardiologists can be instrumental in diagnosis and management of tachyarrhythmias that may develop in dogs with stage C heart failure. Dogs with progressive C to D heart failure also can be very challenging cases to manage, and may benefit from cardiology referral or management. O�en, the integrated approach of cardiologists and generalists working together for chronic heart failure management can be very effec�ve. General prac��oners can see pa�ents for rou�ne rechecks, and cardiologists may see them less frequently for an echocardiogram or for more in-depth assessment of syncopal or arrhythmic pa�ents.
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Expected survival �mes for stage C mitral valve disease may be around 1 year. The QUEST study documented MST of 9 months in dogs given furosemide and pimobendan.14 The earlier ACE inhibitor studies demonstrated an increased in MST of ~ 3 months, and addi�on of spironolactone to benazepril was demonstrated to reduce all -cause mortality and cardiovascular mortality, with a 40% reduc�on in risk of cardiac death over the 1 year study.15,17 Average survival �me of dogs receiving “Quad” therapy has not been evaluated in clinical trials at this �me, but likely is on average longer than a year. Survival �me is much shorter for stage C DCM pa�ents, who o�en only liver for a few months to 6 months. They o�en have concurrent severe arrhythmias as well as heart failure.
Quality of life factors that influence a client’s willingness to con�nue treatment include the clinical impact of disease on breathing comfort and severity of cough, poten�al challenges associated with medica�on, cost of treatment and follow-up, and other systemic diseases or comorbidi�es impac�ng energy and appe�te. The general prac��oner is again poised to help counsel owners on end of life decisions as heart failure progresses. They have been the trusted doctor through their pa�ent’s life from puppy to geriatric, and have established a trus�ng rela�onship with the client to aid in these difficult decisions.
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Footnotes
B Vcheck, Bionote, Big Lake, Minnesota
References
1. Ma�n MJ, Boswood A, Church DB, et al. Prevalence of and Risk Factors for Degenera�ve Mitral Valve Disease in Dogs Atending Primary-care Veterinary Prac�ces in England. Journal of Veterinary Internal Medicine 2015;29:847-854.
2. Birkegård AC, Reimann MJ, Mar�nussen T, et al. Breeding Restric�ons Decrease the Prevalence of Myxomatous Mitral Valve Disease in Cavalier King Charles Spaniels over an 8- to 10-Year Period. Journal of Veterinary Internal Medicine 2016;30:63-68.
3. Stepien RL, Rak MB, Blume LM. Use of radiographic measurements to diagnose stage B2 preclinical myxomatous mitral valve disease in dogs. Journal of the American Veterinary Medical Associa�on 2020;256:1129-1136.
4. Malcolm EL, Visser LC, Phillips KL, et al. Diagnos�c value of vertebral le� atrial size as determined from thoracic radiographs for assessment of le� atrial size in dogs with myxomatous mitral valve disease. J Am Vet Med Assoc 2018;253:1038-1045.
5. Boswood A, Gordon SG, Häggström J, et al. Temporal changes in clinical and radiographic variables in dogs with preclinical myxomatous mitral valve disease: The EPIC study. J Vet Intern Med 2020;34:11081118.
6. Chetboul V, Serres F, Tissier R, et al. Associa�on of plasma N-terminal pro-B-type natriure�c pep�de concentra�on with mitral regurgita�on severity and outcome in dogs with asymptoma�c degenera�ve mitral valve disease. J Vet Intern Med 2009 Sep -Oct ;23(5):984 -94 Epub 2009 Jul 1 2009;23:984-994.
7. Reynolds CA, Brown DC, Rush JE, et al. Predic�on of first onset of conges�ve heart failure in dogs with degenera�ve mitral valve disease: the PREDICT cohort study. J Vet Cardiol 2012;14:193-202.
8. Boswood A, Haggstrom J, Gordon SG, et al. Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study-A Randomized Clinical Trial. J Vet Intern Med 2016;30:1765-1779.
9. Boswood A, Gordon SG, Haggstrom J, et al. Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Preclinical Myxomatous Mitral Valve Disease Receiving Pimobendan or Placebo: The EPIC Study. J Vet Intern Med 2018;32:72-85.
10. Kvart C, Haggstrom J, Pedersen HD, et al. Efficacy of enalapril for preven�on of conges�ve heart failure in dogs with myxomatous valve disease and asymptoma�c mitral regurgita�on. J Vet Intern Med 2002;16:80-88.
11. Atkins CE, Keene BW, Brown WA, et al. Results of the veterinary enalapril trial to prove reduc�on in onset of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency. J Am Vet Med Assoc 2007 Oct 1;231 (7 ):1061 -9 2007;231:10611069.
12. Oyama MA, Fox PR, Rush JE, et al. Clinical u�lity of serum N-terminal pro-B-type natriure�c pep�de concentra�on for iden�fying cardiac disease in dogs and assessing disease severity. J Am Vet Med Assoc 2008 May 15 ;232 (10):1496 -503 2008;232:1496-1503.
13. Lombard CW, Jons O, Bussadori CM. Clinical efficacy of pimobendan versus benazepril for the treatment of acquired atrioventricular valvular disease in dogs. J Am Anim Hosp Assoc 2006 Jul -Aug ;42 (4):249 -61 2006;42:249-261.
14. Haggstrom J, Boswood A, O'Grady M, et al. Effect of pimobendan or benazepril hydrochloride on survival �mes in dogs with conges�ve heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study. J Vet Intern Med 2008 Sep -Oct ;22 (5):1124 -35 Epub 2008 Jul 11 2008;22:1124-1135.
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15.E�nger SJ, Benitz AM, Ericsson GF, et al. Effects of enalapril maleate on survival of dogs with naturally acquired heart failure. The Long-Term Inves�ga�on of Veterinary Enalapril (LIVE) Study Group. J Am Vet Med Assoc 1998;213:1573-1577.
16.Group TIS. Acute and short-term hemodynamic, echocardiographic, and clinical effects of enalapril maleate in dogs with naturally acquired heart failure: results of the Invasive Mul�center PROspec�ve Veterinary Evalua�on of Enalapril study. The IMPROVE Study Group. J Vet Intern Med 1995;9:234-242.
17.Coffman M, Guillot E, Blondel T, et al. Clinical efficacy of a benazepril and spironolactone combina�on in dogs with conges�ve heart failure due to myxomatous mitral valve disease: The BEnazepril Spironolactone STudy (BESST). J Vet Intern Med 2021;35:1673-1687.
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A Dobie’s Life With DCM: Navigation Through the Stages of Heart Disease
Kristin MacDonald, DVM, Ph.D., DACVIM (Cardiology)
31 CALIFORNIA ® VETERINARY MEDICAL ASSOCIATION
A Dobie’s Life With DCM: Naviga�on Through the Stages of Heart Disease
Kristin MacDonald, DVM, Ph.D., DACVIM Cardiology
VCA Animal Care Center of Sonoma, Rohnert Park, CA
Dilated Cardiomyopathy
Dilated cardiomyopathy (DCM) is the fourth leading cause of death in dogs, and comprises 10% of heart disease in dogs. It is a notoriously stealthy disease to iden�fy in the preclinical stages, and yet can cause sudden death without any prior clinical signs. There is a gene�c cause of DCM in several breeds, and the remainder of dogs have idiopathic DCM or have secondary myocardial failure due to nutri�onal causes, tach cardiomyopathy, toxins such as doxorubicin, or myocardi�s. 90% of reported cases in the literature are seen in these predisposed breeds: Newfoundland, St. Bernards, Doberman Pinschers, Great Danes, Irish Wol�ounds, Boxers, and English Cocker Spaniels.
The Doberman Pinscher develops an autosomal dominant form of DCM, and two different muta�ons have been linked with North American breeding and DCM, including DCM1 (PDK4 muta�on) and DCM2 (��n) muta�on. DCM1 muta�on has a high prevalence of 45-63%, with 68% penetrance, with an average age of clinical signs of 7.3 years in males and 8.7 years in females.1 The PDK muta�on causes a change in myocardial energe�cs with an energy deficient state due to a shi� in lower energy efficiency of glycolysis than faty acid oxida�on. DCM2 has a 50% prevalence with 47% penetrance, and involves the sarcomeric protein ��n, whose func�on is to provide passive s�ffness and ac�ve contrac�on through unfolding and refolding of its spring-like structure. Dual DCM1 and DCM2 muta�ons are present in 20% of Dobermans, and is associated with more severe disease. Fi�een percent of Dobermans have DCM without a muta�on in DCM1 or DCM2. Although there is equal sex distribu�on of the DCM muta�ons in Doberman Pinschers, the clinical disease is more severe in males, with 73.7% of males having over clinical signs compared to 26% of females.2
Boxer dogs develop arrhythmogenic right ventricular cardiomyopathy (ARVC) with two associated muta�ons: DCM1 (stria�n) and DCM2 (regulatory gene).3 There is incomplete, �me dependent penetrance, and there are likely other factors or muta�ons involved in ARVC and differences in breeding pools between North American lines and European lines. Stria�n is a desmosomal protein which is necessary to maintain cellular adhesion. Heterozygous muta�on is associated with 82% penetrance, and homozygous affected have more severe disease with 100% penetrance. Boxers may develop ARVC in absence of these muta�ons.
A gene�c basis of DCM is also present in several other breeds including: X-linked inheritance in Great Danes (making male predisposi�on), autosomal recessive inheritance in Irish Wolf Hounds (prevalence of DCM 58%, clinical signs seen at mean age of 4 years), autosomal recessive
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inheritance in Standard Schnauzers with causa�ve muta�on iden�fied in an RNA binding mo�f, phospholamban muta�on in the Welsh Springer Spaniel, and a juvenile form of DCM iden�fied in the Portuguese Water Dog. 4
Nutri�onal causes of myocardial failure (i.e. DCM phenotype) include taurine deficiency and diet associated cardiomyopathy in dogs fed atypical, grain free, or legume rich diets. Several breeds are predisposed to develop taurine deficiency induced cardiomyopathy including the Cocker Spaniel, Newfoundland, and Golden Retriever. Supplementa�on of taurine typically leads to improvement in the myocardial failure. Taurine deficiency should be evaluated for with whole blood and plasma taurine blood concentra�ons in dogs with DCM, or empiric supplementa�on should be given in case of deficiency. Atypical diets including grain free diets or diets rich in legumes have been associated with a DCM phenotype in some dogs, including breeds typically not predisposed for DCM. The FDA has concluded their inves�ga�on since there is not a straigh�orward causa�ve rela�onship, but clinically there appears to be an associa�on in some cases. Dogs with a DCM phenotype fed atypical diets had more severe cardiac disease, where a diet enhanced pathology was suspected.5,6 There is o�en a marked improvement in cardiac disease and improved survival in dogs fed atypical diets that have been switched to tradi�onal diets as well as supported with standard medical management. No dogs with standard diets or atypical diets which were not changed were alive a�er 9 months compared to 30% of dogs whose atypical diets were changed to standard diets. Taurine deficiency does not appear to be associated with diet associated cardiomyopathy in most cases.
Stage A Dilated Cardiomyopathy
Gene�c screening tests are available for Boxer dogs and Doberman Pinschers at NCSU Cardiac Gene�cs laboratory. Star�ng at 3 years of age, an annual holter monitor is recommended and likely an echocardiogram in predisposed breeds.
Stage B Dilated Cardiomyopathy Diagnos�c Tes�ng
The preclinical stage of DCM is much more challenging to iden�fy than mitral valve degenera�on, since many dogs have unremarkable cardiovascular physical examina�ons. Nearly half of preclinical stage B DCM dogs have a murmur present on ausculta�on, and a murmur is auscultated in approximately 1/3 of dogs. Stage B1 DCM consists of arrhythmia such as ventricular arrhythmia or atrial fibrilla�on, in the absence of cardiac enlargement or myocardial failure. Dogs in this stage can be at risk for sudden death, syncope or collapse, and may benefit from an�arrhythmic medica�ons. Ideal screening of predisposed breeds for DCM or medium to large breed dogs with a murmur or arrhythmia includes an echocardiogram, ecg and o�en a holter for comprehensive evalua�on of intermitent but clinically relevant arrhythmias. An echocardiogram is necessary to determine whether there is myocardial failure and cardiomegaly. This determines whether the dog is a stage B1 versus stage B2 DCM, and implicates treatment decisions as well as risk of anesthesia.
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Dogs with severe myocardial failure have increased risk of anesthesia, where risk versus benefit would need to be considered, and careful anesthe�c planning. Dogs predisposed to DCM should have an annual echocardiogram and holter for best clinical prac�ces.
What can the general prac��oner do if these advanced diagnos�c tests are not elected or are unavailable? A 5-minute ecg can be done to evaluate for ventricular arrhythmia, and presence of 1 VPC in 5 minutes is predic�ve of stage B1 DCM with high specificity of 97% in Doberman Pinschers. This should be priori�zed in preanesthe�c workup of medium to large breed dogs. A surrogate for an echocardiogram is the Nt-ProBNP test, which may iden�fy dogs with myocardial failure with moderate sensi�vity (77- 100%) and specificity (77-90%). ProBNP concentra�ons >900 in Dobermans or >500 in other breeds are cutoffs. Combina�on of NtProBNP and holter monitor enhances sensi�vity (94%) and specificity (88%). 7 Dogs with an elevated ProBNP would be priori�zed to be referred for an echocardiogram, and if planned the anesthe�c procedure would be delayed if possible. Holter monitoring services are available where the monitors can be rented, and there are cardiologists are o�en on staff for evalua�on of the holter monitor results for an addi�onal fee.
Treatment of Stage B1 DCM
Ventricular arrhythmias are the characteris�c abnormality in stage B1 DCM, especially in Doberman Pinschers and Boxer Dogs. An ecg and holter monitor will help to guide whether an�arrhythmic treatment is needed. Ventricular ectopic beats of >50/24 hrs. in a Doberman or >300/24 hrs. in Boxer dogs is considered abnormal, as well as complex arrhythmias including R on T, couplets, triplets, or ventricular tachycardia.7 Sotalol is the drug of choice for treatment of ventricular arrhythmias unless there is severe myocardial failure and heart failure, since it has nega�ve inotropic affects and may cause intolerable weakness in those pa�ents. Mexile�ne, a class I an�arrhythmic with similar proper�es to lidocaine, can be added to sotalol if ventricular arrhythmia remains uncontrolled. Atrial fibrilla�on may be seen in giant breed dogs at stage B1 DCM, and may be a predecessor of development of myocardial failure over �me. Nega�ve chronotropic an�arrhythmic medica�on may be needed to slow the ventricular response rate, including dil�azem or sotalol. A mean HR on a 24 hr holter of <125 bpm is associated with beter outcome in dogs with atrial fibrilla�on.
Monitoring of stage B1 DCM includes annual echocardiograms and arrhythmia assessment with either ecg or op�mally with a holter every 6-12 months.
Treatment of Stage B2 DCM
The PROTECT study was a prospec�ve, blinded, randomized, placebo controlled study evalua�ng 76 Doberman Pinschers with occult Stage B2 DCM (n= 39 dogs treated with pimobendan; n= 37 dogs treated with placebo).8 The primary endpoint was �me to conges�ve heart failure, which was significantly longer in dogs treated with pimobendan (718 days) compared to placebo (441 days; P= 0.0088).
35
The secondary endpoint was all cause mortality, which was extended in dogs treated with pimobendan (623 days) compared to dogs treated with placebo (466 days; P= 0.03). In summary, Doberman Pinschers with Stage B2 DCM treated with pimobendan had approximately 9-month extension of symptom-free �me before development of heart failure, and lived approximately 5 more months than dogs treated with placebo. Extrapola�on of data to other large breed dogs with Stage B2 DCM is commonly done in clinical prac�ce. The use of ACE inhibitors in Stage B2 DCM may be considered as well. A retrospec�ve study of Dobermans with severe occult DCM with mean frac�onal shortening of 15% placed on either benazepril or no treatment reported an extension in �me to heart failure of approximately 3 months in dogs treated with benazepril (454 days benazepril vs. 365 days no treatment). 9
Stage C Dilated Cardiomyopathy
Onset of cough, syncope, tachypnea (sleeping RR >30 breaths/min), and dyspnea indicate that heart failure may have developed, and requires further assessment with thoracic radiographs. Development of a S3 gallop heart sound is o�en found when dogs have decompensated with DCM, and was a predictor for early cardiac death in one study. 10 There may be adven��ous lung sounds, tachypnea, and dyspnea. Some dogs will develop biventricular failure with muffled lung sounds caused by pleural effusion as well as a pendulous abdomen due to ascites. Arrhythmias are more common with decompensated DCM, including atrial fibrilla�on and ventricular arrhythmia. Distal extremi�es are o�en cold, femoral arterial pulses are weak, and CRT is prolonged due to low cardiac output. Thoracic radiographs typically demonstrate cardiomegaly, le� atrial dila�on, pulmonary venous distension, and perihilar to caudodorsal inters��al to alveolar pulmonary infiltrates. There may be generalized cardiomegaly, dila�on of the caudal vena cava, pleural effusion, and loss of abdominal detail due to ascites in dogs with biventricular failure. Systolic blood pressure may be low when there is low output heart failure. Echocardiography depicts progressive severe volume overload to the le� ventricle and le� atrial dila�on, with typically mild func�onal mitral regurgita�on due to annular dila�on. Markers for elevated le� atrial filling pressures may include various Doppler echocardiographic indices, with the most powerful index being E (early mitral filing velocity)/ IVRT (Isovolumetric relaxa�on �me) >2.5.11
The standard therapy for CHF of all causes includes furosemide (1-4 mg/kg PO BID-TID), an angiotensin conver�ng enzyme (ACE) inhibitor, and pimobendan. The dose and route of administra�on of furosemide varies depending on the severity of the CHF and the stability of the pa�ent. Dogs with mild heart failure may be managed with lower furosemide doses (1-2 mg/kg PO q24 hr – BID), while dogs with severe or refractory heart failure require the high oral doses of 3- 4 mg/kg PO TID.
36
Furosemide is within the most powerful class of diure�cs, the loop diure�cs, which inhibit the Na+/K+/2Cl- cotransporter in the thick ascending loop of Henle, leading to urinary loss of water, sodium, chloride, potassium, calcium, and magnesium. It is highly protein bound (86-91%), which traps the diure�c in the vascular space to deliver it to the proximal renal tubule, where 55% is excreted in the urine, and 45% is eliminated by the liver.12 Therefore, there must be adequate blood flow to deliver the furosemide to the kidney (a problem with low output heart failure), and adequate renal func�on to excrete the drug. Dobutamine may be necessary in dogs with low output heart failure to aid in delivery of furosemide to the kidneys for diure�c effect to be seen. Oral bioavailability is only ~50% with marked individual variability. When administered intravenously, the diure�c effect is seen 5 minutes post-IV injec�on, with a peak diure�c effect 30 minutes post IV injec�on, and dura�on of diuresis 2- 3 hrs. Venodila�on is seen 5-15 minutes a�er IV injec�on. When given orally, the diure�c effect is seen by 1 hr, with a peak effect at 1-2 hrs., and dura�on of diuresis 6 hrs.
Pimobendan can be given for acute heart failure, with hemodynamic benefits seen within 30-45 minutes, and con�nued for chronic home therapy. Pimobendan improved survival in 15 Dobermans with DCM (mean survival 128 days versus 63 days for placebo group) and had greater �me before treatment failure.13 Similarly, another small scale blinded, placebo controlled study in 16 Dobermans with CHF showed a marked improvement in survival in dogs treated with pimobendan as well as background therapy of benazepril, spironolactone, and furosemide compared to placebo and background therapy (median survival �me 130 days vs. 14 days respec�vely).14
ACE inhibitors have been the standard choice for RAAS antagonism, and are indicated for treatment of CHF in people, dogs, and cats. Dogs and people benefit from improved quality of life as well as survival. The IMPROVE trial showed that enalapril resulted in modest acute reduc�ons of pulmonary capillary wedge pressure and arterial blood pressure in dogs, but greater long term clinical improvement was seen only in the DCM group and not the mitral regurgita�on group.15 Other clinical trials found improved symptoms and survival in both DCM and mitral regurgita�on groups. Enalapril was shown to reduce risk of worsened heart failure by 46% in dogs with heart failure, as well as prolonged �me to treatment failure, improved heart failure class and reduc�on in pulmonary edema. Benefits were o�en seen a�er 1-2 months of treatment. ACE and aldosterone escape or breakthrough is a problem in approximately 30-50% of people, dogs, and cats treated chronically with ACE inhibitors. It is characterized by progressive increases in ATII and aldosterone over �me despite low ACE ac�vity. Explana�ons include addi�onal pathways to convert ATI to ATII, and addi�onal s�mulators for aldosterone secre�on. Aldosterone antagonists may be added in conjunc�on with ACE inhibi�on for aldosterone breakthrough.
