STANDARDS of CARE. It has been estimated that idiopathic epilepsy affects EMERGENCY AND CRITICAL CARE MEDICINE

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1 Peer Reviewed JANUARY/FEBRUARY 2006 VOL 8.1 STANDARDS of CARE EMERGENCY AND CRITICAL CARE MEDICINE FROM THE PUBLISHER OF COMPENDIUM MANAGEMENT OF CANINE IDIOPATHIC EPILEPSY Michelle Brogan Carnes, MS, DVM Neurology/Neurosurgery Resident Lisa Tieber, MS, DVM Neurology/Neurosurgery Resident Todd W. Axlund, DVM, MS, DACVIM (Neurology) Associate Professor of Neurology and Neurosurgery Department of Clinical Sciences College of Veterinary Medicine Auburn University It has been estimated that idiopathic epilepsy affects up to 5.7% of the canine population and accounts for at least 1% of all canine health issues. Idiopathic epilepsy is defined as a chronic condition characterized by recurring seizures for which an underlying cause has not been identified. The seizures associated with idiopathic epilepsy are not due to an identified structural brain abnormality or systemic dysfunction but rather an inherently abnormal area of brain parenchyma that leads to seizure activity. The clinical progression of idiopathic epilepsy varies among dogs. Some seizures can easily be controlled with antiepileptic drugs (AEDs) while others are refractory; in the latter, seizures may be refractory from the start or become so with time. Most dogs will respond to the guidelines outlined in this article; those that do not should be referred to a neurologist. The primary goal of therapy for idiopathic epilepsy is to decrease the frequency and severity of the seizures by using AEDs. There are three primary reasons to initiate AED therapy: The kindling effect, or the idea that seizures beget more seizures After a seizure, successive seizures are more easily induced and every additional seizure makes the pathway required for the next seizure to become more hardwired, eventually leading to seizures that are refractory to AED therapy. The metabolic abnormalities a seizure causes and the potentially fatal complications Owner and pet satisfaction The perceived reduced quality of life and increased expense associated with ownership of an uncontrolled epileptic dog can have a detrimental influence on pet owners and may ultimately lead to the decision to euthanize an otherwise healthy pet. DIAGNOSTIC CRITERIA Historical Information Gender Predisposition: Male dogs slightly outnumber female dogs in most studies. Age Predisposition: Most epileptic dogs suffer their first seizure between 1 and 5 years of age. Breed Predisposition Genetic basis in some breeds: beagles, Belgian Tervurens, British Alsatians, collies, dachshunds, golden retrievers, keeshonden, Labrador retrievers, vizslas, German shepherd dogs, Bernese mountain dogs. Also in this issue: 7 Feline Infectious Peritonitis Questions? Comments? soc.vls@medimedia.com, fax , or post on the Feedback page at 1

2 A gene has been identified in the following breeds; however, the epilepsy-like syndromes seen in these dogs are not considered to be idiopathic epilepsy: Northern epilepsy-like syndrome in English springer spaniels. Lafora s disease in miniature wirehaired dachshunds. High incidence without proven genetic component: cocker spaniels, Irish setters, miniature schnauzers, poodles, Saint Bernards, Siberian huskies, wirehaired fox terriers. Owner Observations Patients may exhibit abnormal behavior, such as restlessness or vocalization, during the hours to days before a seizure (prodrome) or may hide or seek their owners seconds to minutes before a seizure (aura). The seizure itself (ictus) typically lasts 1 to 3 minutes and usually is of the generalized tonic clonic form. The postictal period is transient but can last several minutes to several days; marked neurologic deficits (see below) may be noted during this time. Generalized tonic clonic seizures are most common and characterized by the following: Unconsciousness. Rigidity (tonus). Opisthotonus. Apnea. Repetitive limb movements (clonus). Focal seizures with or without secondary generalization may also be seen. Other Historical Considerations/Predispositions Most seizures occur when the patient is at rest or asleep. Seizures may be precipitated by emotional or physical stress, sleep deprivation, missed dose(s) of antiseizure medication, estrus, metabolic derangements, or drugs (e.g., phenothiazines). Physical Examination Findings During the postictal period (minutes to days following the seizure), patients may exhibit variable neurologic presentations, such as ataxia, disorientation, blindness, or postural reaction deficits. Repeating the physical and neurologic examinations in the interictal period (period of normalcy between seizure events) may be necessary to determine whether neurologic deficits persist. After the postictal period, physical examination is usually unremarkable. Laboratory Findings Complete blood cell count and serum chemistries are normal in patients with idiopathic epilepsy. $ Other causes of seizures hypoglycemia, hypocalcemia, polycythemia, hepatic dysfunction, renal dysfunction, hyperlipidemia must be ruled out. KEY TO COSTS $ indicates relative costs of any diagnostic and treatment regimens listed. $ costs under $250 $$ costs between $250 and $500 $$$ costs between $500 and $1,000 $$$$ costs over $1,000 JANUARY/FEBRUARY 2006 VOL 8.1 STANDARDS of CARE EMERGENCY AND CRITICAL CARE MEDICINE Editorial Mission: To provide busy practitioners with concise, peer-reviewed recommendations on current treatment standards drawn from published veterinary medical literature. This publication acknowledges that standards may vary according to individual experience and practices or regional differences. The publisher is not responsible for author errors. Compendium s Standards of Care: Emergency and Critical Care Medicine is published 11 times yearly (January/February is a combined issue) by Veterinary Learning Systems, 780 Township Line Road, Yardley, PA The annual subscription rate is $83. For subscription information, call , fax , soc.vls@medimedia.com, or visit Copyright 2006, Veterinary Learning Systems. Editor-in-Chief Douglass K. Macintire, DVM, MS, DACVIM, DACVECC Editorial, Design, and Production Lilliane Anstee, Vice President, Editorial and Design Maureen McKinney, Editorial Director Cheryl Hobbs, Senior Editor Michelle Taylor, Senior Art Director Bethany L. Wakeley, Studio Manager Chris Reilly, Assistant Editor Kristin Sevick, Editorial Assistant Andrea Vardaro, Editorial Assistant Editorial Review Board Mark Bohling, DVM University of Tennessee Harry W. Boothe, DVM, DACVS Auburn University Derek Burney, DVM, PhD, DACVIM Houston, TX Joan R. Coates, DVM, MS, DACVIM University of Missouri Curtis Dewey, DVM, DACVIM, DACVS Plainview, NY Nishi Dhupa, DVM, DACVECC Cornell University D. Michael Tillson, DVM, MS, DACVS Auburn University 2 J A N U A R Y / F E B R U A R Y V O L U M E 8. 1