37
Spironolactone is a compe��ve aldosterone receptor blocker, commonly used in treatment of conges�ve heart failure in dogs. Surprisingly, there are minimal clinical studies evalua�ng the effects of spironolactone in dogs with stage C DCM. Spironolactone was evaluated in a prospec�ve, placebo controlled study in a small number of stage C Doberman Pinschers, and did not confer survival benefit, but was associated with decreased incidence of atrial fibrilla�on (p= 0.037).10 The mean dose in this study was 1.35 mg/kg PO BID. A dose of 2 mg/kg PO q24 hr is recommended for adequate blockade of the mineralocor�coid receptor.16
Torasemide is used for treatment of progressive heart failure, and is receiving more aten�on for early heart failure therapy. It is 10-20 �mes more potent than furosemide, and dura�on of diuresis is double furosemide. 17,18 The author typically doses torasemide 1/10 of the daily dose of furosemide divided BID when making the conversion, and rechecks a renal panel within 7 days. For example, if a dog receives 100 mg a day of furosemide, this is equivalent to a 10 mg daily torsemide dose, which would be split into 5 mg PO BID of final torsemide dose. Torsemide pharmacokine�cs/dynamics in comparison to furosemide include double the half-life of 120 minutes (torsemide) vs. 9.7 minutes (furosemide), longer dura�on of diuresis of 12 hours (torsemide) compared to 6 hours (furosemide) and similar onset �me (1 hour) and �me to peak effect (2-4 hours). Careful monitoring of renal bloodwork is needed a�er switching from furosemide to torsemide.
Refractory, or Stage D heart failure, is defined as requirement of > 8 mg/kg/day of furosemide for control of fluid accumula�on. These pa�ents require dose escala�on of most cardiac medica�ons including pimobendan (TID, may increase dose), ACE inhibitors, spironolactone, and switch to torsemide.
Prognosis for stage C DCM is poor with short median survival �mes ranging from 4-6 months on standard therapy including pimobendan, furosemide, +/- RAAS blockers.
38
References
1.Calvert CA, Hall G, Jacobs G, et al. Clinical and pathologic findings in Doberman Pinschers with occult cardiomyopathy that died suddenly or developed conges�ve heart failure: 54 cases (1984-1991). J Am Vet Med Assoc 1997;210:505-511.
2.Wess G, Schulze A, Butz V, et al. Prevalence of Dilated Cardiomyopathy in Doberman Pinschers in Various Age Groups. Journal of Veterinary Internal Medicine 2010;24:533-538.
3.Meurs KM, Mauceli E, Lahmers S, et al. Genome-wide associa�on iden�fies a dele�on in the 3ʹ untranslated region of Stria�n in a canine model of arrhythmogenic right ventricular cardiomyopathy. Human Gene�cs 2010;128:315-324.
4.Simpson S, Edwards J, Ferguson-Mignan TF, et al. Gene�cs of Human and Canine Dilated Cardiomyopathy. Int J Genomics 2015;2015:204823.
5.Walker AL, DeFrancesco TC, Bonagura JD, et al. Associa�on of diet with clinical outcomes in dogs with dilated cardiomyopathy and conges�ve heart failure. J Vet Cardiol 2022;40:99-109.
6.Adin D, DeFrancesco TC, Keene B, et al. Echocardiographic phenotype of canine dilated cardiomyopathy differs based on diet type. J Vet Cardiol 2019;21:1-9.
7.Wess G. Screening for dilated cardiomyopathy in dogs. J Vet Cardiol 2022;40:51-68.
8.Summerfield NJ, Boswood A, O'Grady MR, et al. Efficacy of Pimobendan in the Preven�on of Conges�ve Heart Failure or Sudden Death in Doberman Pinschers with Preclinical Dilated Cardiomyopathy (The PROTECT Study). Journal of Veterinary Internal Medicine 2012;26:1337-1349.
9.O'Grady MR, O'Sullivan ML, Minors SL, et al. Efficacy of Benazepril Hydrochloride to Delay the Progression of Occult Dilated Cardiomyopathy in Doberman Pinschers. Journal of Veterinary Internal Medicine 2009;23:977-983.
10.Laskary A, Fonfara S, Chambers H, et al. Prospec�ve clinical trial evalua�ng spironolactone in Doberman pinschers with conges�ve heart failure due to dilated cardiomyopathy. J Vet Cardiol 2022;40:84-98.
11.Schober KE, Hart TM, Stern JA, et al. Detec�on of Conges�ve Heart Failure in Dogs by Doppler Echocardiography. Journal of Veterinary Internal Medicine 2010;24:1358-1368.
12.Hirai J, Miyazaki H, Taneike T. The pharmacokine�cs and pharmacodynamics of furosemide in the anaesthe�zed dog. J Vet Pharmacol Ther 1992;15:231-239.
13.Fuentes VL, Corcoran B, French A, et al. A double-blind, randomized, placebo-controlled study of pimobendan in dogs with dilated cardiomyopathy. J Vet Intern Med 2002 May -Jun ;16 (3):255 -61 2002;16:255-261.
14.O'Grady MR, Minors SL, O'Sullivan ML, et al. Effect of pimobendan on case fatality rate in doberman pinschers with conges�ve heart failure caused by dilated cardiomyopathy. J Vet Intern Med 2008 Jul -Aug ;22 (4):897 -904 2008;22:897-904.
15.Group TIS. Acute and short-term hemodynamic, echocardiographic, and clinical effects of enalapril maleate in dogs with naturally acquired heart failure: results of the Invasive Mul�center PROspec�ve Veterinary Evalua�on of Enalapril study. The IMPROVE Study Group. J Vet Intern Med 1995;9:234-242.
16.Guyonnet J, Elliot J, Kaltsatos V. A preclinical pharmacokine�c and pharmacodynamic approach to determine a dose of spironolactone for treatment of conges�ve heart failure in dog. J Vet Pharmacol Ther 2010 Jun 1;33 (3):260 -7 2010;33:260-267.
17.Peddle GD, Singletary GE, Reynolds CA, et al. Effect of torsemide and furosemide on clinical, laboratory, radiographic and quality of life variables in dogs with heart failure secondary to mitral valve disease. J Vet Cardiol 2012;14:253-259.
18.Chetboul V, Pouchelon JL, Menard J, et al. Short-Term Efficacy and Safety of Torasemide and Furosemide in 366 Dogs with Degenera�ve Mitral Valve Disease: The TEST Study. J Vet Intern Med 2017;31:1629-1642.
39
Incidental Murmurs in Cats-What Do I Do Now?
Kristin MacDonald, DVM, Ph.D., DACVIM (Cardiology)
41 CALIFORNIA ® VETERINARY MEDICAL ASSOCIATION
Incidental Murmurs in Cats-What Do I Do Now?
Kristin MacDonald, DVM, Ph.D., DACVIM Cardiology
VCA- Animal Care Center of Sonoma
An incidental murmur is detected as an unexpected finding during evaluation not initially focused on the cardiovascular system.1 Common clinical scenarios include detection of a murmur during a routine wellness examination, during a preanesthetic examination, or during evaluation of other systemic disease. Incidental murmurs infer that the animal is not demonstrating obvious clinical signs of heart disease to the client or veterinarian. Murmurs are divided into two main categories: pathologic murmurs and non-pathologic murmurs. Pathologic murmurs are caused by structural heart disease. Etiologies are subdivided into two main categories: congenital disease and acquired heart disease. Non- pathologic murmurs are not caused by cardiac disease, and are divided into functional murmurs caused by underlying systemic diseases (i.e. anemia) or innocent murmurs with no physiologic explanation for the murmur. There are certain murmur characteristics that are often associated with pathologic murmurs: 1) >3/6 murmur intensity 2) murmur radiates from point of maximal intensity 3) other cardiovascular abnormalities are present such as arrhythmia, abnormal femoral arterial pulses, abnormal jugular veins, presence of additional heart sounds like a gallop, mid-systolic click, or split heart sound 4) continuous or diastolic component to murmur is present.
Incidental murmurs in cats
Overtly healthy cats are commonly diagnosed with murmurs, with high prevalence rates reported to range from 15 -40% of adult cats examined in either veterinary hospitals or shelters.10-12 Cardiac disease may be the cause of the murmur, yet the incidence of heart disease in cats with murmurs widely ranges from 30-77%.2-4 Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats, and in one study, 62% of cats with an incidental murmur had hypertrophic cardiomyopathy.5 The most common non-pathologic murmur in cats is a benign finding called dynamic right ventricular outflow tract obstruction (DRVOTO), which was the cause of a murmur in 8-32% of cats in several studies.6-8 Dynamic murmurs which have variable intensity (i.e. louder when stressed and softer when relaxed) are present in 90% of cats with a murmur, but does not distinguish pathologic from non-pathologic murmurs. The most common causes of murmurs in cats are both dynamic, including the pathologic murmur systolic anterior motion of the mitral valve (SAM) with HCM (cause of 39% of murmurs) followed by the non-pathologic murmur DRVOTO (cause of 32% of murmurs).2
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Cats should also be carefully clinically assessed for systemic causes of functional murmurs including anemia, hyperthyroidism, and systemic hypertension. CBC, biochemistry, urinalysis and thyroxine level are standard diagnostic tests when working up an older cat with incidental murmur. Systolic blood pressure, likewise, is an important test to evaluate for systemic hypertension, whose incidence increases with age in cats. Presence of a gallop heart sound or arrhythmia increases the likelihood that heart disease is a cause of the murmur in cats. Auscultation of other cardiac abnormalities such as a gallop heart sound or arrhythmia might be even more valuable than the detection of a murmur for identifying cats at increased risk for CHF or arterial thromboembolism.15 Reassessment for resolution of murmur after treatment of systemic diseases causing functional murmurs is recommended, and if the murmur persists an echocardiogram is highly recommended.
Murmur grades of III/VI or louder, male sex, and older age were predictive of preclinical HCM in overtly healthy cats with a murmur in one study of over 780 cats. 2 HCM is a highly prevalent disease in cats, with rates of 14-16% in the general feline population to as frequent as 1 in 3 cats that are older than 9 years of age.2,9
Murmurs in kittens may be caused by congenital heart disease or may be functional. IV/VI systolic murmurs or louder or continuous murmurs are suggestive of congenital heart disease. In a study of 30 kittens aged up to 4 months old, 40% of murmurs were caused by congenital heart disease and 60% were non-pathologic functional murmurs due to either anemia or innocent murmurs.6 Overall prevalence of congenital heart disease in cats ranges from 1.5- 5%.
8Although uncommon, HCM can be first detected in cats as young as 6 months, especially in predisposed purebred cats. Other causes of HCM phenotype such as myocarditis can cause murmurs in kittens, and may be reversible. An echocardiogram is prioritized in young cats with persistent murmurs that are III/VI or greater, or in cats with other pathologic murmur attributes such as continuous murmurs or IV/VI or louder.
Diagnostic tests in cats with incidental murmurs
Echocardiography is the test of choice to evaluate asymptomatic cats with an incidentally detected murmur. Echocardiography is used to identify if cardiac disease is present, and diagnose the specific etiology and severity of heart disease. Treatment recommendations are often determined based on the pathophysiologic abnormalities identified on echocardiography such as left ventricular hypertrophy, myocardial failure, left atrial dilation, spontaneous contrast, or intracardiac thrombus. Assessment of left atrial size is an essential tool for risk stratification for congestive heart failure or arterial thromboembolism.
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Cats with left atrial dilation have increased diastolic filling pressure and are at risk for development of heart failure or may have active heart failure at the time of examination, even if they are not overtly manifesting obvious symptoms.
Cats with echocardiographic evidence of left atrial dilation need to be further evaluated with thoracic radiographs to assess for congestive heart failure. Echocardiography is also essential for assessment of spontaneous echocardiographic contrast, which is present when red blood cells aggregate, and often precedes development of an intracardiac thrombus. Cats with spontaneous echocardiographic contrast or an intracardiac thrombus (often within the left atrium or auricle) need to be placed on an anticoagulant (clopidogrel as first choice), and the owner appropriately counseled regarding the high likelihood of an impending arterial thromboembolism.
Thoracic radiographs may be considered in cats with a murmur, yet are often insensitive for detection of cardiac abnormalities in asymptomatic cats. An echocardiogram remains the diagnostic test of choice to evaluate asymptomatic cats with a murmur. An echocardiogram is even stronger encouraged in cat’s obvious cardiomegaly on radiographs. However, radiographs are the test of choice to evaluate dyspneic cats. A vertebral heart size of >9.3 is strongly supportive of advanced cardiac disease in symptomatic cats. A limitation of radiographs is the inaccuracy of assessing cardiomegaly in cats- only approximately 50% of cats with acute left heart failure had left atrial dilation on thoracic radiographs when subjectively assessed in one study.10
The serum biomarker Nt-ProBNPb, may identify cats with cardiac disease or heart failure. It may be useful to determine likelihood of cardiac disease as a cause of murmur in patients when an echocardiogram is not available or is not financially possible. It has highest accuracy when used to differentiate heart failure from primary respiratory disease in dyspneic cats, with sensitivities reported to range from 86- 94% and specificities of 86-89%.11,12 A point of care testa is commercially available and measures NT-proBNP in cats, with a positive test defined at >100 pmol/L. A positive test is supportive of a diagnosis of cardiac disease.13 The utility of NTproBNP for detection of occult cardiomyopathy is variable, as false negative results are more common than in symptomatic cats, especially in mild disease. Nt-proBNP was higher in 23 asymptomatic cardiomyopathic cats compared to l4 control (P<0.001, median for control= 24 pmol/L, median for asymptomatic cardiomyopathy= 283 pmol/L), and NT-pro-BNP > 70 pmol/L was highly sensitive (87.5%) and specific (100%) for detection of asymptomatic cats with cardiomyopathy. 14 The point of care NT-proBNP SNAP test (positive >100 pmol/L) was sensitive (88%) and specific (81%) for detection of moderate to severe occult feline cardiomyopathy.13
45
The ProBNP SNAP test is highly insensitive (43%) when used to screen for heart disease in overtly healthy cats in general practice, but sensitivity improves when used in asymptomatic cats with presence of a heart murmur (sensitivity 71%, specificity for heart disease 92%).15
In the absence of diagnostic tests such as echocardiography, empiric treatment of cats with an incidental murmur with therapeutic agents is not recommended. This is because the murmur may be non-pathologic, or caused by mild heart disease that does not require medication.
Treatment of asymptomatic heart disease in cats
Treatment of asymptomatic cats is debatable. Most of the debate centers on treatment of asymptomatic HCM, as this is the most common heart disease in cats and is commonly detected in the preclinical state. The same scenario exists in human medicine, and treatment of asymptomatic people is on an “empiric basis without controlled data to either support or contradict is potential efficacy”. Treatment goals include reduction in LV hypertrophy, reduction in systolic anterior motion (SAM) of the mitral valve if it is more than mild, and improvement in diastolic function. There is a lack of prospective, controlled studies evaluating beta blockers and calcium channel blockers in cats with HCM. Asymptomatic cats with severe HCM may be treated with beta blockers. A retrospective, uncontrolled, non-randomized study reported no effect of atenolol on clinical outcomes in asymptomatic cats, but the baseline characteristics were not equal between groups since cats treated with atenolol had more severe HCM and larger left atrial size.16 ACE inhibitors are not typically used to treat asymptomatic HCM, since a prospective, placebo controlled study that the author conducted showed no effect of ramipril on LV mass assessed by cardiac MRI, diastolic function, neurohormones, and blood pressure in 26 Maine coon and Maine coon-cross cats with mild to severe familial HCM without CHF.17 The author also conducted a prospective, placebo controlled study evaluating spironolactone in treatment of asymptomatic HCM, and found no difference in diastolic function or systolic function assessed by TDI, LV mass, or left atrial size, yet one-third of cats developed severe cutaneous drug reaction when receiving 2 mg/kg spironolactone PO BID.18
To put into context the results of these studies and clinical implications of these data, the author considers atenolol for treatment of moderate to severe HCM. In cats with severe atrial dilation but no heart failure, an ACE inhibitor may be considered given the high likelihood of progression to heart failure. Antiplatelet therapy (clopidogrel 18.75 mg PO q24 hr with food) is prescribed for cats with moderate to severe atrial dilation, spontaneous contrast present in the atrium, or intracardiac thrombus.
46
The author prescribes pimobendan in cats with other severe cardiomyopathies such as dilated cardiomyopathy, unclassified cardiomyopathy, or restrictive cardiomyopathy. However, most cats with cardiomyopathies other than HCM are often diagnosed when they manifest symptoms of heart failure, maybe because murmurs are less common in those diseases.
Treatment of secondary causes of LV hypertrophy
If systemic hypertension or hyperthyroidism is diagnosed, treatment for those specific diseases may ameliorate left ventricular hypertrophy if it is secondary to those diseases. Assessment of causes and risk factors for systemic hypertension will help guide therapy. Amlodipine is an arterial vasodilator that is first line therapy for systemic hypertension. In cats with protein losing nephropathy and systemic hypertension, telmisartan, an angiotensin receptor blocker, would be preferred for both lessening the proteinuria as well as arterial vasodilation. An ACE inhibitor may be added if there is a lack of clinical response. Hyperthyroid cats are typically treated with methimazole or radioactive I131. Left ventricular hypertrophy would be expected to lessen or resolve if it is secondary to the systemic disease over several months, and if there is a lack of reduction in hypertrophy or progressive left ventricular hypertrophy, then there may also be underlying primary hypertrophic cardiomyopathy. Elevated ProBNP levels may not normalize after treatment of systemic causes of LV hypertrophy if there is concurrent HCM. Prognosis for cats with secondary cardiomyopathy is good with effective treatment of the systemic disease, and in a long-term study 80% of cats lived over 10 years.19
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Footnotes
a Boswood A, et al. Effect of pimobendan in dogs with preclinical myxomatous mitral valve disease and cardiomegaly: The EPIC study - A randomized clinical trial, accepted for publication J Vet Intern Med 7 -26-2016.
b Idexx Feline Cardiopet® proBNP Test, Westbrook, ME
References
1.Côté E, Edwards NJ, Ettinger SJ, et al. Management of incidentally detected heart murmurs in dogs and cats. J Vet Cardiol 2015;17:245-261.
2.Payne JR, Brodbelt DC, Luis Fuentes V. Cardiomyopathy prevalence in 780 apparently healthy cats in rehoming centres (the CatScan study). J Vet Cardiol 2015;17 Suppl 1:S244-257.
3.Wagner T, Fuentes VL, Payne JR, et al. Comparison of auscultatory and echocardiographic findings in healthy adult cats. J Vet Cardiol 2010;12:171-182.
4.Côté E, Manning AM, Emerson D, et al. Assessment of the prevalence of heart murmurs in overtly healthy cats. J Am Vet Med Assoc 2004;225:384-388.
5.Franchini A, Abbott JA, Lahmers S, et al. Clinical characteristics of cats referred for evaluation of subclinical cardiac murmurs. J Feline Med Surg 2021;23:708-714.
6.Ferasin L, Ferasin H, Cala A, et al. Prevalence and Clinical Significance of Heart Murmurs Detected on Cardiac Auscultation in 856 Cats. Vet Sci 2022;9.
7.Rishniw M, Thomas WP. Dynamic right ventricular outflow obstruction: a new cause of systolic murmurs in cats. J Vet Intern Med 2002 Sep -Oct ;16 (5):547 -52 2002;16:547-552.
8.Dirven MJ, Cornelissen JM, Barendse MA, et al. Cause of heart murmurs in 57 apparently healthy cats. Tijdschr Diergeneeskd 2010;135:840-847.
9.Paige CF, Abbott JA, Elvinger F, et al. Prevalence of cardiomyopathy in apparently healthy cats. J Am Vet Med Assoc 2009 Jun 1;234 (11):1398 -403 2009;234:1398-1403.
10.Schober KE, Maerz I, Ludewig E, et al. Diagnostic accuracy of electrocardiography and thoracic radiography in the assessment of left atrial size in cats: comparison with transthoracic 2-dimensional echocardiography. J Vet Intern Med 2007 Jul -Aug ;21(4):709 -18 2007;21:709-718.
11.Fox PR, Oyama MA, Reynolds C, et al. Utility of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) to distinguish between congestive heart failure and non-cardiac causes of acute dyspnea in cats. J Vet Cardiol 2009 May ;11 Suppl 1:S51 -61 Epub 2009 Apr 24 2009;11 Suppl 1:S51-S61.
12.Connolly DJ, Soares Magalhaes RJ, Fuentes VL, et al. Assessment of the diagnostic accuracy of circulating natriuretic peptide concentrations to distinguish between cats with cardiac and non-cardiac causes of respiratory distress. J Vet Cardiol 2009 May ;11 Suppl 1:S41 -50 Epub 2009 Apr 25 2009;11 Suppl 1:S41-S50.
13.Machen MC, Oyama MA, Gordon SG, et al. Multi-centered investigation of a point-of-care NT-proBNP ELISA assay to detect moderate to severe occult (pre-clinical) feline heart disease in cat s referred for cardiac evaluation. J Vet Cardiol 2014;16:245-255.
14.Fox PR, Rush JE, Reynolds CA, et al. Multicenter evaluation of plasma N-terminal probrain natriuretic peptide (NT-pro BNP) as a biochemical screening test for asymptomatic (occult) cardiomyopathy in cats. J Vet Intern Med 2011;25:1010-1016.
15.Lu TL, Côté E, Kuo YW, et al. Point-of-care N-terminal pro B-type natriuretic peptide assay to screen apparently healthy cats for cardiac disease in general practice. J Vet Intern Med 2021;35:1663-1672.
16.Schober KE, Zientek J, Li X, et al. Effect of treatment with atenolol on 5-year survival in cats with preclinical (asymptomatic) hypertrophic cardiomyopathy. J Vet Cardiol 2013;15:93 -104.
17.MacDonald K, MD K, RF L, et al. The effect of ramipril on left ventricular mass, myocardial fibrosis, diastolic function and plasma neurohormones in Maine Coon cats with familial hypertrophic cardiomyopathy with no heart failure. JVIM 2006.
18.MacDonald KA, Kittleson MD, Kass PH. Effect of spironolactone on diastolic function and left ventricular mass in maine coon cats with familial hypertrophic cardiomyopathy. J Vet Intern Med 2008 Mar -Apr;22 (2):335 -41 Epub 2008 Mar 10 2008;22:335-341.
19.Spalla I, Locatelli C, Riscazzi G, et al. Survival in cats with primary and secondary cardiomyopathies. Journal of Feline Medicine and Surgery 2016;18:501-509.
48
Kitty Crisis: Heart Failure and Arterial Thromboembolism Management
Kristin MacDonald, DVM, Ph.D., DACVIM (Cardiology)
49 CALIFORNIA ® VETERINARY MEDICAL ASSOCIATION
Kitty Crisis: Heart Failure and Arterial Thromboembolism Management
Kristin A. MacDonald, DVM, Ph.D., DACVIM (Cardiology) VCA Animal Care Center of Sonoma County
The dreaded day has come: your client arrives home to their beloved kitty gasping for air and you agree to see them on an urgent basis. This fragile kitty needs careful and timely evaluation to determine the cause of the dyspnea and appropriate treatment. The fork in the road is determining if the dyspnea is due to heart failure or respiratory disease. Look for clues that may lead you to prioritize heart failure as a high differential, starting the history. Maybe the cat has a history of an incidental murmur in the past. Heart failure is not typically a long-term, chronic disorder if untreated, and a typical course of duration is acute, with breathing abnormalities noted for days to a couple weeks. Maybe the kitty underwent an anesthetic procedure, was given steroids recently, or fluid administration. These may be precipitating events that can lead to heart failure in cats with underlying silent cardiomyopathy.
Congestive heart failure is the sequela of severe cardiac disease. In cats, severe heart disease is often clinically missed until the cat develops congestive heart failure. Th e incidence of heart failure in preclinical HCM cats followed for 10 years ranged from 1224%, with higher risk in cats >5.6 years of age. 1,2 A majority of cats (91%) diagnosed with other cardiomyopathies including DCM and UCM/RCM have congestive heart failure at the time of first diagnosis.
An antecedent event was found within 2 weeks of diagnosis in half of HCM cats with heart failure in one study, and included in order of occurrence: intravenous fluid administration (17/61), recent anesthesia or surgery (15/61, within a mean of 5 days), recent corticosteroid administration (13/61), trauma (7/61), upper respiratory tract infection (3/61), or miscellaneous causes.3 Methyl-prednisolone was the most common corticosteroid administered (70%) followed by a parenteral form of triamcinolone (30%). Ketamine hydrochloride was the most common anesthetic agent administered (8/9 cats with known anesthetic protocol) followed by tiletamine- zolazepam (1/9). Possible mechanisms of methylprednisolone contributing to heart failure were further studied in 12 normal cats. Methylprednisolone was shown to increase plasma volume by 13.4 % (>40% in 25% of cats) and reduce red blood cell count, hematocrit, hemoglobin concentration, as well as serum sodium and chloride concentrations in normal cats.4 However, echocardiographic variables and blood pressure did not change after methylprednisolone administration in these normal cats. In cats with marked diastolic or systolic dysfunction, the increased plasma volume may further elevate diastolic filling pressures and lead to development of heart failure.
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In a subgroup analysis of cats presenting for heart failure after methyl-prednisolone administration, 58% (7/12) of cats recovered without requirement of long-term medical therapy and lived for > 1432 days without recurrence of heart failure.
Physical examination
A heart murmur is not specific nor sensitive for diagnosis of heart failure as the cause of dyspnea in cats, but may be a clue that there is heart disease. Slightly over half of cats with heart failure had a murmur auscultated, and tachycardia with HR >200 bpm was only present in one-quarter of cats.5 In fact, cats with heart failure had lower heart rates than cats with preclinical heart disease.5 However, presence of other cardiac abnormalities such as a gallop heart sound (48% of cats with CHF) or arrhythmia (48% of cats with heart failure) might be even more valuable than the detection of a murmur for identifying cats at increased risk for CHF or arterial thromboembolism.5 Dyspnea and tachypnea are common clinical signs of heart failure. Paradoxical breathing, where the abdomen moves inward during inhalation and expands on exhalation, is highly predictive for pleural space disease with the most common cause pleural effusion, with a sensitivity of 90%, specificity of 58%, and odds ratio of 10 for pleural space disease.6
Diagnostic testing
Thoracic radi ograph s are useful to assess whether there are pulmonary infiltrates or pleural effusion, and may identify significant cardiomegaly. Calculation of the vertebral he art size may be useful to quantify cardiac size and confirm cardiomegaly. The long- and short-axis measurements of the heart, expressed in vertebral lengths starting at the fourth thoracic vertebrae, are added to yield vertebral heart size (VHS). Normal VHS is 7 .4 +/- 0.3 in cats.7 Presence of cardiomegaly is not always identified in cats with cardiogenic pulmonary edema, as evidenced by only 65% of cats in one study having cardiomegaly, and left atrial dilation was present in only 48% of cats in that study.8 Another study documented more frequent occurrence of cardiomegaly (96%) and left atrial dilation (64%) in cats with cardiogenic pulmonary edema.9 Left sided congestive heart failure (CHF) may be evidenced by presence of patchy interstitial to alveolar pulmonary infilt rates with no typical pattern of distribution, unlike the dog that has a classic pattern of perihilar to caudal distribution. Distribution pattern of cardiogenic pulmonary edema in cats is most often diffuse and non-uniform (61%) and may range from interstitial infiltrates to alveolar infiltrates in more severe cases. Multiple lung lobes are typically affected. Pulmonary venous distension, while in theory should be present, is identified in 50% of cats with cardiogenic pulmonary edema.9 Pulmonary venous and pulmonary arterial dilation occurred in 70% of cats with cardiogenic pulmonary edema, and isolated pulmonary arterial dilation occurred in 65% of cats.9 Pleural effusion may be caused by left or right heart failure. Dorsal deviation of the trachea has not been shown to be specific f or cardiomegaly in cats with pleural effusion. 10
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Thoracic radiographs are essential to monitor for presence and severity of heart failure as well as adequacy of heart failure treatment.
Measurement of cir cu lating biomarkers, such as brain natriuretic peptide (BNP), may identify cats with cardiac disease or CHF. BNP is synthesized normally in the atria, but there is increased synthesis in the ventricle with cardiac disease. N-terminal proBNP (NT-proBNP) is a fragment formed by the cleavage of proBNP, and has a longer circulating half-life than BNP. It appears to have the most accuracy when used to differentiate heart failure from primary respiratory disease in dyspneic cats.
In a study of 66 dyspneic cats with primary respirator y disease and 101 cats with dyspnea secondar y to heart failure, NT-proBNP was significantl y increased in cats with he art failure (P<0.001, median for CHF= 846 pmol/L; 1º respiratory = 53 pmol/L). 11 NT-proBNP >180 was highly sensitive (94%) and specific (86%) for detection of CHF in dyspneic cats. Another study in dyspneic cats documented that a NT-ProBNP >220 was highl y sensitive (9 4%) and sensitive (88 %) for diagnosis of he art failure vs. primar y respirator y disease.12 Likewise, NtproBNP was sensitive (86%) and specific (89%) to diagnose heart failure as a cause of pleural effusion in cats.13 A point of care testa is commercially available and measures NTproBNP in cats, with a positive test defined at >100 pmol/L. A positive test is supportive of a diagnosis of cardiac disease.14 A positive result it is not specific for diagnosis of heart failure in dyspneic cats, yet a negative test makes h eart failure much less likely Feline NTproBNP SNAP test was highly sensitive (95%) and specific (88%) for diagnosis of h eart failure in dyspneic cats with pleural effusion.15 Subsequent studies of dyspneic cats with either heart failure or primary respiratory disease have demonstrated similarly high sensitivity (94100%) and specificity (72- 87%) for diagnosis of heart failure.15 Utilizing the ProBNP SNAP test on pleural effusion is not recommended due to the poor specificity (65%) for diagnosis of cardiogenic pleural effusion.13
Other diagnostic tests:
Systolic blood pressure and serum thyroxine concentration must be measured in cats with concentric hyp ertrophy to rule out secondary causes of concentric left ventricular hypertrophy. Plasma and whole blood taurine concentrations should be measured in any animal with myocardial failure. Normal plasma and whole blood taurine con centrations are > 60 nmol/ml and > 250 nmol/ml respectively. If due to financial constraint only one sample can b e submitted, whole blood taurine is preferable since unlike plasma taurine, whole blood taurine will not be decreased due to anorexia. Taurine def iciency induced DCM must not be missed as it is a curable form of DCM compared to the grave prognosis of idiopathic DCM.
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Treatment of Congestive Heart f a ilure
Treatment of CHF is similar regardless of the specific cardiac disease present, and includes furosemide and an angiotensin converting enzyme (ACE) inhibitor. Furosemide may be given parenterall y (1-3 mg/kg every 1-4 hours) in cats with fulminant CHF, and the furosemide dose should be rapidly tapered once the respiratory rate and effort begin to improve. Although efficacy is unknown, the venodilator nitroglycerin may be applied transdermally every 6 hours for 2 days (until tolerance develops) for hospitalized patients. Oxygen therapy is n ecessary in severe cases, and the fractional inspired oxygen percentage should be decreased to 50% or less if possible within 12 hours to avoid furthe r barotrauma. An ACE inhibitor can be slightly postponed in cats re ceiving aggressive diuresis, until the cat is eating, drinking, and not severel y dehydrated since it may potentiate azotemia in dehydrated cats. Chronic oral dosing of furosemide may be started at 1 mg/kg PO q24 hr. BID and increased ove r t ime as the severity of CHF worsens to a maximal ceiling dose of 4 mg/kg PO TID
Pimobendan (0.25 mg/kg PO BID ) is used in cats with myocardial failure and heart failure, and also may be useful in cats with unclassified or restrictive cardiomyopathy, a diagnosis made by echocardiography. Controvers y exists regarding the use of pimobendan for cats with HCM and heart failure
Potential pharmacodynamics benefits of pimobendan could include: preload reduction and positive lusitropy (increases diastolic relaxation), and positive inotrop y (in cats with myocardial failure from end-stage HCM). A retrospective study documented survival benefit in cats with heart failure secondary to HCM with no myo cardial failure that were treated with pimobendan and other standard cardiac medications (MST 626 days) compared to cats not given pimobendan (MST 103 days).18 However, the group of cats n ot receiving pimobendan had a shorter survival time than is often clinically expected, yet literature reports highly variable survival times in retrospective studies (92 days; 654 days) in cats with heart failure due to HCM A more recent prospective study of cats with HCM and heart failure showed no improvement in time to heart failure or death in the pimobendan group over 180 days (P= 0.89), and in fact worsened outcome in cats with left ventricular outflow tract obstruction, and improved outcome in cats without SAM 16
Switching from furosemide to torsemide may be helpful to manage refractory heart failure (> 8 mg/kg/day of furosemide) or for cats unable to be given TID furosemide for progressive heart failure. Spironolactone can also be considered with daily dose <2 mg/kg/day due to potential of cutaneous drug reaction. Some degree of azotemia is expected in cats re ceiving aggressive diuretic therapy.
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Feline Arterial Thromboembolism
Cardiogenic arterial thromboembolism is the overwhelming most common cause of ATE in cats, followed by neoplasia, then other systemic diseases . Clinical presentation of feline ATE is straightforward. Most cats are tachypneic (91%), hypothermic (66%), but only 57% have auscultation abnormalities such as a murmur or gallop. Tachypnea may be due to pain or congestive heart failure. Thoracic radiographs reveal cardiomegaly (90%) and congestive heart failure (70%) in a majority of cats. In fact, heart failure is the most common cause of death in cats long-term if they survive the initial ATE event, with 12/30 cats dying from heart failure with a median survival time of 77 days for concurrent ATE and CHF, compared to only 3/30 dying/euthanized from recurrent ATE, with median time to recurrent ATE 118 days.17 Poor prognostic indicators in hospital include hypothermia on presentation, multiple limbs, lack of motor function, bradycardia, and serum phosphorus.
Thrombolysis (either autogenously or by thrombolytic agents) causes release of large amounts of potassium, hydrogen, and lactate from the dead muscle cells, and leads to acute lifethreatening reperfusion syndrome. Often there is identification of acute bradycardia due to hyperkalemia, so careful monitoring of heart rate is needed for hospitalized patients. Clinical sequelae include severe metabolic acidosis, and death is from cardiac arrest due to severe hyperkalemia. Earlier electrocardiographic abnormalities during hyperkalemia include in order of severity: tall tented T waves, atrial standstill, widening of the QRS complexes, and lastly ventricular fibrillation. Reperfusion syndrome may occur hours to several days after ATE. Immediate treatment of reperfusion syndrome includes administration of: Sodium bicarbonate 0.5 meq/kg IV slow, Dextrose 1 gram IV, Insulin 0.5 units/kg IM, Atropine 0.04 mg/kg if atrial standstill or marked bradycardia is present, and calcium gluconate 5 mg/kg IV over 10 minutes if there is a marked cardiac arrhythmia.
Anticoagulant or antiplatelet therap y is necessar y in cat s that have suffered from arterial thromboembolism or who have echocardiographic evidence of a thrombus or spontaneous contrast within the left atrium, and may be considered in cats with moderate or severe left atrial dilation. Aspirin (5 mg – 81 mg PO q 3 days) has relatively underwhelming and variable success in prevention of thromboembolism In cats suffering from art erial thromboembolism, survival with or without thrombolytic therap y is only 30-40%. Recurrence rate with aspirin (standard o r low dose) is variable and ranges from 28-90%.18,19 Clopidogrel (18.75 mg PO q24 hrs.) is a potent platelet ADP receptor antagonist that is currently favored for prophylaxis of ATE, and was superior to aspirin in the FATCAT clinical trial for time to development of recurrent ATE in cats recovering from ATE (median time to recurrent ATE 443 days clopidogrel vs. 192 days aspirin; MST all cause 248 clopidogrel vs.116 aspirin).
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Clopidogrel has been shown to inhibit platelet aggregation, increase oral mucosal bleeding time, and reduce plasma serotonin concentration in normal cats at doses as low as 18.75 mg PO q 24 hours.
Low molecular weight heparins (LMWH) such as rivaroxaban, dalteparin and enoxaparin are attractive alternatives to unfractionated heparin given their increased bioavailability and prolonged half-life. Compared to unfractionated heparin, LMWHs work more specifically upstream in the coagulation cascade against Factor X with much lower activity against thrombin (Factor II). Since there is less anti-II activity, LMWHs do not alter PT and APTT times, and therapeutic efficacy must be assessed by measurement of anti-Xa activit y. Rivaroxaban (Xarelto®), an oral factor LMWH, has been evaluated in healthy cats and there is an ongoing clinical trial in cats recovering from ATE.28,29 A dose of 0.5-1 mg/kg/day in cats or ¼ of a 10 mg tablet orally every 24 hr is recommended. 20,21 There are only a few pilot studies evaluating pharmacokinetics of dalteparin and enoxaparin in h ealthy cats. 1- 1.5 mg/kg of enoxaparin SQ appears to adequately suppress factor Xa activity, but the optimal dosing interval is less cle arly d efined. 22 Enoxaparin dosing frequencies of BID to TID are likely ne cessary for sustained anti-Xa activity. Parenteral enoxaparin is preferred for in patient treatment, and outpatient treatment with oral rivaroxaban (2.5 mg PO q24 hr) is most convenient. In a 5 year retrospective study of feline ATE, combination of clopidogrel and rivaroxaban in 18 cats demonstrated a marked prolongation to recurrent ATE of 502 days with a low 16.7% recurrence rate compared to historical data.22 The combination antiplatelet and anticoagulant therapy with clopidogrel and rivaroxaban is an attractive chronic ATE treatment for cats, and may shape early clinical decisions for whether to pursue treatment of acute ATE vs. elect humane euthanasia.
In cats suffering from arterial thromboembolism, thrombolytic therapy with streptokinase, tissue plasminogen activator, or urokinase are generally not recommended as they are associated with approximately 50% mortality, which is similar to conservative supportive therapy. Pain management, gentle rewarming without a heating pad, and physical therapy with gentle massage, passive range of motion exercises, and stand therapy can be given to cats recovering from ATE.
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F ootnotes
aIdexx SNAP® Feline Cardiopet® proBNP Test, Westbrook, ME
References
1.Fox PR, Keene BW, Lamb K, et al. International collaborative study to assess cardiovascular risk and evaluate long-term health in cats with preclinical hypertrophic cardiomyopathy and apparently healthy cats: The REVEAL Study. J Vet Intern Med 2018;32:930 -943.
2.Trehiou-Sechi E, Tissier R, Gouni V, et al. Comparative echocardiographic and clinical features of hypertrophic cardiomyopathy in 5 breeds of cats: a retrospective analysis of 344 cases (2001-2011). J Vet Intern Med 2012;26:532-541.
3.SA S, AH T, DM F, et al. Corticosteroid - Associated Congestive Heart Failure in 12 Cats. Intern J Appl Res Vet Med 2009;2:159-170.
4.Ployngam T, Tobias AH, Smith SA, et al. Hemodynamic effects of methylprednisolone acetate administration in cats. Am J Vet Res 2006 Apr;67 (4):583 -7 2006;67:583-587.
5.Smith S, Dukes-McEwan J. Clinical signs and left atrial size in cats with cardiovascular disease in general practice. Journal of Small Animal Practice 2012;53:27-33.
6. Le Boedec K, Arnaud C, Chetboul V, et al. Relationship between paradoxical breathing and pleural diseases in dyspneic dogs and cats: 389 cases (2001-2009). J Am Vet Med Assoc 2012;240:1095-1099.
7.Litster AL, Buchanan JW. Vertebral scale system to measure heart size in radiographs of cats. J Am Vet Med Assoc 2000 Jan 15 ;216 (2):210 -4 2000;216:210-214.
8.Benigni L, Morgan N, Lamb CR. Radiographic appearance of cardiogenic pulmonary oedema in 23 cats. J Small Anim Pract 2009 Jan ;50 (1):9 -14 Epub 2008 Aug 13 2009;50:9-14.
9.Schober KE, Wetli E, Drost WT. RADIOGRAPHIC AND ECHOCARDIOGRAPHIC ASSESSMENT OF LEFT ATRIAL SIZE IN 100 CATS WITH ACUTE LEFT-SIDED CONGESTIVE HEART FAILURE. Veterinary Radiology & Ultrasound 2014;55:359-367.
10.PS S, T S, CE A. The utility of thoracic radiographic measurement for the detection of cardiomegaly in cats with pleural effusion. Vet Radiol 1990;31:89-91.
11.Fox PO, MA, MacDonald K, Reynolds C. Comparison of NT-proBNP concentration in cats with acute dyspnea from cardiac or respiratory disease. J Vet Intern Med 2008;22.
12.Connolly DJ, Soares Magalhaes RJ, Fuentes VL, et al. Assessment of the diagnostic accuracy of circulating natriuretic peptide concentrations to distinguish between cats with cardiac and non-cardiac causes of respiratory distress. J Vet Cardiol 2009 May ;11 Suppl 1:S41 -50 Epub 2009 Apr 25 2009;11 Suppl 1:S41-S50.
13.Hezzell MJ, Rush JE, Humm K, et al. Differentiation of Cardiac from Noncardiac Pleural Effusions in Cats using Second-Generation Quantitative and Point-of-Care NT-proBNP Measurements. Journal of Veterinary Internal Medicine 2016;30:536-542.
14.Machen MC, Oyama MA, Gordon SG, et al. Multi-centered investigation of a point-of-care NT-proBNP ELISA assay to detect moderate to severe occult (pre-clinical) feline heart disease in cats referred for cardiac evaluation. J Vet Cardiol 2014;16:245-255.
15.Ward JL, Lisciandro GR, Ware WA, et al. Evaluation of point-of-care thoracic ultrasound and NT-proBNP for the diagnosis of congestive heart failure in cats with respiratory distress. J Vet Intern Med 2018;32:1530-1540.
16.Schober KE, Rush JE, Luis Fuentes V, et al. Effects of pimobendan in cats with hypertrophic cardiomyopathy and recent congestive heart failure: Results of a prospective, double-blind, randomized, nonpivotal, exploratory field study. Journal of Veterinary Internal Medicine 2021;35:789 -800.
17.Borgeat K, Wright J, Garrod O, et al. Arterial Thromboembolism in 250 Cats in General Practice: 2004 –2012. Journal of Veterinary Internal Medicine 2014;28:102-108.
18.Smith SA, Tobias AH, Jacob KA, et al. Arterial thromboembolism in cats: acute crisis in 127 cases (1992 -2001) and long-term management with low-dose aspirin in 24 cases. J Vet Intern Med 2003;17:73-83.
19.Hogan DF, Andrews DA, Green HW, et al. Antiplatelet effects and pharmacodynamics of clopidogrel in cats. J Am Vet Med Assoc 2004;225:1406-1411.
20.Dixon-Jimenez AC, Brainard BM, Brooks MB, et al. Pharmacokinetic and pharmacodynamic evaluation of oral rivaroxaban in healthy adult cats. J Vet Emerg Crit Care (San Antonio) 2016;26:619 -629.
21.Blais MC, Bianco D, Goggs R, et al. Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE): Domain 3-Defining antithrombotic protocols. J Vet Emerg Crit Care (San Antonio) 2019;29:60 -74.
22.Lo ST, Walker AL, Georges CJ, et al. Dual therapy with clopidogrel and rivaroxaban in cats with thromboembolic disease. J Feline Med Surg 2022;24:277-283.