3 Other Diagnostic Findings Magnetic resonance imaging (MRI)/computed tomography (CT): No structural brain abnormalities. $$ $$$ Cerebrospinal fluid (CSF) analysis: No abnormalities. $ Electrocardiogram (ECG): Normal rate and rhythm. $ Blood pressure: Normotensive. $ Thyroid function testing: May reveal hypothyroidism, but a cause-and-effect relationship has not been proven. $ Hyperlipidemia has been associated with seizures in schnauzers. Infectious disease titers canine distemper virus, ehrlichiosis, Rocky Mountain spotted fever, borreliosis, toxoplasmosis, neosporosis, and fungal organisms are negative. $ Summary of Diagnostic Criteria Age of onset: 1 to 5 years. Seizures are often infrequent and isolated at onset. Neurologic examination is normal in the interictal period. No identifiable cause can be elucidated following a complete diagnostic work-up (complete blood cell count, serum chemistry, serum thyroid level, urinalysis, MRI/CT, CSF analysis). All laboratory and diagnostic tests are within normal limits. Idiopathic epilepsy is a diagnosis of exclusion. Diagnostic Differentials Cause of Epilepsy Anomalies or development disease: Hydrocephalus, lissencephaly, subarachnoid cysts. Ruled out via MRI scan. Metabolic disease: Hepatic encephalopathy (portosystemic shunt, liver failure), renal failure, electrolyte abnormalities (hypoglycemia, hypocalcemia), hypoglycemia, polycythemia, hyperlipidemia. Complete blood cell count and serum chemistry panel are useful in evaluating patients for metabolic diseases. Infectious or inflammatory disease: Viral, fungal, bacterial, protozoal, immune-mediated. MRI scan may be useful. CSF analysis and infectious disease titers are necessary to rule out infectious or inflammatory diseases. Neurologic examination may show multifocal deficits. Toxicity: Lead, organophosphates, strychnine, tetanus, ethylene glycol. Laboratory tests for lead, organophosphates, and ethylene glycol. STANDARDS of CARE: EMERGENCY AND CRITICAL CARE MEDICINE Analysis of isolates from stomach contents. History and neurologic examination. Trauma: Ruled out based on history and neurologic examination. Previous trauma (months to years ago) may be associated with a latency period before the development of seizures. Neoplasia: MRI and CT scan. Neurologic examination may reveal a variety of interictal abnormalities, such as contralateral hemineglect, hemiparesis, and behavior change. Vascular disease: Infarction (embolic or thrombotic). Blood pressure measurement. Coagulation panel (prothrombin time, activated partial thromboplastin time, activated clotting time, fibrinogen degradation products). MRI scan. CSF fluid analysis. Episodic Nonepileptic Problems Pain: May be associated with a cervical disk: Cervical muscle fasciculations can be seen, which can be a manifestation of pain. Neurologic examination to localize the pain. Spinal radiographs and MRI scan. Transient vestibular events: Neurologic examination localizes signs to the vestibular system. MRI scan. CSF analysis. Syncope: Typically characterized by decreased muscle tone and apnea. History, physical examination, neurologic examination, and cardiac evaluation (thoracic radiography, electrocardiography, echocardiography, Holter monitoring) are essential to differentiate seizures from other disorders. No postictal signs. Paroxysmal events: Narcolepsy; cataplexy. History and neurologic examination. Atropine response test (0.1 mg/kg IV once) can provide temporary remission of signs for up to 3 hours. Collapse: Myopathies (exercise-induced collapse of Labrador retrievers, myotonia). 3