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CALIFORNIA ®
VETERINARY MEDICAL ASSOCIATION
Faint or Fit? Assessment of Seizure Versus Syncope
Jim Lavely, DVM, DACVIM, Neurology
Kristin MacDonald, DVM, Ph.D., DACVIM (Cardiology)
Presenting jointly
Jim Lavely, DVM, DACVIM (Cardiology)
Kristin MacDonald, DVM, Ph.D., DACVIM (Cardiology)
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Faint or Fit? Assessment of Seizure Versus Syncope
Jim Lavely, DVM, DACVIM (Neurology)
(Co-presenter)
Kristin MacDonald, DVM, Ph.D., DACVIM (Cardiology)
VCA Animal Care Center
Rohnert Park, CA
Episodes of loss of postural tone or altered mentation can be a diagnostic dilemma for veterinarians. Seizures and syncopal episodes are often mischaracterized by the owner and can be difficult to clinically differentiate even by astute veterinarians. Diagnostic evaluation and treatments are very different, and anesthesia can have increased risk in an animal with severe cardiac disease-causing syncope which was clinically mischaracterized as a seizure.
PATHOPHYSIOLOGY
Syncope
Syncope is defined as cerebral hypoperfusion causing a transient loss of postural tone and consciousness. Cerebral hypoperfusion is typically sufficient to produce syncope when cerebral arterial pressure falls below 25 mmHg. Cerebral hypoperfusion is caused by a lack of cerebral blood flow for 6- 8 seconds or longer, due to either arterial vasodilation or low cardiac output. Syncopal episodes can be divided into two main categories: cardiogenic or neurocardiogenic. Cardiogenic causes include severe brady or tachyarrhythmias, or ventricular outflow tract obstruction. Less severe arrhythmias with concurrent severe myocardial disease can also cause marked decrease in cardiac output and syncopal episodes. Other factors include the current metabolic demand influenced by exercise and systemic vasodilation that occurs with exercise. There are several possible mechanisms of syncope in animals with ventricular outflow tract obstructions including myocardial ischemia with exertion and ventricular arrhythmias, increased ventricular pressure activation triggering the Bezold Jarish Reflex increasing vasovagal tone, and exercise induced vasodilation in conjunction with inability to increase cardiac output due to outflow tract obstruction. Neurocardiogenic syncope, also known as reflexive syncope, is a normal physiologic reflex that is inappropriately or overexuberantly triggered from a stimulus, which leads to increased vagal tone and reduced sympathetic tone. The cardioinhibitory effects of increased vagal tone include bradycardia and decreased contractility. Vasodepressor effects of reduced sympathetic tone manifest as vasodilation. Sometimes there is a combination of cardioinhibitor and vasodepressor effects. Common triggers include cough, excitement, exercise, urination, or defecation
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Seizure
Seizures are the manifestation of abnormal synchronous electrical activity in the brain and are the most common neurological disorder in dogs. Seizures may be categorized as generalized, when whole body involvement is present or partial, when a portion of the body is affected. Consciousness is unimpaired during simple partial seizures and is altered during complex partial seizures. A pre-ictal period prior to the seizure and a postictal period lasting minutes to hours after the seizure are common with generalized seizures.
CLINICAL FEATURES
Clinical features of seizures and syncope can blend together to be impossible to distinguish based on history and the appearance of the episode. Often clients refer to any episode of collapse and loss of consciousness as a seizure. Specific details when obtaining a history should include any potential triggered stimulus or activity prior to event, whether there were behavioral changes before or after the event, duration of event, and characteristics of the event. Some astute owners are able to evaluate the precordial impulse to assess if it is pounding fast or absent, and assess mucous membrane color for pallor or cyanosis as evidence of possible cardiac etiology of episodes. Obtaining an accurate history in animals is more challenging than in people, who can reflect on perceived pre-episode abnormalities that can help discriminate between seizure vs. syncope.
Syncope
Syncopal episodes are often triggered by a stimulus such as exercise, excitement, or cough. They are typically abrupt in onset and short duration of seconds to a minute, with rapid and complete recovery. There is no pre-ictal or post-ictal period, although animals may be lethargic upon recovery. There may be an initial increase in muscle tone followed by flaccid tone, but tonic- clonic muscle movement is not a classic feature However, convulsive syncope can occur and can mimic a seizure. In people, convulsive syncope was identified variably, depending on if the study was retrospective (4% episodes were convulsive) vs. prospective studies (40% of episodes).1 Syncope is not associated with autonomic signs such as hypersalivation, nor is nystagmus a feature. Animals may lose control of their bowels with either seizure vs. syncope, and both may cause the patient to be mentally non-responsive (termed transient loss of consciousness).
Physical examination abnormalities of syncopal patients often include abnormal cardiac auscultation including a systolic murmur. Localization of a right sided systolic murmur should raise suspicion of pulmonary hypertension. Many small older syncopal dogs often have mitral valve degeneration, which may or may not be associated with syncope yet warrants a full cardiac workup. Arrhythmias may be detected in dogs with cardiogenic syncope if it is a sustained bradyarrhythmia or tachyarrhythmia, but may be absent in patients with intermittent severe arrhythmias.
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Absence of a murmur or arrhythmia does not rule out cardiogenic syncope in dogs or cats.
Dogs with dilated cardiomyopathy, pulmonary hypertension, or intermittent severe arrhythmias may have normal cardiac auscultation. Abnormal pulmonary auscultation, including adventitious lung sounds or muffled lung sounds, and dyspnea are common in patients with congestive heart failure or pulmonary hypertension.
Seizure
Frequently the client’s presenting complaint is seizures. But are they really seizures?
Distinguishing seizures from other seizure like events can be challenging. History is crucial. Signalment, time of onset, activity at onset, duration of event, and pre and post event activity are important pieces of the puzzle. Seizures often occur in the evening to morning hours, commonly occur at rest and may have a pre or post ictal period. Syncopal events are less likely to occur at rest. Seizures (ictus) often last for 1-2 minutes. Psychomotor seizures may last longer and other partial seizures may be quite brief. Vestibular disease typically last days, although paroxysmal vestibular events can be brief. Neurological examination typically differentiates a seizure from vestibular disease. However, the neurological examination during or immediately after a seizure can be abnormal due to the seizure activity.
A variety of paroxysmal episodes exist that can mimic seizures or syncopal events.2
Dyskninesias such as the head bobbing/tremor episodes can occur in multiple breeds including the bulldog, Labrador Retriever, Golden Retriever and Doberman Pinscher. Differentiating these dyskinesias from partial seizures can be challenging. EEG, evaluating for the underlying cause for the seizures and an anticonvulsant trial can be helpful. Canine epileptoid cramping syndrome may be seen in Border Terriers. Age of onset may be from 6 weeks to 7 years of age. A gluten sensitivity is thought to cause the tremor/cramping syndrome.3 Affected dogs will retain consciousness during the episodes. Exercise induced collapse in Labrador retrievers and cataplexy can mimic the appearance of syncopal events. Episodic falling in Cavalier King Charles Spaniels can also mimic syncopal events. Affected dogs are typically 3 to 7 months of age. An increase in muscle one bunny hooping gait, kyphosis, decreased head carriage and a “deer stalking” posture may be seen and eventually collapse.2,4 Scottie Cramp typically occur in Scottish Terriers less than 12 months of age, although can be seen in older dogs as well. Episodes are triggered by stress/excitement. Episodes of increased tone, kyphosis and falling over may last 5 to 20 minutes. Episodes may look similar to Episodic falling in the Cavalier King Charles Spaniel. Paroxysmal non kinesigenic dyskinesia in the chinook can also mimic seizures. Episodes are not triggered by movement or exercise and can last up to 60 minutes.2
DIAGNOSTIC TESTS
CBC, chemistry and UA are indicated to rule out systemic conditions that could lead to seizures, weakness or collapse. Abdominal ultrasound is indicated and can be particularly useful to evaluate for metastatic neoplasia, hepatic disease and adrenal tumors.
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MRI and cerebrospinal fluid analysis are indicated in seizure patients. EEG can be done to evaluate for epileptiform activity within the brain. Limitations in EEG availability and the relatively poor sensitivity in detecting epileptiform activity with a single EEG likely decrease the utilization of EEG. Thus when seizures are suspected an anticonvulsant trial can also be helpful.
A full cardiac workup is indicated in patients with cardiovascular or pulmonary abnormalities identified physical examination or in patients whose episodes are ambiguous and atypical of generalized seizures. Small breed older dogs with a history of cough or respiratory abnormalities should raise suspicion of potential underlying pulmonary hypertension as a cause of the episodes, and should be screened for with a full cardiac workup prior to moving forward with advanced neurologic testing such as cranial MRI. Anesthesia is required for neurologic workup of seizures, and if the events are actually syncopal and associated with severe underlying cardiac disease, the anesthetic risk and likelihood of adverse anesthetic event may be high. Therefore, the cardiology workup typically is prioritized as first in patients whose episodes are ambiguous for seizure vs. syncope or are genetically predisposed breeds for cardiac disease. Absence of a murmur on auscultation or an arrhythmia on 5-minute resting electrocardiogram does not rule out a cardiac etiology of episodes, and further comprehensive cardiac workup is needed. Blood pressure, electrocardiogram, echocardiogram, and thoracic radiographs constitute a comprehensive cardiology workup. In genetically predisposed breeds, additional workup of occult DCM or arrhythmogenic RV cardiomyopathy (Boxers) should include a holter monitor. Likewise, further assessment of possible intermittent arrhythmia as a cause of syncopal episodes often requires a multi-day holter or event monitor. An event monitor helps determine if an arrhythmia is the cause of the event, and is activated by the owner at the time of the event. In a study of 58 dogs and 2 cats, an event monitor determined cause of event to be arrhythmogenic in 35% of animals versus non-arrhythmogenic in 65%.5 Diagnostic yield was highest (95.6%) in animals with underlying cardiac disease. Atropine challenge test can be done in dogs with bradyarrhythmias, and a full blood panel including chemistry, electrolytes, and CBC done to evaluate for systemic causes of bradyarrhythmias including hyperkalemia. Dogs responding to atropine challenge have an increase in HR typically >150 bpm with no sinus arrest or AV block. These patients may be candidates for medical management of primary bradyarrhythmias such as terbutaline or an anticholinergic medication. Seizure patients that are refractory to medications or are questionable in diagnosis need to be re-evaluated for syncopal etiology. Seven to thirteen percent of people with refractory epilepsy or with questionable epilepsy diagnosis were actually suffering from syncopal episodes, with a majority of syncope due to vasovagal cause.6;7 Another study found that 39% of people diagnosed with refractory epilepsy were actually suffering from convulsive syncope, which was identified by further cardiac studies including tilt table testing, carotid sinus massage, or implantable loop ecg recorders.8
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Like in human medicine, reassessment of diagnosis is reasonable in animals that are not responding to treatment for either seizures or cardiac syncope, especially if there is a questionable diagnosis. Boxer dogs particularly can be perplexing given the prevalence of both cardiac disease (arrhythmogenic right ventricular cardiomyopathy) and neoplastic brain disease. Sometimes arrhythmias may be incidentally detected and treated, and if episodes persist it may be necessary to have further neurologic evaluation.
TREATMENT
Syncope
Pulmonary hypertension
Treatment of PH is aimed at correcting the specific hemodynamic abnormality. Treatment of heart disease including heart failure or pulmonary hypertension can often ameliorate the syncopal episodes. Left CHF is treated with diuretics, angiotensin converting enzyme (ACE) inhibitors, spironolactone, and pimobendan. Resolution of symptomatic CHF often reduces post-capillary PH and clinical signs of syncope. Surgical or interventional techniques may be used to correct left to right shunting congenital heart diseases but should not be attempted in patients with right to left shunts since it will hasten death. There is a lack of evidence that pimobendan is helpful for precapillary PH as a pulmonary vasodilator, but it can be used to treat right heart failure, as well as standard heart failure medications including furosemide, ACE inhibitors, and spironolactone. ACE-inhibitors have been shown to delay pulmonary vascular remodeling in experimental animals and have produced beneficial hemodynamic effects in people with cor pulmonale. Digoxin improved cardiac output and reduced circulating norepinephrine concentration in people with primary PH and symptomatic right heart failure, and could be considered for treatment of severe PH and right heart failure in veterinary patients. Although high risk patients, treatment of dogs with heartworm disease with the split protocol of melarsomine and anti-inflammatory doses of prednisone is recommended since there may be improvement in the PH post-treatment.
Selective pulmonary arterial vasodilator therapy is the mainstay of treatment of PH in people, including prostacyclin CRIs or synthetic prostacyclin analogs given inhaled or by frequent SC injections. These classes of drugs are either cost prohibitive or the method of delivery not amenable for use in chronic home treatment of PH in animals. Sildenafil is the mainstay treatment for animals with pre-capillary PH or persistent moderate to severe mixed pre- and post-capillary PH without active left heart failure. Phosphodiesterase V inhibitors (sildenafil, tadalafil) lead to selective increases in cGMP in the pulmonary vasculature, leading to increased nitric oxide and pulmonary arteriolar vasodilation. The half-life of sildenafil in dogs is 6.1 hours, making TID dosing typically necessary (1-3 mg/kg PO TID).
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Symptomatic benefits of sildenafil in dogs with PH include: reduction in syncope, improved exercise capacity, improved quality of life scores, reduction in clinical signs such as dyspnea, and reduction in echocardiographic estimate of pulmonary artery pressure.1 Sildenafil was associated with a 4-fold increase in probability of surviving in dogs with pre-capillary PH secondary to respiratory disease.10 Tadalafil (2 mg/kg PO q24 hr) is a long-acting PDE5 inhibitor that has been shown to be non-inferior to sildenafil in dogs with PH.
Arrhythmias
Bradyarrhythmia treatment depends on response to atropine challenge test. A positive response to atropine challenge test may predict potential benefit of medical positive chronotropic therapy such as terbutaline or anticholinergic medication.11 In a long-term study of sick sinus syndrome patients, medical management with positive chronotropic drugs successfully controlled syncope long-term in 54% of 61 symptomatic SSS dogs, and acted as a bridge to permanent pacemaker implantation in 20%. Symptomatic bradyarrhythmias not responding to atropine challenge, or not responding to positive chronotropic medical therapy require a permanent pacemaker. Medical management of supraventricular tachyarrhythmias such as atrial fibrillation or supraventricular tachycardia is often with diltiazem +/- digoxin, and other choices in patients with adequate systolic function may include sotalol. Sotalol is also the drug of choice for treatment of ventricular arrhythmias in patients without decompensated severe myocardial failure. Mexiletine is often the first choice in patients with decompensated DCM, as it does not have negative inotropic effects, as well as concurrent treatment of the DCM and CHF.
Neurocardiogenic syncope
Neurocardiogenic syncope is more challenging to treat. Identification and treatment of a precipitating cause such as coughing may be palliative, as well as lifestyle modification. Cough suppressants along with pulmonary therapy for underlying respiratory problem or heart failure therapy are often helpful to lessen the trigger for the reflexive syncope. Patients with cardioinhibitory syncope (bradycardia from vasovagal reflex) may benefit from a pacemaker, yet syncope may persist if there is also a vasodilatory response.
Syncope
Treatment of heart disease including heart failure or pulmonary hypertension can often ameliorate the syncopal episodes. Treatment of PH is aimed at correcting the specific hemodynamic abnormality. Left CHF is treated with diuretics, angiotensin converting enzyme (ACE) inhibitors, and pimobendan. Resolution of symptomatic CHF often reduces post-capillary PH and clinical signs of syncope. Animals with pre-capillary PH or mixed pre and post-capillary PH require pulmonary arterial vasodilator, which is typically sildenafil (1-3 mg/kg PO TID). Bradyarrhythmia treatment depends on response to atropine challenge test.
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A positive response to atropine challenge test may predict potential benefit of medical positive chronotropic therapy such as terbutaline or anticholinergic medication.9 In a long-term study of sick sinus syndrome patients, medical management with positive chronotropic drugs successfully controlled syncope long-term in 54% of 61 symptomatic SSS dogs, and acted as a bridge to permanent pacemaker implantation in 20%. Symptomatic bradyarrhythmias not responding to atropine challenge, or not responding to positive chronotropic medical therapy require a permanent pacemaker. Medical management of supraventricular tachyarrhythmias such as atrial fibrillation or supraventricular tachycardia is often with diltiazem +/- digoxin, and other choices in patients with adequate systolic function may include sotalol. Sotalol is also the drug of choice for treatment of ventricular arrhythmias in patients without decompensated severe myocardial failure. Mexiletine is often the first choice in patients with decompensated DCM, as it does not have negative inotropic effects, as well as concurrent treatment of the DCM and CHF.
Neurocardiogenic syncope is more challenging to treat. Identification and treatment of a precipitating cause such as coughing may be palliative, as well as lifestyle modification. Cough suppressants along with pulmonary therapy for underlying respiratory problem or heart failure therapy are often helpful to lessen the trigger for the reflexive syncope. Patients with cardioinhibitory syncope (bradycardia from vasovagal reflex) may benefit from a pacemaker, yet syncope may persist if there is also a vasodilatory response.
Seizure
Anticonvulsant therapy is typically started when seizure frequency increases, particularly when 2 or more seizures occur within 6 months. A baseline period is helpful to determine the natural seizure frequency and can help assess response to anticonvulsant therapy. However, this baseline period should not be too long as earlier antiepileptic treatment may lead to better seizure control. Patients with cluster seizures, status epilepticus or secondary epilepsy should have anticonvulsant therapy started without delay. Anticonvulsant therapy is targeted to decrease the frequency and severity of seizures, increasing quality of life with as few adverse effects as possible.
CONCLUSION
A thorough history and physical examination is needed to help prioritize which events are neurologic or cardiac in animals suffering from transient loss of consciousness. Often clinical features overlap between syncope and seizures. A cardiology workup may be prioritized prior to neurologic diagnostics in animals with ambiguous clinical features of seizure versus syncope, or animals with cardiopulmonary abnormalities identified on physical examination. Reassessment of diagnosis of seizure vs. syncope may be needed in patients not responding to treatment.
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Reference List
1. Sheldon R. How to Differentiate Syncope from Seizure. Cardiol Clin 2015; 33(3):377-385.
2. Urkasemsin G, Olby NJ. Canine paroxysmal movement disorders. Vet Clin Small Anim 2014;44: 1091-1102.
3. Lowrie M, Garden O.A. Hadjivassiliou M, et al. Characterization of paroxysmal gluten-sensitive dyskinesia in border terriers using serological markers. J Vet Intern Med 2018;32(2): 775 –781.
4. Gill JL, Tsa KL, Krey C et al. A canine BCAN microdeletion associated with episodic falling syndrome. Neurobiology of Disease 2012;45: 130–136.
5. Bright JM, Cali JV. Clinical usefulness of cardiac event recording in dogs and cats examined because of syncope, episodic collapse, or intermittent weakness: 60 cases (1997-1999). J Am Vet Med Assoc 2000; 216(7):11101114.
6. Smith D, Defalla BA, Chadwick DW. The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic. QJM 1999; 92(1):15-23.
7. Josephson CB, Rahey S, Sadler RM. Neurocardiogenic syncope: frequency and consequences of its misdiagnosis as epilepsy. Can J Neurol Sci 2007; 34(2):221-224.
8. Zaidi A, Clough P, Cooper P, Scheepers B, Fitzpatrick AP. Misdiagnosis of epilepsy: many seizure-like attacks have a cardiovascular cause. J Am Coll Cardiol 2000; 36(1):181-184.
9. Ward JL, DeFrancesco TC, Tou SP, Atkins CE, Griffith EH, Keene BW. Outcome and survival in canine sick sinus syndrome and sinus node dysfunction: 93 cases (2002-2014). J Vet Cardiol 2016; 18(3):199-212.
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CALIFORNIA ®
VETERINARY MEDICAL ASSOCIATION
Spring Seminar March 8-10, 2024
Speaker Bio
Jim Lavely, DVM, ACVIM, DACVIM Neurology
Dr. Jim Lavely received his DVM degree from The Ohio State University in 1999. After completing an internship at Angell Memorial Animal Hospital, he underwent his neurology and neurosurgery residency training at UC Davis. Dr. Lavely is a boardcertified neurologist and enjoys working with a team of neurologists at VCA Animal Care Center of Sonoma County in Rohnert Park, Ca. Dr. Lavely has published several articles including the topics of CNS infections, pediatric neurology and seizures. He has conducted research regarding the diagnosis of myasthenia gravis and has participated in anticonvulsant clinical trials. Dr. Lavely has spoken at multiple national conferences as well as internationally. When not working you may find Dr. Lavely skiing with his wife and two daughters.
Dr. Jim Lavely
Need a Fix for That Fit? An Anticonvulsant Therapy
Jim Lavely, DVM, DACVIM, Neurology
69
CALIFORNIA ® VETERINARY MEDICAL ASSOCIATION
Need A Fix for That Fit: Anticonvulsant Therapy
James Lavely, DVM, DACVIM
VCA Animal Care Center of Sonoma County
Seizures are the manifestation of abnormal synchronous electrical activity in the brain and are the most common neurological disorder in dogs. Seizures may be categorized as generalized, when whole body involvement is present or partial, when a portion of the body is affected. Consciousness is unimpaired during simple partial seizures and is altered during complex partial seizures. A pre-ictal period prior to the seizure and a post ictal period lasting minutes to hours after the seizure are common with generalized seizures. Pre and post ictal signs may include anxiety, attention seeking, panting and pacing. The recognition of seizures can sometimes be difficult as vestibular episodes, dyskinesias and syncopal episodes can appear seizure like. A thorough evaluation for the underlying cause for seizures should be pursued to optimize anticonvulsant therapy. Patients with an underlying etiology other than idiopathic epilepsy may require medication in addition to anticonvulsant therapy. In addition, patients with secondary epilepsy often require anticonvulsant therapy sooner than those with primary/idiopathic epilepsy.
Idiopathic epilepsy is classified as recurrent seizures without an apparent cause. Interictal neurological examination is normal. Results of bloodwork, MRI and CSF are all normal. Seizures typically are first noted between the ages of 1 and 5. Generalized tonic clonic seizures are typically seen, although focal seizures are also possible. Idiopathic epilepsy is sometimes used to imply familial epilepsy as it is inherited in Beagles, Golden Retrievers, Irish Wolfhounds, English Springer Spaniels, Labrador Retrievers, Vizslas, Bernese Mountain Dogs, Boxers, Belgian Tervurens, British Alsatians, Keeshonds and Standard Poodles. Autosomal recessive inheritance is most common.1 Anticonvulsant therapy is typically started when seizure frequency increases, particularly when 2 or more seizures occur within 6 months. A baseline period is helpful to determine the natural seizure frequency and can help assess response to anticonvulsant therapy. However, this baseline period should not be too long as earlier antiepileptic treatment may lead to better seizure control. Patients with cluster seizures, status epilepticus or secondary epilepsy should have anticonvulsant therapy started without delay. Anticonvulsant therapy is targeted to decrease the frequency and severity of seizures, increasing quality of life with as few adverse effects as possible.
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Bromide hyperpolarizes the neuron through its replacement of chloride ions.2 Bromide has a half life (T ½) of 21-24 days and is excreted by the kidneys. The lack of hepatic metabolism makes potassium bromide, 30 to 40 mg/kg/day in food, a good choice for young dogs. The therapeutic range is 1.0 to 3.0 mg/ml. If dogs are in status epilepticus or have cluster seizures, the long T ½ of bromide can make it more difficult to use effectively. In these situations, a drug with a shorter T ½ may be a better choice. A loading dose of potassium bromide can be given at 450 to 600 mg/kg PO total over the course of 2 to 5 days. When a loading dose is needed, I typically administer 40 mg/kg PO TID x 5 days and then reduce the dose to 40 mg/kg PO q 24 hours. Adverse effects include sedation, ataxia, PU/PD, polyphagia, gastrointestinal and a possible association with pancreatitis. Increased dietary salt intake increases renal excretion.2
Phenobarbital increases the seizure threshold and decreases the spread to surrounding neurons. It enhances the inhibitory postsynaptic effects of GABA, inhibits glutamate activity and decreases calcium flux across neuronal membranes. Peak levels are achieved 4-6 hours post oral administration and its T ½ is 1 ½ to 3 days. Phenobarbital metabolism increases with chronic therapy. Adverse effects include sedation, ataxia, polyphagia, PU/PD and increased liver enzymes. The potential for liver failure increases at higher plasma levels 35-40 μg/ml (therapeutic range 15-40 μg/ml). Routine liver monitoring is recommended.2 Phenobarbital’s shorter T ½ allows for quicker manipulation of plasma levels, making it a good choice for dogs with frequent seizures. A double blinded, randomized, parallel study of 46 naïve epileptic dogs indicated therapeutic success (at least 50% reduction in seizures) in 90 % (18/20) of dogs treated with phenobarbital versus 74% (17/23) of dogs treated with bromide.3
Assessment of hypothyroidism is extremely difficult in dogs receiving phenobarbital. Total T4 (TT4) and freeT4 (FT4) values may be significantly decreased in dogs receiving phenobarbital. Total T3 changes minimally and TSH increases after several months of phenobarbital therapy. Serum cholesterol also increases after phenobarbital administration. It is unclear if the decrease in TT4 and FT4 is clinically significant. Increased thyroxinemonoiodination to T3 at the cellular level may occur, compensating for hypothyroxinemia. If so TT4, FT4 and TSH values are meaningless.4 TT4 values return to normal within 6 weeks of phenobarbital withdrawal. FT4 values may remain decreased for 10 weeks past cessation of phenobarbital therapy.5
Levetiracetam binds synaptic vesicular protein SV2A. Levetiracetam may prevent hypersynchronization of burst firing and seizure propagation. The T ½ is 4 hours in dogs and 5 hours in cats. Initial dosing was recommended at 10-20 mg/kg PO TID. However, a honeymoon effect was noted.
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After several months of therapy seizure control was lost.6 This honeymoon phenomenon and pharmacokinetic evaluation has led to a recommended starting dose of 20 mg/kg PO TID.7 Extended release levetiracetam is started at 30 mg/kg PO q 12 hrs.8 Adverse effects appear minimal with sedation/ataxia and vomiting occurring uncommonly. Eighty nine percent of the drug is excreted unchanged through the kidneys. The cytochrome P 450 system does not appear to be involved. However concurrent phenobarbital administration has been shown to decrease levetiracetam T ½ and decreases levetiracetam blood levels. Thus, dogs on both phenobarbital and levetiracetam concurrently may require higher dosages of levetiracetam.9
Zonisamide is a sulfonamide-based anticonvulsant drug. Zonisamide blocks voltage –dependent sodium channels and T –type calcium channels. Its T ½ is about 15 hours in the dog and 35 hours in cats. Zonisamide is metabolized by hepatic microsomal enzymes and is also renally excreted. Its T ½ is reduced with concurrent phenobarbital administration. Zonisamide is administered 5-10 mg/kg PO BID in dogs, with the higher dose range for dogs also receiving phenobarbital. Cats are given 5-10 mg/kg PO q 24 hours, due to the longer T ½. Zonisamide is typically well tolerated with anorexia, sedation and ataxia being the most common adverse effects.10 However acute renal tubular necrosis in a dog11 and hepatopathy was reported in 2 dogs12,13 associated with zonisamide therapy.
Gabapentin binds voltage gated calcium channels and decreases intracellular calcium influx. It is excreted unchanged by the kidneys with about 30-40% hepatic metabolism in the dog.14 The T ½ in dogs is 3-4 hours. The initial dose is 10 mg/kg PO TID. Sedation and ataxia are the most common adverse effects.10 The liquid formulation contains xylitol and thus should not be given to dogs. Dogs requiring liquid or smaller doses should have the drug compounded so that it does not contain xylitol.
Pregabalin is a GABA analog structurally similar to gabapentin. Pregabalin has a higher affinity for the α2δ subunit of neuronal voltage-gated calcium channels than does gabapentin. The T ½ of pregabalin is 7 hours in dogs14 and 10.4 hours in cats.15 Pregabalin is administered 2 – 4 mg/kg PO BID to TID. Adverse effects include sedation and ataxia and are not uncommon. Thus a starting dose of 2 mg/kg PO BID to TID with a gradual increase in dose by 1 mg/kg is recommended in dogs.14 A dose of 1-2 mg/kg PO BID is recommended in cats.15
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Felbamate enhances the inhibitory effects of GABA, blocks voltage dependent sodium channels and blocks NMDA receptors. The T ½ in dogs is 5-6 hours and is administered at a starting dose of 15 mg/kg PO TID. Doses as high as 70 mg/kg PO TID may be required in some dogs. Felbamate can cause aplastic anemia and fatal hepatopathy in people, thus its use is limited. In dogs, about 30% of felbamate undergoes hepatic metabolism with the rest excreted unchanged in the urine. Adverse effects in dogs include hepatic, mild thrombocytopenia and leukopenia.10
There has been interest in the potential for use of cannabidiol (CBD) in seizure therapy. CBD does not bind to type I cannabinoid receptors, but may have anticonvulsant properties via different mechanisms. CBD is thought to bind to transient receptor potential channels that lead to decrease glutamate release, inhibition of adenosine reuptake and activation of 5-hydroxytryptophan 1A receptors.16 CBD is metabolized by hepatic cytochrome P450 isoenzymes and the gastrointestinal tract.17 Three studies evaluating the use of CBD in dogs have shown little to no therapeutic response. The first, a randomized controlled study, evaluated epileptic dogs already receiving standard anticonvulsant medication. 12 dogs received 2.5 mg/kg of CBD infused oil PO q 12 hrs. and 14 dogs received placebo oil. The CBD infused oil was derived from industrial hemp and was certified to have ≤0.3% THC. Significant patient drops out occurred. 2 of 9 dogs in the CBD group and 2 of 7 dogs in the placebo group responded (≥50 % reduction in seizures).16 Given the lack of responders, another study was done using 4.5 mg/kg CBD oil PO q 12 hrs. in a crossover study of 39 dogs. There were 9 responders in the CBD group and 8 responders in the placebo group. Adverse effects were greater in the CBD group with decreased appetite (14 vs 4), soft stool (10 vs 4) and vomiting (10 vs 4) most common. CBD treated dogs consistently had higher ALP (mean baseline 278 vs mean of 1585 after 3 months of treatment). Mean baseline ALT was 64.4 and increased to 114.5 following 3 months of CBD therapy.18 A third study evaluated 14 dogs using 2 mg/kg of a CBD/CBDA rich hemp extract in a randomized crossover study. 6/14 dogs in the CBD group responded vs no dogs in the placebo group. Increased ALP, ataxia, somnolence, polyphagia and GI signs were mildly greater in the CBD treated group.17 Regulations and laws regarding CBD should be consulted as affiliation with its use carries potential medical and legal risks.
Dietary management of seizures utilizing medium chain triglycerides (MCT) have been studied. Feeding a diet with 9% to 10 % of the caloric density increased serum beta hydroxybutyric acid (BHB) concentrations.19,20 Capric acid (C10), a MCT, is a noncompetitive AMPA receptor antagonist inhibiting excitatory neurotransmission. This action is thought to explain its anticonvulsant effect.20 Two studies utilized a 6-month double blinded crossover placebo-controlled design.
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Dogs in both studies remained on their previous anticonvulsant medication. 10 of 21 dogs responded to a 10% MCT diet in one study.19 5 of 28 dogs responded to a 9% MCT oil supplemented diet in another study.20
Benzodiazepines are potent anticonvulsants that enhance the inhibitory effects of GABA. The T ½ of diazepam is 3.2 hours in dogs and about 15-20 hours in cats. Tolerance develops with maintenance use of benzodiazepines. Thus, the short duration of action in dogs and the development of tolerance limit the use of benzodiazepines to the emergency setting.2,10 Diazepam at 0.5 mg/kg IV or 1-2 mg/kg rectally is recommended for immediate treatment of seizures. Concurrent phenobarbital administration increases the metabolism of diazepam. Thus, the higher dose range is recommended for rectal diazepam when concurrently receiving phenobarbital therapy. Diazepam 0.5 mg/kg/hour may be administered as a constant rate infusion (CRI). The dose is then titrated based on seizure control and sedation.10 Midazolam is water soluble and is a nice choice for emergency treatment when a CRI is needed thru a peripheral catheter, via intramuscular injection or intranasal. Midazolam’s T ½ in dogs is 77 minutes.21 A dose of 0.07 to 0.2 mg/kg is recommended as a bolus for immediate seizure control and a dose of 0.05 to 0.5 mg/kg/hour when given as a CRI. When a benzodiazepine has been used to stop the acute seizure, it is important to also administer a longer acting anticonvulsant to prevent further seizures.10
Clorazepate is metabolized to nordiazepam and has a T ½ of 4-6 hours in dogs. Tolerance does not develop as readily compared to diazepam. Clorazepate may be helpful in short term control of breakthrough seizures at a dose of 0.5 - 1 mg/kg PO BID to TID. Clorazepate increases phenobarbital levels. Serum phenobarbital levels should be monitored with its use 2 and 4 weeks after starting clorazepate therapy.2,10
Anticonvulsant therapy for cats is often frustrating if phenobarbital is not successful. The use of potassium bromide is not recommended in cats due to the potential for asthma secondary to bromide therapy. Signs may resolve once bromide therapy is discontinued. The longer half life of diazepam in cats makes it a possible candidate for long term anticonvulsant therapy. However, the use of oral diazepam is limited due to the potential risk of severe/fatal liver disease in cats. Extensive studies regarding safety and efficacy of newer anticonvulsants in cats are lacking. Gabapentin 5-10 mg/kg PO TID may be used; however it has not been highly efficacious for seizures in small animals. Newer anticonvulsants such as levetiracetam 20 mg/kg PO TID and zonisamide 5-10 mg/kg PO q 24 hours in cats appear promising.
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Due to the limited number of studies and anecdotal experience (lower incidence of seizures in cats compared to dogs) care should be used when using these medications. Starting at the lower end of the dose range may be of benefit. Serial monitoring of the CBC and serum chemistry is recommended.
Recommendations against the use of acepromazine in dogs with a history of seizures have been common. The reason has been a possible decrease in the seizure threshold with its use. However, evidence to warrant a contraindication for the use of acepromazine in seizure patients is lacking. The use of acepromazine in seizure patients is unlikely to result in seizures. A retrospective study evaluated 36 dogs with a history of seizures that were given acepromazine for sedation or as a pre-anesthetic. None of the 36 dogs seizured within 16 hours of use.22
Serial evaluation of phenobarbital and bromide levels has historically been recommended. However, routine monitoring of levels often does not lead to a change in dosage and can become costly for clients. Furthermore, therapeutic levels and toxic levels are guidelines extrapolated from people, are based on population statistics and may not be accurate when extrapolated to an individual canine or feline patient.
Determining anticonvulsant levels is most beneficial when: 1. A dose change is needed and toxicity is a concern. The formula (desired blood level /current blood level) x current dose = The newly recommended dose 2. A refractory patient becomes controlled. This allows the identification of a therapeutic level for that individual patient, provided the seizure disorder does not worsen. 3. The patient is sensitive to the toxic effects of the anticonvulsant (Bromide most common offender). Obtaining a blood level as soon as clinical signs of toxicity abate identifies the toxic level for that patient. Evaluation of blood levels may not be important when patients are currently and historically well controlled and free of adverse effects. Ideally, patients receiving phenobarbital should have a level obtained once they reach steady state given the risk of hepatoxicity at levels > 35 μg/ml. Therapeutic levels for levetiracetam, zonisamide and pregabalin are relatively unknown for dogs at this time. Thus, routine monitoring of levels is typically not done with usage of these drugs. It is important to be aware that bromide levels are affected by Cl-. Increased dietary Cl- or IV fluids containing Cl- will increase renal excretion of bromide and thus lower serum bromide levels. A patient receiving bromide therapy may lose seizure control as a result of a change in diet or IV fluids. Conversely, a decrease in dietary Cl- may lead to toxicity (sedation and ataxia) as renal bromide excretion is reduced and serum bromide levels subsequently increase. Thus, dietary changes should be minimized in patients receiving bromide therapy.
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When transitioning from one anticonvulsant to another several factors may influence the recommendations for the transition. If significant adverse effects are not apparent then it is reasonable to add the additional drug while continuing the initial anticonvulsant at the maintenance dose. If the initial anticonvulsant drug is to be withdrawn it should be tapered over the course of several months. This is important as it is often difficult to definitively know how effective the initial drug was. Weaning the initial drug over several months may help prevent withdrawal seizures. If sedation or ataxia is noted with the addition of the new anticonvulsant either drug may be tapered to limit adverse effects. If seizure control is successful without adverse effects, maintenance therapy with multiple drugs may be warranted and thus the initial drug may not be withdrawn. If a second or third drug is implemented because of adverse effects, tapering the drug with the most likely adverse effects is recommended. If adverse effects are of mild to moderate concern then tapering a drug such as phenobarbital may be done q 2-4 weeks by 25 % each time. Potassium bromide may be reduced more quickly at times due to its longer T ½. Rapid tapering/withdrawal is necessary when adjusting medications because of severe adverse effects from existing therapy. In this situation the existing therapy should be stopped immediately or over the course of a few days. It is important to concurrently start another anticonvulsant with a shorter T ½ so that steady state is rapidly achieved. Furthermore, the additional drug should have a different profile of adverse effects.
References:
1. Licht BG, Lin S, Luo Y, et al. Clinical characteristics and mode of inheritance of familial focal seizures in standard poodles. J Am Vet Med Assoc 2007;231(10):1520-1528
2. Boothe DM. Anticonvulsant therapy in small animals. Vet Clin Small Anim Pract 1998;28(2):411-448
3. Dawn Merton Boothe DM, Dewey C, Carpenter DM. Comparison of phenobarbital with bromide as a first-choice antiepileptic drug for treatment of epilepsy in dogs. J Am Vet Med Assoc 2012;240:1073–108.
4. Müller PB, Wolfsheimer KJ, Taboada J, et al. Effects of long term phenobarbital treatment on the thyroid and adrenal axis and adrenal function tests in dogs. J Vet Intern Med 2000;14:157164.
5. Gieger TL, Hosgood G, taboada J, et al. Thyroid function and serum hepatic enzyme activity in dogs after phenobarbital administration. J Vet Intern Med 2000;14(3):277-281.
6. Volk HA, Matiasek LA, Feliu-Pascual AL et al. The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs. The Vet J. 2008; 176: 310–319.
7. Moore SA, Muñana KR, Papich JA, et al. Levetiracetam pharmacokinetics in healthy dogs following oral administration of single and multiple doses. Am J Vet Res 2010;71:337–341
8. Beasley MJ, Boothe DM. Disposition of Extended Release Levetiracetam in Normal Healthy Dogs After Single Oral Dosing. J Vet Intern Med 2015;29:1348–1353
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9. Muñana KR, Nettifee-Osborne MG, Papich JA. Effect of Chronic Administration of Phenobarbital, or Bromide, on Pharmacokinetics of Levetiracetam in Dogs with Epilepsy J Vet Intern Med 2015;29:614–619.
10.Thomas WB. Idiopathic epilepsy in dogs and cats. Vet Clin Small Anim Pract 2010;40:161179.
11. Cook AK, Allen AK, Espinosa D, et al. Renal tubular acidosis associated with zonisamide therapy in a dog. J Vet Intern Med 2011;25:1454-1457.
12.Miller ML, Center SA, Randolph JF, et al. Apparent acute idiosyncratic necrosis associated with zonisamide administration in a dog. J Vet Intern Med 2011;25:1156-1160.
13.Schwartz M, Munana KR, Olby NJ. Possible drug-induced hepatopathy in a dog receiving zonisamide monotherapy for treatment of cryptogenic epilepsy. J Vet Med Sci 2011;73(11):1505-1508.
14.Dewey CW, Cerda-Gonzalez S, Levine JM, et al. Pregabalin as an adjunct to phenobarbital, potassium bromide, or a combination of phenobarbital and potassium bromide for treatment of dogs with suspected idiopathic epilepsy. J Am Vet Med Assoc 2009;235:1442–1449.
15.Cautela MA, Dewey CW, Schwark WS, et al. Pharmokinetics of oral pregabalin in cats after single dose administration. In Proceedings ACVIM Forum. Anaheim,Ca: 2010, p 739.
16.McGrath S, Bartner L, Rao S, et al. Randomized blinded controlled clinical trial to assess the effect of oral cannabidiol administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with intractable idiopathic epilepsy. J Am Vet Med Assoc 2019; 254:1301-1308.
17.Garcia GA, Kube S, Carrera-Justiz S, et al. Safety and efficacy of cannabidiol-cannabidiolic acid rich hemp extract in the treatment and efficacy of refractory epileptic seizures in dogs. Fron Vet Sci 2022; 9:01-12.
18.Rozental AJ, Weisbeck BG, Corsato Alvarenga I, et al. The efficacy and safety of cannabidiol as adjunct treatment for drug-resistant idiopathic epilepsy in 51 dogs: a double-blinded crossover study. J Vet Intern Med 2023;37:2291-2300.
19.Law TH, Davies ES, Pan Y, et al. A randomised trial of a medium -chain TAG diet as treatment for dogs with idiopathic epilepsy. British Journal of Nutrition 2015; 114, 1438–1447.
20.Berk BA, Law TH, Packer RM, et al. A multicenter randomized controlled trial of mediumchain triglyceride dietary supplementation on epilepsy in dogs. J Vet Intern Med. 2020;34:1248–1259.
21.Read MR. Midazolam. Compendium 2002;24:774-777.
22.Tobias KM, Marioni-Henry K, Wagner R. A retrospective study on the use of acepromazine maleate in dogs with seizures. J Am Anim Hosp Assoc 2006;42:283-289.
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CALIFORNIA ®
VETERINARY MEDICAL ASSOCIATION
Insane in the Brain: Inflammatory Brain Disease
Jim Lavely, DVM, DACVIM, Neurology
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Insane in the Brain: Inflammatory CNS Disease
James Lavely, DVM, DACVIM Neurology
Inflammatory brain disease
Canine inflammatory brain diseases are common neurological abnormalities. The cause of these conditions is not known. However, it is generally thought to be immune mediated. Clinical signs associated with each condition are dependent on the area of the brain affected. Inflammatory brain disease should be considered in any dog with multifocal CNS disease. Other Ddx include infectious causes, metastatic neoplasia and hepatic encephalopathy.
Granulomatous Meningoencephalomyelitis (GME)
GME accounts for 5% to 25 % of all CNS disorders in dogs. Young to middle aged small breed dogs are most commonly affected. However, any age or breed may develop GME. Histologically, GME is characterized by perivascular cuffs of primarily mononuclear cells within white matter. The accumulation of inflammatory cells is typically microscopic; however, areas can coalesce to form a focal granulomatous mass. Histologically, the brainstem is commonly involved. Multifocal disease is common, and all regions of the CNS; Cerebrum, cerebellum, brainstem and spinal cord (cervical) may be affected. Ocular GME has also been reported. Clinical signs vary based upon the region of the CNS involved. Onset may be acute or chronic.1 The etiology of GME remains unclear. A T cell-mediated delayed–type hypersensitivity reaction with an autoimmune basis is suspected. Infectious etiologies have been explored and have not been identified. The combination of a nonspecific immunologic response, genetic and environmental factors are all considered likely to play roles in the cause of GME. 2
CBC, serum chemistry and urinalysis are unremarkable. CSF is the single most useful test in inflammatory brain disease.3 CSF typically yields a mononuclear pleocytosis with elevated protein, however a mixed pleocytosis with an increased percentage of neutrophils is not uncommon. MR imaging may identify contrast enhancing lesions as well evidence of brain edema.
The mainstay of treatment is corticosteroids. In rapidly deteriorating dogs, or in dysphagic dogs dexamethasone sodium phosphate 0.2 mg/kg Dex SP IV or SC BID may be given Dogs are then transitioned to prednisone at 1 mg/kg PO BID. In severe or refractory cases cytosine arabinoside may be given at 50 mg/m2 BID for two consecutive days and then repeated if necessary q 3 weeks. Alternatively, procarbazine at 25 mg/m2 PO q 24 hours,4 cyclosporine 3 to 15 mg/kg PO BID,5 azathioprine, mycophenolate or lomustine may be given. Routine monitoring of the CBC should be done when these drugs are given. Serial urinalysis +/- culture is also recommended in immunosuppressed dogs. Ideally the effectiveness of treatment is monitored by both improvements in clinical signs as well as serial CSF evaluation. Prednisone is tapered over a several month period. Many dogs require long-term prednisone therapy. Adjunctive therapy such as cytosine arabinoside, cyclosporine, procarbazine or azathioprine may lessen the dependence on corticosteroids and lead to a more favorable prognosis.
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The prognosis for GME has been considered guarded. The median survival time for dogs with focal signs was 114 days (range 3 to >1,1215 days), whereas dogs with multifocal signs had a median survival time of 8 days (range 1 to 274 days) in one study.1 The prognosis may be better than this, as confirmation of GME requires histological examination (necropsy or less commonly surgical biopsy). Several studies have shown a better prognosis. One study reported a median survival time of 14.0 months with procarbazine and prednisone treatment compared to 0.62 months for dogs not receiving treatment. Diagnosis was made ante mortem with CSF analysis and MR imaging.6 Another study showed a median survival time of 930 days with use of cyclosporine or in combination with corticosteroids or ketoconazole.5 A study comparing combined prednisolone and lomustine use to prednisolone alone indicated a median survival time of 457 days compared to 329 days, respectively. The difference in survival time between groups was not statistically significant.7 A study evaluating the use of prednisone and cytosine arabinoside in 10 dogs with inflammatory brain disease of unknown etiology indicated a median survival time of 531 days. The study included dogs with suspected GME as well as NLE or NME.8 More recently the use of glucocorticoid therapy alone for the treatment of meningoencephalomyelitis of unknown etiology was re-evaluated and indicated a median survival time of 602 days in 16 dogs.9 Another retrospective study evaluated multiple treatment regimens for meningitis of unknown origin and found no statistical difference in median survival times between corticosteroid monotherapy (716 days, N=26), combination of corticosteroids and ciclosporin (916 days, N=15), combination of corticosteroids and either leflunomide, cytosine arabinoside, or a combination of 2 or more adjunctive medications (1186 days, N=13). Adverse effects were reported in 47 dogs and included PU/PD (37/47), polyphagia (37/47), diarrhea (29/47) and lethargy (28/47). Euthanasia was reported due to relapse (15/35), lack of therapeutic response (9/35) and adverse effects (2/35).10
Necrotizing Encephalitis
Necrotizing encephalitides (NE) are inflammatory diseases causing necrotic cystic lesions within the gray and white matter of the cerebrum. In Pugs, Chihuahuas and Maltese terriers the necrotic condition is often adjacent to the cerebral gray-white matter junction and is thus termed necrotizing meningoencephalitis (NME). In the Yorkshire terrier necrotizing encephalitis causes cystic white matter lesions in the cerebrum and typically has inflammatory lesions in the brainstem and cerebellum. Dogs with primarily white matter lesions are thus described as having necrotizing leukoencephalitis (NLE). Due to the breed specific variance in lesion location, it is uncertain if these diseases are in fact variants of the same disease or different diseases.11 Less commonly NLE has been identified in Pugs, Chihuahuas and Maltese terriers and NME has been identified in the Yorkshire Terrier. Thus, it is possible that these disorders may represent a spectrum of the same disease at various stages. Similar to GME, a combination of immunologic, genetic or environmental triggers are likely responsible for NE.2 Chromosome 12 within MHCII has been associated with a genetic risk for NME and additional association to chromosome 4 in the maltese and chromosome 15 in the pug.12 Male and female, young to middle age dogs are typically affected, however dogs as old as 10 years of age have been
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reported. Seizures are common. Mentation changes, circling and placing deficits may also be seen. Vestibular signs may predominate when the brainstem is affected. CSF typically indicates a mononuclear pleocytosis with elevated protein. MR imaging helps confirm the location and presence of cavitative lesions. MR imaging may also differentiate the disease from GME Recommended treatment is prednisone starting at 1 mg/kg PO BID and is tapered slowly over several months Adjunctive therapy with additional immunosuppressive medications may also be used. The prognosis for necrotizing encephalitis is poor. Mean survival time with corticosteroid treatment was 97 days in one study.13 Dogs with necrotizing encephalitis may be less responsive to therapy than those treated for suspected GME.
Idiopathic Cerebellitis
Idiopathic cerebellitis (i.e. White Shaker Dog syndrome) occurs in small breed dogs of any coat color. Dogs classically present with tremors that worsen with movement. Cranial MR imaging is typically normal or may have very subtle changes in the cerebellum. CSF analysis typically identifies a mild pleocytosis. GME typically has a greater pleocytosis compared to idiopathic cerebellitis. However, at times GME can have a mild pleocytosis making differentiation difficult. The prognosis with idiopathic cerebellitis is typically good with immunosuppressive prednisone therapy. Dogs can often be tapered off of prednisone after a few months of therapy. Relapse can occur with premature withdrawal of prednisone therapy.
Steroid Responsive Meningitis Arteritis (SRMA)
SRMA occurs in young- adult medium to large breed dogs. A breed predisposition occurs in Beagles, boxers and Bernese mountain dogs. SRMA is suspected to be an immune mediated inflammatory disorder primarily affecting the leptomeninges and associated vessels Dogs typically present with signs of apparent cervical pain, stiff gait, reluctance to move or fever. Serum and CSF may have significantly increased IgA levels. C reactive protein may also be elevated in serum and CSF. CSF is considered the most important diagnostic test. CSF typically indicates a marked neutrophilic pleocytosis. The pleocytosis may be up to several thousand cells/ul. Immunosuppressive therapy with prednisone +/- adjunctive immunosuppressive is utilized long term. Serial evaluation of CSF or C reactive protein can help monitor therapy.14
Many inflammatory conditions of the CNS are thought to be immune mediated disorders and necessitate immunosuppressive therapy to achieve clinical success. However, clinical signs and test results can be similar with CNS infections as well. Immunosuppressive therapy with underlying infection can lead to severe negative consequences. Thus, thorough evaluation for infection via CBC, urinalysis +/- urine culture MRI, CSF (+/- culture), infectious serology, is important. Serial monitoring of clinical signs and lab work can also be helpful.
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References:
1. Munana KR, Luttgen PJ. Prognostic factors for dogs with granulomatous meningoencephalomyelitis: 42 cases (1982-1996). J Am Vet Med Assoc 1998;212(2): 19021906.
2. Schatzberg SJ. Idiopathic granulomatous and necrotizing inflammatory disorders of the canine central nervous system. Vet Clinics Small Anim 2010;40: 101-120.
3 Lamb CR, Croson PJ, Cappello R, Cherubini GB. Magnetic resonance imaging findings in 25 dogs with inflammatory cerebrospinal fluid. Vet Rad & Ultrasound 2005;46(1):17-22.
4 Cuddon PA, Coates JR, Murray M. New treatments for granulomatous meningoencephalomyelitis. In proceedings 20th ACVIM. Dallas:2002, p 319-321.
5 Adamo PF, Rylander H, Adams WM. Ciclosporin use in multi-drug therapy for meningoencephalomyelitis of unknown aetiology in dogs. J Small Anim Pract. 2007;48(9):48696.
6. Coates JR, Barone G, Dewey CW et al. Procarbazine as Adjunctive treatment of dogs with presumptive antemortem diagnosis of granulomatous meningoencephalomyelitis: 21 cases (1998-2004). J Vet Int Med 2007;21:100-106.
7 Flegel T, Boettcher IC, Matiasek K, et al. Comparison of oral administration of lomustine and prednisolone or prednisolone alone as treatment for granulomatous Meningoencephalomyelitis or necrotizing encephalitis in dogs. J Am Vet Med Assoc 2011;238:337–345.
8. Zarfoss M, Schatzberg S, Venator K, et al. Combined cytosine arabinoside and prednisone therapy for meningoencephalitis of unknown aetiology in 10 dogs. J Small Anim Pract 2006;47: 588–595
9. Mercier M, Barnes Heller H. Efficacy of glucocorticoid monotherapy for treatment of canine meningoencephalomyelitis of unknown etiology: a prospective study in 16 dogs. Veterinary Med & Science 2015;1: 16-22.
10 Heidermann PL, Erhald B, Koch BC etal. Investigation of side effects to treatment and cause of death in 63 Scandinavian dogs suffering from meningoencephalitis of unknown origin: a retrospective study. Acta Veterinaria Scandinavica 2023; 65:46
11. Higgins RJ, Dickinson PJ, Kube SA et al. Necrotizing meningoencephalitis in 5 Chihuahua dogs. Vet Pathol 2008 May;45(3):336-46.
12 Windsor R, Stewart S, Schmidt J, et al. A potential early clinical phenotype of necrotizing meningoencephalitis in genetically at-risk pug dogs. J Vet Intern Med 2022;36:1382-1389.
13. Levine JM, Fosgate GT, Porter B, et al. Epidemiology of necrotizing meningoencephalitis in pug dogs. J Vet Intern Med 2008:22:961-968.
14. Tipold A, Stein VM. Inflammatory diseases of the spine in small animals. Vet Clinics Small Anim 2010;40: 871-879
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CALIFORNIA
My Cat’s a Head Case: Feline Brain Disease
Jim Lavely, DVM, DACVIM, Neurology
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® VETERINARY MEDICAL ASSOCIATION
My Cat’s a Head Case: Feline Brain Disease
James Lavely, DVM, DACVIM-Neurology
Neoplasia is a common cause of intracranial disease in cats. The most common clinical signs are altered consciousness, circling, seizures, lethargy and inappetence.1 Clinical signs depend on location of the neoplasm and peritumoral edema. Vestibular signs are at times present secondary to increased intracranial pressure or cerebellar herniation. Cats with cerebral disease can have contralateral menace deficits, contralateral placing deficits, seizures, altered mentation and circling to the same side as the lesion. Cats with brainstem disease can have ipsilateral CN deficits, ipsilateral placing deficits and also circle to the same side as the lesion. Cats with cerebellar disease may have an ipsilateral menace deficit, ataxia and circling. The mean age of cats with intracranial neoplasia is 11.3 years of age with a male to female ratio of 1.5:1.1 MRI allows for identification of a space occupying mass or edema. Spinal fluid analysis is often abnormal, but also often nonspecific. Direct visualization of lymphoblasts can lead to a diagnosis of lymphoma.
Meningioma is the most common intracranial neoplasm in dogs and cats. 58.1 % of cats with brain tumors in one study had meningioma. Multiple meningiomas were present within the brain of 17.2% of the cats with meningiomas in that study. Meningiomas arise from the meninges and are thus extra-axial in location. They most commonly are supratentorial in location, but also are not uncommonly associated with the tela choroidea in the third ventricle.1 Meningiomas on MRI are typically heterogeneously hyperintense on T2 imaging, iso or hypointense on T1 imaging and markedly contrast enhance. A dural tail sign is common and the adjacent calvarium is often thickened (hyperostosis). The appearance of mineralization or hemorrhage within the tumor is not uncommonly apparent. Peritumoral edema is often mild, but can be marked. Mass effect is often present potentially leading to transtentorial or cerebellar herniation.2 CSF evaluation is typically mildly abnormal to normal with a median WBC of 5 cells/µL and total protein (TP) of 59.5 mg/dl.1 Cats with meningiomas are treated with prednisolone to decrease peritumoral edema. Prednisolone is started at 0.5 mg/kg PO q 12 hours and tapered to the lowest effective dose. If clinical deterioration occurs the dose is increased to the previous effective dose. In addition to prednisolone, surgery is the preferred therapy. The median survival time in cats treated with surgery was 685 days post operatively vs. 18 days when medical therapy alone was used.1 In another study the median survival time for cats treated with surgical excision was 37 months.3 Anticonvulsant therapy is used to control seizures.
Lymphoma is the most common secondary brain tumor and second most common intracranial neoplasm. Lymphoma accounted for 14.4 % of intracranial neoplasms in a large retrospective study. Three of seventeen cats tested for FeLV were positive for the infection. The median survival time with corticosteroid therapy was 21 days (range 9-270 days) in 9 cats. The most common areas affected were the brainstem, cerebrum and meninges.1 Lymphoma can appear in an extra-axial or intra-axial location. Lymphoma is typically hyperintense on T2 imaging, iso or hypointense on T1 imaging and markedly contrast enhances on MRI. A dural tail sign occasionally may occur as well as hyperostosis. Peritumoral edema is common and can lead to
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mass effect. At times MRI can be normal.2 CSF evaluation indicated a mean WBC of 14.4 cells/µL with 76% neutrophils and a TP of 54.5 mg/dl in one study.1 CSF evaluation can definitively identify CNS LSA; however, the sensitivity is generally poor.
Pituitary tumors are the third most common brain intracranial tumor. Cats are typically older (median 10.1 years) and more commonly male (3.7:1 male to female ratio). Cats most commonly present with a history of blindness, altered mentation, lethargy and anorexia. Feline pituitary tumors are more likely to be functional endocrine tumors compared to dogs. Half of pituitary tumors are associated with endocrine disease with diabetes most commonly present followed by adrenal dysfunction.1 Pituitary tumors extend dorsally from the sella turcica and can compress the diencephalon. Pituitary tumors typically contrast enhance on MRI. Pituitary macroadenomas are treated with prednisolone therapy to control peritumoral edema and alleviate neurological signs. Survival time with corticosteroid therapy is almost 2 months1, but likely depends on the size of the tumor, degree of brain compression and clinical signs. Radiation therapy in cats has a median survival time of 17.4 months (range 8.4-63.1 months). Neurological improvement usually occurs within 2 months of radiation therapy. Improvement in concurrent hyperadrenocortcism or acromegaly begins to occur within 1-5 months of radiation therapy.4
Gliomas are the 4th most common intracranial tumor in cats. Astrocytomas and oligodendrogliomas are equally as common. Gliomas are intra-axial in location and typically occur in the more ventral portion of the brain. A supratentorial location is most common and thus seizures are a common clinical sign. The mean age of cats with gliomas is 12.9 years of age1 which is older than that typically seen in dogs. Gliomas are typically round, but can be lobulated. On MRI they are typically hyperintense on T2 imaging, hypointense on T1 imaging and often has a pattern of ring enhancement. The degree of enhancement is variable.2 On CSF evaluation median WBC is 55.5 cells/µL with a TP of 25 mg/dl. A gliosarcoma (glioblastoma grade IV astrocytoma) was recently reported in a 5-year-old cat.5
Ependymomas and choroid plexus tumors are neuroepithelial tumors. Ependymomas are reported more commonly than choroid plexus tumors in the cat. Ependymomas typically are located in the wall of the third ventricle, but not uncommonly the lateral ventricle. The intraventricular location can cause secondary hydrocephalus. Ependymomas typically strongly contrast enhance on MRI. CSF analysis in two cats with ependymoma had a median WBC of 49.5 cells/µL and TP of 63.5 mg/dl.1
Cryptococcus and FIP commonly cause intracranial signs. FIP commonly affects the 3rd and 4th ventricles. Seizures and vestibular signs are commonly seen with cryptococcosis depending on the location of the lesion. Brain involvement is common with toxoplasmosis. However, neurological signs secondary to toxoplasma are relatively uncommon.
The cerebellum develops until about 10 weeks of age. Cerebellar hypoplasia is typically caused by intrauterine viral infection, most commonly the parvovirus of feline panleukopenia. The virus targets cells with active DNA synthesis such as the external germinal layer of the cerebellum. Destruction of the cerebellum’s granule cells and Purkinje cells results in hypoplasia.6
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Cerebellar/vestibular signs including ataxia, a wide based stance and hypermetria are noted as the kitten begins to walk at a few weeks of age.
Cats have a high dietary requirement of thiamine (Vitamin B1) and can develop thiamine deficiency for a variety of reasons: 1. Canned diets are susceptible to thiamine loss due to the high heat during processing 2. sulfur preservatives can destroy thiamine 3. thiamine is oxidized by gamma irradiation and 4. ultraviolet light and fish viscera, shellfish and some bacteria have high thiaminase activity. Thiaminases are destroyed by cooking. However, since processing can also destroy thiamine inadequate thiamine levels can still occur. Thiamine deficiency can lead to neurological signs such as seizures, ataxia, vestibular signs, decreased mentation, cervical ventroflexion, vision loss and mydriasis. In people, brain lesions develop within 2-3 weeks of thiamine deficiency. MRI of cats with thiamine deficiency indicate bilaterally symmetrical hyperintense lesions on T2 and FLAIR imaging. The lesions may be hypointense on T1 imaging and do not contrast enhance. Lesions may occur in the lateral geniculate nuclei, caudal colliculi, medial vestibular nuclei, red nuclei, cerebellar nodulus, facial nuclei, periaqueductal gray matter and the cerebral cortex. Lesions identified on MRI can resolve following thiamine supplementation. The diagnosis can be confirmed via measuring thiamine in feline blood by HPLC. This test is more sensitive and specific than measuring erythrocyte transketolase activity. Testing whole blood is preferred over serum. Thiamine diphosphate the biologically active form of Vit B1 is not present in significant quantity in plasma. Furthermore, plasma thiamine concentrations reflect recent dietary intake, but not whole-body stores. Thiamine deficiency is reversible if identified and treated. Thiamine deficiency should be suspected if a dietary history consistent with thiamine deficiency is present or when MR imaging identifies bilaterally symmetrical lesions on T2 and FLAIR MR imaging without contrast enhancement.7
A unique syndrome involving necrosis of the hippocampal occurs in cats. Affected cats typically present with acute onset of seizures that often are refractory to anticonvulsants and can progress to cluster seizures or status epilepticus. Aggression, salivation, mydriasis and mentation changes are also common signs. Affected cats often die spontaneously. Hippocampal necrosis most commonly occurs between the ages of 1 and 6 years. Histopathologic examination of the brain indicates bilateral lesions within the hippocampus and sometimes the piriform lobe. The rest of the brain appears normal. The hippocampal lesions may represent varying stages from acute neuronal degeneration to malacia. The cause for the disorder is unknown, but a toxic cause is considered likely as bilateral symmetrical lesions often result from toxic or metabolic disturbances. An ischemic cause is considered unlikely as ischemia is not present in other areas of the brain and a cause for an underlying cerebrovascular disorder has not been identified in affected cats. Hippocampal necrosis is not thought to be secondary to the seizures themselves as most animals euthanized due to severe seizures do not have neuronal damage. Two clusters (groups of 2 and 4 cats) of cats from the same geographic area around the same time of onset suggest an environmental or toxic cause. Halogenated quinoxaline compounds have been associated with selective degeneration of the hippocampus and piriform lobe in dogs. Halogenated quinoxaline compounds were used to treat diarrhea in people, but were removed from the market prior to cats being reported with hippocampal necrosis.8 Thus, the cause for the disorder is unknown at this time.
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Cerebrovascular disease is an abnormality in the brain resulting from pathology of its blood supply. Commonly referred to as a “stroke”, cerebrovascular disease may be ischemic or hemorrhagic. Occlusion of a cerebral blood vessel by an embolism or thrombus leads to ischemic stroke. Rupturing of a cerebral blood vessel leads to hemorrhagic stroke and results in hemorrhage into or around the brain. Ischemic strokes are rare in the cat. Feline ischemic encephalopathy in which unilateral cerebral or brainstem ischemia occurs with a peracute onset of clinical signs has been reported. Some cases have been linked to Cuterebra migration. The migrating parasite or the host response is thought to result in vasospasm in the cerebral vasculature. The middle cerebral artery is commonly affected.9 Cardiac disease or systemic hypertension predisposes cats to a vascular event. Despite the predisposition, vascular events in cats are uncommon, likely because of the difference in bloody supply to the brain in cats compared to dogs and people. In dogs and people, the vascular supply to the rostral half of the brain is supplied by the internal carotid and the caudal half of the brain is supplied by vertebral blood. In cats the proximal 2/3 of the internal carotid artery is obliterated within months after birth.10 The adult cat brain is supplied by branches of the maxillary artery and connect through a network of vessels, the rete mirabile The rete mirabile is involved in thermoregulation and may decrease pulsation before blood reaches the brain. Very little vertebral blood reaches the cat’s brain. These species differences likely decrease the incidence of stroke in the cat. Vascular events to the spinal cord are more common as the spinal cord’s blood supply does not pass through the rete mirabile. Blood pressure evaluation, thoracic radiographs and echocardiography may be useful to non-invasively assess the possibility of a vascular event. Evidence of spontaneous contrast (i.e. “smoke”) or an intracardiac thrombus on echocardiography indicates a high risk of arterial thromboembolism. MRI can be helpful in diagnosing a stroke. Infarctions typically follow the vascular pattern and are often sharply demarcated and wedge shaped in appearance. Contrast enhancement is usually not present until 7-10 days, as reperfusion takes place. Intracranial hemorrhage can be identified by gradient echo (GRE) MRI. Hemorrhage is identified by susceptibility artifact, hypointense foci, on GRE. CSF is often normal in stroke patients, but can be inflammatory, likely from tissue damage associated with necrosis. Treatment involves supportive care and treating any underlying/predisposing causes for the stroke. Anticoagulant therapy is not typically used, unless echocardiography indicates smoke or a procoagulable state has been supported by D dimer evaluation. Fluid therapy is used to maintain blood pressure and thus a cerebral perfusion pressure (CPP) of at least 70 mm Hg. Increased intracranial pressure (ICP) is also of potential concern.9 It is important to realize that systemic blood pressure can be elevated to maintain CPP (CPP= BP-ICP). Thus, if ICP is increased an increased blood pressure may be the body’s response to maintain CPP. In this situation using drugs to lower blood pressure could be detrimental. When increased ICP is suspected mannitol 0.5 g/kg IV over 10-20 minutes should be used to lower ICP and thus may also lower BP. Glucose containing solutions should be avoided as hyperglycemia has been associated with poor outcome in human stroke patients. The prognosis with stroke is often good, provided that neurologic injury is not extremely severe and that an underlying cause does not prevent recovery. Significant improvement is often seen within several weeks.9
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Traumatic brain injury is common in cats. A thorough examination should be done to evaluate for concurrent injuries from the trauma. Initial therapy should focus on maintaining cardiopulmonary needs. IV fluid therapy and oxygen therapy should be used to help maintain cerebral perfusion. IV fluids should be used to correct hypovolemia and hypotension. Elevated PaCO2 levels cause cerebral vasodilation and increase CBF and ICP and thus should be avoided. Maintaining SpO2 ≥ 95 (PaO2 ≥80 mm Hg) and PaCO2 between 35-40 mmHg is needed to maintain cerebral O2 delivery and prevent increases in ICP. 11 Brain injury can result in loss of cerebral autoregulation. Cerebral ischemia can occur when CPP falls below 40 mm Hg. Thus, mean arterial blood pressure should be kept between 50- and 150-mm Hg to maintain CPP. Below a BP of 50 ischemia is more likely to occur (normal ICP is <10 mm Hg) and when BP is >150 cerebral edema or hemorrhage could worsen. When BP is >150 or when increased ICP is suspected mannitol should be administered. Elevation of the head without occluding the jugular veins may help decrease ICP.12 Monitoring neurological status is essential to identify when ICP may be rising and brain herniation may be imminent. Monitoring mentation, pupil size and PLR frequently is very important. Miotic pupils indicate cerebral injury. Mydriasis can indicate brain herniation. Bilateral mydriasis with absent PLR usually indicates irreversible injury to the midbrain or brain herniation and carries a poor prognosis. Fixed, unresponsive and midrange pupils are typically identified with cerebellar herniation.11 Mannitol should be administered if mentation worsens or if pupils indicate deterioration. Hyperventilation can temporarily reduce ICP. However chronic or excessive hyperventilation can reduce global CBF. Thus, hyperventilation is not recommended unless PaCo2 can be closely monitored. CT scan or MRI is indicated with moderate to severe neurological deficits or when neurological signs are progressive.11 Craniectomy may be indicated if a depressed skull fracture or subdural hematoma is identified on cranial imaging
The degree of hyperglycemia has been correlated to the severity of head trauma in dogs and cats. Hyperglycemia in patients with cerebral ischemia increases free radical production, excitatory amino acid release, cerebral edema and cerebral acidosis. Hyperglycemia is associated with increased mortality rates and neurologic outcomes in people and experimentally induced head trauma in animals. Thus, the use of dextrose solutions and the use of corticosteroids should be avoided or minimized.13
Enzyme deficiencies lead to abnormal accumulations of various substances within the nervous system and are thus referred to as storage diseases. Lysosomal storage diseases are autosomal recessive inherited and affect male and females equally. Onset of signs is insidious and affected cats may survive months to years. Cerebellar or vestibular signs and tremors are common in neuronal storage diseases. Ceroid lipofuscinosis results in cerebral signs with seizures and decreased vision. Skeletal and connective tissue abnormalities are seen in several different lysosomal storage diseases including mucopolysaccharidoses and in α-mannosidosis seen in domestic short hairs.14 In MPS I bilateral corneal opacity and facial anomalies are characteristic by 1-2 years of age.15 Storage diseases should be suspected in kittens with neurological signs and concurrent musculoskeletal or ocular abnormalities. The diagnosis can be confirmed via identification of abnormal accumulations on review of blood smear, fine needle aspiration, biopsy of affected organs or via DNA testing.
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Feline infectious peritonitis (FIP) is a common and fatal infectious feline disease caused by a mutant form of feline enteric corona virus (FECV).16 A pyogranulomatous meningoencephalitis and meningomyelitis is seen with CNS involvement. Median age of cats with FIP affecting the CNS is 1 year of age.17 Cats with neurologic FIP may have weight loss, mentation changes, ataxia and hyperesthesia. Ocular abnormalities are not uncommon. Anterior uveitis, hyphema and retinal hemorrhage may be identified on ophthalmologic examination.16 Serum globulins, are often elevated in FIP.18 Seronegative FIP may be seen in cats with low titers, acute fulminant disease less than 10 days and from immune complex consumption.19 MRI may identify periventricular changes consistent with ependymitis. The 3rd and 4th ventricles are commonly affected. Secondary hydrocephalus may also be identified. CSF analysis indicates an elevated protein value (mean 97.3 g/dl)16 and a neutrophilic pleocytosis (mean 28 cells/ul).17 CSF antibodies are likely of serum origin, however conflicting studies make the definitive antibody origin unkown.16,17 A ratio of CSF Ab: serum Ab compared to CSF protein: serum total protein > 1 has typically suggested intrathecal antibody production.16,17 However, a value > 1 may not necessarily imply active CNS infection.17 Prednisone therapy has typically been given to cats with neurologic FIP to decrease CNS inflammation and for immunosuppression. While prednisone therapy +/- other immunosuppressive medications may slow the progression of disease the prognosis has ultimately been poor.
Recently experimental therapy evaluating the use of nucleoside analogs such as remdesivir and GS-441524 in FIP has been promising. In one study utilizing GS -441524, 4 of 31 cats died within 2 to 5 days of treatment. While 18 of 26 cats remained healthy after completing a 12-week treatment course. 8 cats that relapsed were retreated. 25 cats were alive at the time of publication.20
Another study evaluated 307 cats with suspected FIP retrospectively. The cats were treated with either remdesivir, GS-441524 or remdesivir followed by GS-441524. 84.4 % of cats were considered to have a complete response, 5.9 % a partial response and 9.8% no response to therapy. 44 of the 307 cats had predominantly neurological signs. In the neurologically affected group 70.5 % had a complete response, 18.2 % partial response and 11.4 % no response to therapy. 15 of 33 cats (overall treatment group) that relapsed did so during treatment, while 15 other cats relapsed within 60 days of stopping therapy. 8 of 15 cats that relapsed during treatment had a dose escalation. 7 of 8 cats responded to the increased dose. 21
References:
1. Troxel MT, Vite CH, Van Winkle TJ, et al. Feline intracranial neoplasia: retrospective review of 160 cases (1985-2001). J Vet Intern Med 2003; 17:850-859.
2. Troxel MT, Vite CH, Massicotte M, et al. Magnetic resonance imaging features of feline intracranial neoplasia: retrospective analysis of 46 cats. J Vet Intern Med 2004;18:176189.
3. Cameron S, Rishniw M, Miller AD, et al. Characteristics and survival of 121 cats undergoing excision of intracranial meningiomas (1994-2011). Vet Surg 2015;44:772776.
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4. Mayer MN, Greco DS, LaRue SM. Outcomes of pituitary tumor irradiation in cats. J Vet Intern Med 2006;20:1151–1154.
5. Alvarez P, Wessman A, Pascual M, et al. Cerebral gliosarcoma with perivascular involvement in a cat. JFMS Open Rep. 2019 Oct 10;5(2):2055116919879783.
6. Schatzberg SJ, Haley NJ, Barr SC et al. Polymerase chain reaction (PCR) in amplification of parvoviral DNA from the brains of dogs and cats with cerebellar hypoplasia. J Vet Intern Med 2003;17:538-544.
7. Marks SL, Lipsitz D, Vernau KM, et al. Reversible encephalopathy secondary to thiamine deficiency in 3 cats ingesting commercial diets. J Vet Intern Med 2011;25:949–953
8. Fatzer R, Gandini G, Jaggy A, et al. Necrosis of hippocampus and piriform lobe in 38 domestic cats with seizures: A retrospective study on clinical and pathologic findings J Vet Intern Med 2000;14:100–104
9. Garosi LS. Cerebrovascular disease in dogs and cats. Vet Clin Small Anim 2010;40:65-79
10. King AS. Arterial supply to the central nervous system. In: Physiological and clinical anatomy of domestic mammals. Blackwell Science. 1987 p 1-12.
11. Garosi L, Adamantos S. Head trauma in the cat 2. Assessment and management of traumatic brain injury. J Fel Med & Surg 2011;13,815 823.
12. Hopkins AL. Head trauma. Vet Clin Small Anim 1996;26:875-890.
13. Syring RS, Otto CM, Drobatz KJ. Hyperglycemia in dogs and cats with head trauma:122 cases (1997-1999). J Am Vet Med Assoc 2001;218:1124-1129.
14. Skelly BJ, Franklin. Recognition and diagnosis of lysosomal storage diseases in the cat and dog. J Vet Intern Med 2002;16:133-141
15. Summer BA, Cummings JF, de Lahunta A. Degenerative diseases of central nervous system. In Veterinary neuropathology. St Louis (Mo): Mosby; 1995. p 208-350.
16. Foley JE, Lapointe JM, Koblik P, et al. Diagnostic features of clinical neurologic feline infectious peritonitis. J Vet Intern Med 1998;12:415-423.
17. Boettcher IC, Steinberg T, Matiasek K, et al. Use of anti-coronavirus antibody testing of cerebrospinal fluid for diagnosis of feline infectious peritonitis involving the central nervous system in cats. J Am Vet Med Assoc 2007;230(2):199-205.
18. Hartmann K, Binder C, Hirschberger J, et al. Comparison of different tests to diagnose feline infectious peritonitis. J vet Intern Med 2003;17:781-790
19. Foley JE. Feline infectious peritonitis and feline enteric coronavirus. In: Ettinger, Feldman, editors. Textbook of Veterinary Internal Medicine. 6th edition. St. Louis: Elsevier; 2005. p 663-666.
20. Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis. Pedersen NC, Perron M. Bannasch M, et al. Journal of Feline Medicine and Surgery 2019, Vol. 21(4) 271–281.
21. Taylor SS, Coggins S, Barker EN, et al. Retrospective study and outcome of 307 cats with feline infectious peritonitis treated with legally sourced veterinary compounded preparations of remdesivir and GS-441524 (2020-2022). Journal of Feline Medicine and Surgery 2023;1-26.
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I’ll Take Neurology for 300!
Jim Lavely, DVM, DACVIM, Neurology
95 CALIFORNIA ® VETERINARY MEDICAL ASSOCIATION
I’ll Take Neurology For 300!
James A. Lavely, DVM, DACVIM Neurology
Metronidazole toxicity typically occurs with dosages greater than 60 mg/kg/day. Cerebellar Purkinje cell loss and axonal degeneration may occur. Thus, cerebellar and vestibular signs such as ataxia, hypermetria and nystagmus may be seen with toxicity. Toxicity may be seen at lower dosages, particularly with treatment of longer duration. Diazepam treatment q 8 hours may speed recovery by competitive binding at the GABA receptor. Dogs treated with an average dose of 0.43 mg/kg diazepam q 8 hours for 3 days significantly improved at an average of 13.4 hours compared to 4.25 days for dogs not given diazepam.1
Cerebellar abiotrophy is a premature degeneration of cerebellar tissue, most typically purkinje cells. Animals are typically normal at birth and develop cerebellar signs as they age. Cerebellar abiotrophy has been reported in several breeds with a variable age of onset depending upon the breed.2 In animals affected by cerebellar hypoplasia the cerebellum develops abnormally. Cerebellar hyoplasia is typically inherited. Cerebellar hypoplasia most commonly affects kittens infected in utero with the feline panleukopenia virus3
Central vestibular disease results from lesions affecting the brainstem or cerebellum. Paradoxical vestibular disease, a form of central vestibular disease may occur with lesions affecting the caudal cerebellar peduncle, the fastigial nucleus, vestibular nuclei or the flocculonodular lobes. On MRI, lesions affecting the cerebellar pontine angle often result in paradoxical vestibular disease. Lesions affecting the vestibulocochlear nerve or the receptor organs of the inner ear result in peripheral vestibular disease.4 Head tilt, falling, rolling, ataxia, nystagmus, strabismus and nausea are often signs of vestibular disease. Differentiating central vestibular disease from peripheral vestibular may change the order of differential diagnoses. For instance, otitis media/interna in dogs and cats and inflammatory polyps in cats may cause peripheral vestibular disease while neoplasia and vascular events are more often associated with central vestibular disease. Idiopathic vestibular disease may affect either the central or peripheral vestibular systems. With central vestibular disease decreased mentation, cranial nerve deficits and ipsilateral conscious proprioceptive deficits may be present. In paradoxical vestibular disease the head tilt is contralateral to the lesion. Animals with vestibular disease will often have decreased tone in the ipsilateral limbs and increased tone in the contralateral limbs. MRI is the imaging test of choice to evaluate the vestibular system. CSF analysis is important as inflammatory brain diseases such as GME have a predilection for the brainstem. CSF may also help identify central extension of otitis media/interna, lymphoma and infectious diseases such as Cryptococcus and FIP.
Feline neurology can often be frustrating. Common feline neurological diseases include lymphoma, cryptococcosis, FIP and toxoplasmosis. These diseases can affect any location within the CNS and thus should be considered regardless of lesion localization. Meningiomas are common in cats and typically affect the cerebrum, although other locations within the CNS may also be affected. Vascular events may occur, particularly in cats with cardiac disease or systemic hypertension. Blood pressure evaluation, thoracic radiographs and echocardiography may be
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useful to non-invasively assess the possibility of a vascular event. Evidence of spontaneous contrast (i.e. “smoke”) or an intracardiac thrombus on echocardiography indicates a high risk of arterial thromboembolism. Cranial MRI may also be helpful in identifying a lesion consistent with infarction. Cryptococcus antigen testing is highly sensitive and may be useful in assessing cats with neurological disease. Toxoplasma serology identifies antibodies and thus exposure, but does not necessarily indicate causation of neurological disease. However, a positive IgM titer suggests recent infection. Serum globulins are often elevated in FIP. MRI may identify ependymal lesions, periventricular lesions or secondary hydrocephalus consistent with FIP. CSF analysis may be very helpful in differentiating between the various feline neurological diseases. Lymphoma as well as cryptococcal organisms can be directly identified in CSF. FIP often yields a neutrophilic pleocytosis with increased protein. Toxoplasma may yield a mixed pleocytosis with increased CSF protein.
Degenerative disc disease is common in cats. However, it is uncommon for cats to exhibit myelopathic signs secondary to intervertebral disc protrusion.5
Cervical ventroflexion in cats is an indicator of muscle weakness and thus neuromuscular disease. When cervical ventroflexion is identified myasthenia gravis and hypokalemia should be ruled out. Myasthenia gravis is uncommon in cats, however is more common in Abyssinian and Somali cats. Most commonly feline myasthenia gravis presents with generalized weakness without a megaesophagus (28.6 %) or generalized weakness associated with a cranial mediastinal mass (25.7 %). Less commonly focal myasthenia gravis occurs with megaesophagus and dysphagia (14.3%).6 Megaesophagus is more commonly seen in the dog due to the presence of striated muscle throughout the length of the esophagus whereas in the cat the distal 1/3 is smooth muscle. Methimazole therapy has been associated with myasthenia gravis in cats. Acetylcholine receptor antibody testing is highly sensitive with seronegative generalized myasthenia gravis occurring in about 2 % of dogs. Resolution of weakness immediately following intravenous injection of edrophonium “Tensilon test” (0.1-0.2 mg/kg IV in dogs and 0.25-0.5 mg total dose in cats) is highly suggestive of myasthenia gravis. Atropine should be given prior to edrophonium injection in cats as they are more sensitive than dogs to edrophonium. Edrophonium is no longer on the market. A response to neostigmine methyl sulfate (0.01-0.05 mg/kg SC, IM or IV slowly over one minute) has been used as an alternative. 13 of 16 myasthenic dogs had a strong positive response to neostigmine, while 3 had no response. 2 of 3 dogs with polymyositis also had a strong response.7 Thus, false positive responses to neostigmine challenge can occur. Atropine sulfate (0.02 – 0.04 mg/kg) should be readily available at the time of Tensilon or neostigmine testing as adverse effects such as salivation, lacrimation, diarrhea and vomiting may occur. The standard treatment of myasthenia gravis has been pyridostigmine bromide 1-3 mg/kg PO BID to TID. In animals unable to swallow medications safely, pyridostigmine bromide (0.01-0.03 mg/kg/hour) may be administered via constant rate infusion.8 Immunosuppressive therapy has also been used to treat myasthenia gravis. Various immunosuppressive medications have been used such as azathioprine, cyclosporine, mycophenylate and corticosteroid therapy. The high incidence of aspiration pneumonia in myasthenic patients should be considered when choosing either immunosuppressive therapy or anticholinesterase therapy. The prognosis for myasthenia gravis
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is variable. A significant number of dogs, 87%, go into spontaneous remission.8 However, one study indicated that the one-year survival rate was 40.4 %.9
Hypokalemia in cats may cause a polymyopathy. Cats present with generalized weakness, and cervical ventroflexion. Serum CK may be elevated. Clinical signs may resolve once potassium levels are re-established. A lag time between normalization of serum potassium levels and resolution of clinical signs may occur. Potassium loss with chronic renal disease is the most important cause. Congenital hypokalemia is a consideration in Burmese kittens.10
Degenerative myelopathy typically presents as a progressive, non-painful T3-L3 myelopathy. With progression decreased patellar reflexes may be seen and even clinical signs of a cervical myelopathy. Affected dogs are typically over 5 years old. Histopathologically, axonal loss is primarily seen, especially in the lateral funiculi. Average time to euthanasia was reportedly 19 months in the Pembroke Welsh Corgi.11 A study of dogs with suspected degenerative myelopathy indicated that dogs with intense physiotherapy had a longer survival time (8.5 months) than dogs with moderate (4.3 months) and dogs without physiotherapy (1.8 months).12 Degenerative myelopathy was identified as an E40K missense mutation through resequencing of the SOD1 gene in the Pembroke Welsh Corgi, German Shepherd dog, Rhodesian ridgeback, Boxer and Chesapeake Bay retriever. Affected dogs are homozygous for the A allele.13
Incomplete closure of the developing neural tube results in spinal dysraphism and congenital syringohydromyelia. Ataxia, a bunny hopping pelvic limb gait and pelvic limb spinal reflex deficits may be seen. Spinal dysraphism is heritable in Weimaraner. Affected Weimaraner may lack a central canal, a ventral median fissure or have incomplete separation of the ventral horns.14,15
Diagnosis of tetanus is based on clinical signs. In the initial stages clear signs of tetanus may not be apparent. Ocular changes initially may be subtle. Lethargy, anorexia and vomiting are also common initial signs. As the disease progresses protrusion of the third eyelid and enophthalmos may be seen. The ears may become erect and the lips drawn back, known as Risus sardonicus. Contraction of the masticatory muscles may lead to trismus. Dysphagia may result. A generalized stiff gait is apparent with generalized tetanus and may progress to the extreme rigidity of a sawhorse type posture.16
A stiff gait may also be caused by other generalized neuromuscular diseases, degenerative joint disease, polyarthritis and meningitis. Serum CK may be elevated in dogs with polymyopathies and thus inclusion of CK evaluation on serum chemistry testing is essential. Polyarthritis may occur concurrently with meningitis. A study evaluating dogs with immune mediated polyarthritis and spinal pain identified concurrent meningitis in 5 of 11 dogs that had CSF collected. None of the 5 dogs were lame or had palpably swollen joints. Only 1 dog exhibited apparent joint pain. Cervical pain and thoracolumbar pain were common.
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Despite similar treatment for polyarthritis and meningitis identification of CNS involvement is considered important.17 Thus, both CSF evaluation and joint fluid evaluation are considered important with in dogs with apparent spinal pain.
Acute polyradiculoneuritis, botulism and tick paralysis all may cause acute generalized lower motor neuron disease. Differentiation can be difficult. Identification of embedded ticks with rapid resolution of signs supports the diagnosis of tick paralysis. A salivary neurotoxin secreted by Dermacentor and Ixodes tick species impairs presynaptic neuromuscular transmission Botulism is caused by ingestion of type C neurotoxin of Clostridium botulinum and results in inhibition of presynaptic Ach release from cholinergic fiber nerve terminals. Complete recovery should occur with supportive care within 1-3 weeks.8 Acute polyradiculoneuritis is of unknown etiology, but is likely immune mediated. Exposure to raccoon saliva may be the immune stimulus in many, but not all cases. The ventral nerve roots are affected with varying degrees of axonal degeneration, demyelination and infiltration of inflammatory cells. Lumbar CSF may have increased CSF protein. EMG evaluation may be abnormal after about 5 days. Nerve conduction studies typically show slowed F wave latencies and prolonged F ratios. Hyperesthesia may arise. Recovery typically occurs within several weeks to 6 months with supportive care. Corticosteroids are not recommended and have been associated with reduced survival rate in people with the human equivalent of an acute neuropathy called Guillain–Barré syndrome.18
Neuroanatomic localization is very important in developing a list of differential diagnoses and is essential in imaging the appropriate area. Decreased reflexes indicate lower motor neuron involvement. A myelopathic patient with decreased patellar reflexes traditionally indicates a L4L6 myelopathy. A T3-L3 lesion should also be considered, as neurologically normal dogs may lack a patellar reflex response. The absent reflex may be unilateral or bilateral. It is more commonly identified in dogs at 10 years of age or older. 19 The lack of a thoracic limb withdrawal reflex in a tetraparetic dog traditionally indicates a C6-T2 myelopathy. However, a study indicated that the withdrawal reflex deficit led to incorrect neuroanatomic localization in 11/14 dogs when judged by comparison to MRI. Cranial cervical disk herniations (C2-C3 andC3C4) were most often associated with incorrect neuroanatomic localizations due to decreased withdrawal reflexes. Resolution of the withdrawal reflex deficit occurred in 13 of 19 dogs evaluated 6 weeks post operatively.20
Assessment of deep pain sensation can sometimes be difficult. Testing of deep pain is done by clamping/pinching hemostats across the digits and compressing the bone/periosteum. Vocalization, turning sharply or attempting to bite are clear signs that the dog or cat retains pain sensation. Withdrawal of the limb may be a reflex and not necessarily an indicator of true pain sensation and thus is not reliable in determining prognosis. More subtle indications of deep pain sensation may include an increase in respiration. At times agitation and excitement may mask the appearance of pain sensation. Thus, testing in a relaxed atmosphere with or without the owner present may be of benefit. With compressive myelopathies deep pain sensation is present when voluntary motor function is present. Thus, it is not typically assessed unless severe paresis or plegia is present.
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References:
1. Evans J, Levesque D, Knowles K, et al. Diazepam as a treatment for metronidazole toxicosis in dogs: a retrospective study of 21 cases. J Vet Intern Med 2003; 17:304-310
2. Jokinen TS, Rusbridge C, Steffen F, et al. Cerebellar cortical abiotrophy in Lagotto Romagnolo dogs. Journal of Small Animal Practice. 2007; 48:470-473
3. Coates JR, O’Brien DP, Kline KL, et al. Neonatal cerebellar ataxia in cotton de tulear dogs. J Vet Intern Med. 2002; 16:680-689.
4. Garosi LS, Dennis R, Penderis J, et al. Results of magnetic resonance imaging in dogs with vestibular disorders: 85 cases (1996-1999). J Am Vet Med Assoc 2001; 218:385-391
5. Lu D, Lamb CR, Wesselingh K, et al. Acute intervertebral disc extrusion in a cat: clinical and MRI findings. J Fel Med & Surg 2002; 4:65-68.
6. Shelton GD, HO M, Kass PH. Risk factors for acquired myasthenia gravis in cats: 105 cases (19861998). J Am Vet Med Assoc 2000; 216:55-57.
7. Cridge, H, Little A, Jose-Lopez R, etal. The clinical utility of neostigmine administration in the diagnosis of acquired myasthenia gravis. J Vet Emerg Crit Care (San Antonio) 2021;5:647-655.
8. Shelton GD. Myasthenia gravis and disorders of neuromuscular transmission. Vet Clinics NA Small Animal Pract 2002; 32:189-206.
9. Dewey CW, Bailey CS, Shelton GD, et al. Clinical forms of acquired myasthenia gravis in dogs: 25 cases (1988-1995). J Vet Intern Med 1997; 11:50-57.
10. Platt SR. Neuromuscular complications in endocrine and metabolic disorders. Vet Clinics NA Small Animal Pract 2002; 32:125-146.
11. Coates JR, March PA, Oglesbee M et al. Clinical characterization of a familial degenerative myelopathy in Pembroke welsh corgi dogs. J Vet Intern Med 2007; 21:1323-1331.
12. Kathmann I, Cizinauska S, Doherr MG, et al. Daily controlled physiotherapy increases survival time in dogs with suspected degenerative myelopathy. J Vet Intern Med 2006; 20:927-932.
13. Awano T, Johnson GS, Wade CM, et al Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. PNAS 2009; 106:2794-2799.
14. Lavely JA. Pediatric Neurology of the dog and cat. Vet Clin NA Small Anim Pract 2006; 36:475-501.
15. Summers BA, Cummings JF, De Lahunta A. Malformations of the central nervous system. In: Veterinary neuropathology. St Louis (MO): Mosby; 1995. p. 68–94.
16. Greene CE. Tetanus. In: Greene CE, editor. Infectious diseases of the dog and cat. 3rd edition. St. Louis: Elsevier; 2006. p. 395- 402.
17. Webb AA, Taylor SM, Muir GD. Steroid-Responsive Meningitis-Arteritis in Dogs with Noninfectious, Nonerosive, Idiopathic, Immune-Mediated Polyarthritis. J Vet Intern Med 2002; 16:269-273.
18. Cuddon PA. Acquired canine peripheral neuropathies. Vet Clin NA Small Anim Pract 2002; 32:207249.
19. Levine JM, Hillman RB, Erb HN et al. The influence of age on patellar reflex response in dogs. J Vet Intern Med 2002; 16:244-246.
20. Forterre F, Konar M, Tomek A, et al. Accuracy of the withdrawal reflex for localization of the site of cervical disk herniation in dogs: 35 cases (2004–2007). J Am Vet Med Assoc 2008; 232:559-563.
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Lavely,
Neurology I’ll Take Neurology
500! 101 CALIFORNIA ® VETERINARY MEDICAL ASSOCIATION
Jim
DVM, DACVIM,
for
I’ll Take Neurology For 500!
James A. Lavely, DVM, DACVIM Neurology
Staphylococcus is a common cause of discospondylitis. Spinal epidural empyema (i.e. abscess) is most often associated with E. Coli, Bacteriodes spp and S. Intermedius. 1 Thus, antibiotic choice should be targeted at these organisms when a bacterial infection is suspected and culture/sensitivity results are not available. Cephalosporins and amoxicillin/clavulanic acid are both good choices. A fluoroquinolone may be used if a therapeutic response is not initially seen with the previous antibiotic choices. Fungal discospondylitis can be difficult to diagnosis, as a bacterial cause is typically suspected. Aspergillus tereus, Cladophialophora and Paecilomycosis may also cause discospondylitis. Coccidiomycosis can cause vertebral osteomyelitis. Fungal serology and often times biopsy and culture may be required to diagnose fungal infections of the spine. Itraconazole or voriconazole should be considered for fungal discospondylitis and osteomyelitis. While fluconazole is often used for CNS fungal infections because of its penetration in to CSF, it has little activity against Aspergillus.2
Thoracic limb lameness is often initially thought to be of orthopedic origin. Degenerative joint disease, tendon injury, neoplasia, trauma and less commonly osteomyelitis and joint infection encompass non-neurological causes for lameness. Neurologic causes are commonly overlooked initially. Significant muscle atrophy, ataxia, Horner’s syndrome and CP deficits may suggest a neurologic cause for the lameness. Neoplasia (Peripheral nerve sheath tumor and lymphoma) not uncommonly affects the brachial plexus. Pain may or may not be present on palpation of the axilla. Lateralized disc herniations may cause thoracic limb lameness and are often painful. Radiographs of the affected limb and thorax can help identify neoplasia. Spinal MR imaging that includes the brachial plexus is helpful in differentiating disc disease from neoplasia. CSF analysis is important to evaluate for lymphoma and inflammatory CNS diseases. Amputation of the affected limb may be of benefit when peripheral nerve sheath tumors are present. However, good margins are often difficult to obtain in the brachial plexus. Thus, the high likelihood of recurrence makes amputation of questionable benefit when the tumor is quite proximal, at the level of the spinal canal. While radiation therapy is of benefit in peripheral nerve sheath tumors, anecdotally it is of limited benefit when the brachial plexus is involved. Loss of the ipsilateral cutaneous trunci reflex occurs with traumatic brachial plexus injuries, in which avulsion of the caudal brachial plexus occurs. The prognosis with brachial plexus injuries is poor. Traction injuries without avulsion may improve with time and rehabilitation therapy.
Horner’s syndrome most commonly occurs with lesions of the middle ear or with a lesion from T1-T3. A partial Horner’s syndrome may be present with a lesion at T1. The occurrence of an acute C6-T2 myelopathy with concurrent Horner’s syndrome is commonly associated with fibrocartilaginous embolism and less commonly neoplasia
Idiopathic cerebellitis (i.e. White Shaker Dog syndrome) occurs in small breed dogs of any coat color. Dogs classically present with tremors that worsen with movement. Cranial MR imaging is typically normal or may have very subtle changes in the cerebellum. CSF analysis typically identifies a mild pleocytosis. GME typically has a greater pleocytosis compared to idiopathic cerebellitis. However, at times GME can have a mild pleocytosis making differentiation difficult.
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The prognosis with idiopathic cerebellitis is typically good with immunosuppressive prednisone therapy. Dogs can often be tapered off of prednisone after a few months of therapy. Relapse can occur with premature withdrawal of prednisone therapy.
Anticonvulsant therapy for cats is often frustrating if phenobarbital is not successful. The use of potassium bromide is not recommended in cats due to the potential for asthma secondary to bromide therapy. Signs may resolve once bromide therapy is discontinued. The longer half life of diazepam in cats makes it a possible candidate for long term anticonvulsant therapy. However, the use of oral diazepam is limited due to the potential risk of severe liver disease in cats. Extensive studies regarding safety and efficacy of newer anticonvulsants in cats are lacking. Gabapentin may be used, however it has not been highly efficacious for seizures in small animals. Newer anticonvulsants such as levetiracetam 20 mg/kg PO TID and zonisamide 510 mg/kg PO q 24 hours in cats appear promising. Due to the limited number of studies and anecdotal experience (lower incidence of seizures in cats compared to dogs) care should be used when using these medications. Starting at the lower end of the dose range may be of benefit. Serial monitoring of the CBC and serum chemistry is recommended.
Serial evaluation of phenobarbital and bromide levels has historically been recommended However, routine monitoring of levels often does not lead to a change in dosage and can become costly for clients. Furthermore, therapeutic levels and toxic levels are guidelines extrapolated from people, are based on population statistics and may not be accurate when extrapolated to an individual canine or feline patient. Determining anticonvulsant levels is most beneficial when: 1. A dose change is needed and toxicity is a concern. The formula (desired blood level /current blood level) x current dose = The newly recommended dose 2. A refractory patient becomes controlled. This allows the identification of a therapeutic level for that individual patient, provided the seizure disorder does not worsen. 3. The patient is sensitive to the toxic effects of the anticonvulsant (Bromide most common offender). Obtaining a blood level as soon as clinical signs of toxicity abate identifies the toxic level for that patient. Evaluation of blood levels may not be important when patients are currently and historically well controlled and free of adverse effects Ideally, patients receiving phenobarbital should have a level obtained once they reach steady state given the risk of hepatoxicity at levels > 35 μg/ml. Therapeutic levels for levetiracetam, zonisamide and pregabalin are relatively unknown for dogs at this time. Thus, routine monitoring of levels is typically not done with usage of these drugs. It is important to be aware that bromide levels are affected by Cl-. Increased dietary Clor IV fluids containing Cl- will increase renal excretion of bromide and thus lower serum bromide levels. A patient receiving bromide therapy may lose seizure control as a result of a change in diet or IV fluids. Conversely, a decrease in dietary Cl- may lead to toxicity (sedation and ataxia) as renal bromide excretion is reduced and serum bromide levels subsequently increase. Thus, dietary changes should be minimized in patients receiving bromide therapy.
Recommendations against the use of acepromazine in dogs with a history of seizures have been common. The reason has been a possible decrease in the seizure threshold with its use. However, evidence to warrant a contraindication for the use of acepromazine in seizure patients is lacking. The use of acepromazine in seizure patients is unlikely to result in seizures.
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A retrospective study evaluated 36 dogs with a history of seizures that were given acepromazine for sedation or as a pre-anesthetic. None of the 36 dogs seizured within 16 hours of use.3
Assessment of hypothyroidism is extremely difficult in dogs receiving phenobarbital. Total T4 (TT4) and freeT4 (FT4) values may be significantly decreased in dogs receiving phenobarbital. Total T3 changes minimally and TSH increases after several months of phenobarbital therapy. Serum cholesterol also increases after phenobarbital administration. It is unclear if the decrease in TT4 and FT4 is clinically significant. Increased thyroxinemonoiodination to T3 at the cellular level may occur, compensating for hypothyroxinemia. If so TT4, FT4 and TSH values are meaningless.4 TT4 values return to normal within 6 weeks of phenobarbital withdrawal. FT4 values may remain decreased for 10 weeks past cessation of phenobarbital therapy.5
Centronuclear myopathy (CNM), previously known as type II fiber deficiency, autosomal recessive muscular dystrophy of Labradors and hereditary Labrador retriever myopathy, affects young Labrador retrievers (typically 3-4 months of age) of both sexes. Affected puppies may exhibit signs of weakness, kyphosis, cervical ventroflexion, stiff gait and generalized muscle atrophy. Creatine kinase is typically normal to mildly increased. Clinical signs typically progress slowly and stabilize by 12 months of age, although rapid progression occurs sometimes.6 The disease is autosomal recessive with an insertional mutation within PTPLA exon 2.7 A commercial test is available for the mutation. Muscle biopsy abnormalities are variable, but include angular atrophy, small and large group atrophy with a predominant loss of type II myofibers in some cases. Central nuclei are present in 74 % of cases.6
X linked myotubular myopathy has been reported in male Labrador retrievers. Clinical signs begin from 3 to 4 months of age and are similar to CNM. Serum CK is mildly increased. Genetic testing for CNM is negative. Biopsy changes include centrally placed nuclei resembling fetal myotubes and subsarcolemmal abnormalities. A missense mutation in the MTM1 gene has been identified in X linked myotubular myopathy.8
Canine X linked muscular dystrophy (CXMD) has typically affected golden retrievers, but has also been reported in the Labrador retriever. Dogs are affected at birth or <6 weeks of age and are male. Clinical signs include muscle weakness, bunny hopping gait, dysphagia, tongue enlargement and hypersalivation. An absence of membrane dystrophin on muscle biopsy confirms the diagnosis.6
Marijuana toxicity is associated with diffuse CNS signs such as obtundation, ataxia, CP deficits and tremors. Vomiting, hypersalivation, mydriasis, bradycardia or tachycardia may be seen. Urine dribbling consistent with a LMN bladder without complete localization to the cauda equina also suggests possible intoxication. Most animals develop clinical signs within 1 to 3 hours post ingestion.9 Human urine THC testing is negative in dogs due to metabolization to conjugated compounds. These compounds are larger and more delicate than THC metabolites in human urine. Most dogs with marijuana toxicity recover, although severe intoxication may
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lead to death. Treatment is supportive, with gastric lavage and activated charcoal limiting enterohepatic recirculation.10
Neurologic deficits with compressive myelopathies such as seen with intervertebral disc disease, proceed in a stereotypical fashion. CP deficits occur first followed by ambulatory paresis/ataxia → non-ambulatory paresis/ataxia → paraplegia → loss of superficial pain sensation → loss of deep pain sensation. Urinary incontinence typically occurs between the stages of severe paresis to plegia. Thus, animals that have good motor function or are ambulatory do not typically need to be assessed for apparent pain sensation. However, some dogs that are paraplegic without apparent deep pain sensation can regain the ability to ambulate non-voluntarily through the use of crossed extensor reflexes. These “spinal walkers” are urinary incontinent. Thus, deep pain should be tested for in ambulatory paraparetic patients that are incontinent.
Feline infectious peritonitis (FIP) is a common and fatal infectious feline disease caused by a mutant form of feline enteric corona virus (FECV).11 A pyogranulomatous meningoencephalitis and meningomyelitis is seen with CNS involvement. Median age of cats with FIP affecting the CNS is 1 year of age.12 Cats with neurologic FIP may have weight loss, mentation changes, ataxia and hyperesthesia. Ocular abnormalities are not uncommon. Anterior uveitis, hyphema and retinal hemorrhage may be identified on ophthalmologic examination.11 Serum globulins, are often elevated in FIP.13 Seronegative FIP may be seen in cats with low titers, acute fulminant disease less than 10 days and from immune complex consumption.14 MRI may identify periventricular changes consistent with ependymitis. The 3rd and 4th ventricles are commonly affected. Secondary hydrocephalus may also be identified. CSF analysis indicates an elevated protein value (mean 97.3 g/dl)11 and a neutrophilic pleocytosis (mean 28 cells/ul).12 CSF antibodies are likely of serum origin, however conflicting studies make the definitive antibody origin unkown.11,12 A ratio of CSF Ab: serum Ab compared to CSF protein: serum total protein > 1 has typically suggested intrathecal antibody production 11,12 However, a value > 1 may not necessarily imply active CNS infection.13 Prednisone therapy is typically given to cats with neurologic FIP to decrease CNS inflammation and for immunosuppression. While prednisone therapy +/- other immunosuppressive medications may slow the progression of disease the prognosis is ultimately poor.
Recently experimental therapy evaluating the use of nucleoside analogs such as remdesivir and GS-441524 in FIP has been promising. 4 of 31 cats died within 2 to 5 days of treatment. While 18 of 26 cats remained healthy after completing a 12-week treatment course. 8 cats that relapsed were retreated. 25 cats were alive at the time of publication.15
One study surveyed 393 people treating their cats with suspected FIP with unlicensed GS441524-Like antiviral therapy. 380 were alive at publication. 54% were considered cured, 43.3% were being monitored in the 12-week treatment period 12.7% relapsed and 3.3% died.16 The survey nature was an inherent flaw of the study however showed significant promise compared to the historical prognosis.
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Treatment with unlicensed therapy carries potential medical and legal risks.
Another study evaluated 307 cats with suspected FIP retrospectively. The cats were treated with either remdesivir, GS-441524 or remdesivir followed by GS-441524. 84.4 % of cats were considered to have a complete response, 5.9 % a partial response and 9.8% no response to therapy. 44 of the 307 cats had predominantly neurological signs. In the neurologically affected group 70.5 % had a complete response, 18.2 % partial response and 11.4 % no response to therapy. 15 of 33 cats (overall treatment group) that relapsed did so during treatment, while 15 other cats relapsed within 60 days of stopping therapy. 8 of 15 cats that relapsed during treatment had a dose escalation. 7 of 8 cats responded to the increased dose.17
References:
1.Lavely JA, Vernau KM, Vernau W, et al. Spinal epidural empyema in seven dogs. Vet Surg 2006; 35:176-185.
2.Lavely JA, Lipsitz D. Fungal infections of the central nervous system in the dog and cat. Clin Tech Small Anim Pract 2005;20:212-219.
3.Tobias KM, Marioni-Henry K, Wagner R. A retrospective study on the use of acepromazine maleate in dogs with seizures. J Am Anim Hosp Assoc 2006;42:283-289.
4.Müller PB, Wolfsheimer KJ, Taboada J, et al. Effects of long term phenobarbital treatment on the thyroid and adrenal axis and adrenal function tests in dogs. J Vet Intern Med 2000;14:157164.
5.Gieger TL, Hosgood G, taboada J, et al. Thyroid function and serum hepatic enzyme activity in dogs after phenobarbital administration. J Vet Intern Med 2000;14(3):277-281.
6.Cosford KL, Taylor SM, Thompson L et al. A possible new inherited myopathy in a young Labrador retriever. Can Vet J 2008;49:393-397.
7.Pelé M, Tiret L, Kessler JL, et al. SINE exonic insertion in the PTPLA gene leads to multiple splicing defects and segregates with the autosomal recessive centronuclear myopathy in dogs. Human Molecular Genetics 2005;14:1417-1427.
8. Beggs AH, Böhm J, Snead E et al. MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers. Proc Natl Acad Sci 2010;107(33):14697-702.
9. Janczyk P, Donaldson CW, Gwaltney S. Two hundred and thirteen clinical cases of marijuana toxicosis in dogs. Vet Human Toxicol 2004;46:19-21.
10.Teitler JB. Evaluation of a human on-site urine multidrug test for emergency use with dogs. J Am Anim Hosp Assoc 2009;45:59-66.
11. Foley JE, Lapointe JM, Koblik P, et al. Diagnostic features of clinical neurologic feline infectious peritonitis. J Vet Intern Med 1998;12:415-423.
12 Boettcher IC, Steinberg T, Matiasek K, et al. Use of anti-coronavirus antibody testing of cerebrospinal fluid for diagnosis of feline infectious peritonitis involving the central nervous system in cats. J Am Vet Med Assoc 2007;230(2):199-205.
13. Hartmann K, Binder C, Hirschberger J, et al. Comparison of different tests to diagnose feline infectious peritonitis. J vet Intern Med 2003;17:781-790
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