4 Neuromuscular disease (myasthenia gravis). Electromyography and/or nerve conduction studies, muscle biopsy, acetylcholine receptor antibody titer, metabolic alkalosis (seen in exercise-induced collapse). Normal/abnormal movements during sleep: History and neurologic examination. Can be interrupted by waking animal. Lack of postictal signs. TREATMENT RECOMMENDATIONS Initial Treatment Long-term management of epilepsy is ideally accomplished with a single drug; either phenobarbital or bromide is the preferred initial treatment. However, if a patient is not adequately controlled with monotherapy, the two drugs can be used simultaneously. Phenobarbital $ Initial dosing: mg/kg PO bid. If the initial dosing regimen fails to sufficiently control seizures, a proportional increase in the dose is indicated so that blood concentrations increase in increments of 5 µg/ml. Thus, if the patient is at 10 µg/ml, the target of 15 µg/ml would require a 50% dose increase; if the patient is at 20 µg/ml, the target of 25 µg/ml would require approximately a 25% dose increase. Time to steady state: 10 to 14 days. Therapeutic range: 25 to 40 µg/ml. Potential side effects: Sedation, ataxia, polyuria/ polydipsia, polyphagia, hepatotoxicity, and blood dyscrasias (rare); sedation and ataxia usually improve after the first few weeks of therapy. Bromide $ Although either the sodium or potassium salt may be used, potassium is more common. Bromide salts are not approved drugs and must be compounded by a pharmacist or the veterinarian. Because of the amount of time required to reach steady state concentration, a loading dose of bromide may sometimes be indicated at the initiation of treatment. Initial dosing: mg/kg PO bid. Time to steady state: Approximately 3 months (halflife = days). Therapeutic range: 1 3 mg/ml. When used as monotherapy: 2 3 mg/ml. When used in conjunction with phenobarbital: 1 2 mg/ml. Potential side effects: Sedation, ataxia, polyuria/ polydipsia, polyphagia, hyperactivity, and pruritic skin rash. Increased incidence of pancreatitis is seen with combined bromide phenobarbital therapy compared with phenobarbital therapy alone. Potassium bromide should be used with caution in dogs with renal failure; sodium bromide should be avoided in patients with congestive heart failure. Loading Doses In patients with severe seizures or status epilepticus, or when there is a need to rapidly decrease one anticonvulsant while adding another (e.g., because of hepatotoxicity or pancytopenia in patients receiving phenobarbital), loading doses may be indicated: Phenobarbital: IV loading dose (mg) = desired serum level (µg/ml) body weight (kg) 0.8 L/kg; calculated loading dose should be divided and given over a 24-hour period. Potassium bromide: 500 mg/kg PO divided and given with food. The total calculated dose can be given over 5 days or as quickly as 24 to 48 hours. Sodium bromide: Because of the lower molecular weight of the sodium bromide (102 D) versus potassium bromide (119 D), the IV loading dose is 85% of the calculated dose of potassium bromide (i.e., 85% of 500 mg/kg or 425 mg/kg). Alternative/Optional Treatments/Therapy Though no large-scale controlled studies have been conducted using the following drugs in veterinary patients, there have been anecdotal reports of some success with these therapies in patients refractory to other AEDs. These drugs are more expensive than phenobarbital and bromide and thus are typically used as add-on therapy to standard anticonvulsant drug regimens. Felbamate (Felbatol, Medpointe, Somerset, NJ). $$ Initial dose: 15 mg/kg PO tid. Potential side effects: Hepatic dysfunction; blood dyscrasias. Gabapentin (Neurontin, Parke-Davis). $$ Initial dose: 10 mg/kg PO tid. Potential side effects: Possible sedation. Zonisamide (Zonegran, Elan Biopharmaceuticals, San Diego, CA). $$$ Initial dose: 5 10 mg/kg PO bid (10 mg/kg for dogs already on phenobarbital). Potential side effects: Transient sedation, mild ataxia, inappetence, and vomiting. Topiramate (Topamax, Ortho-McNeil). $$ Initial dose: mg/kg PO bid. Potential side effects: Gastrointestinal upset; irritability. 4 J A N U A R Y / F E B R U A R Y V O L U M E 8. 1

5 Levetiracetam (Keppra, UCB Parma, Smyrna, GA). $$ Initial dose: 20 mg/kg PO tid. Potential side effects: None reported. Supportive Treatment Following a particularly severe seizure (e.g., status epilepticus) or an episode of cluster seizures, some patients may require supportive care in the immediate postictal period. An IV catheter should be placed. Pretreatment blood samples should be obtained from dogs currently receiving AED therapy. Samples should also be collected for routine blood work (complete blood cell count and serum chemistry) and urinalysis. Subsequent seizures should be controlled with diazepam and phenobarbital, if necessary. Diazepam: 0.5 mg/kg IV or 1 2 mg/kg per rectum; may be repeated up to a total of 3 doses). Phenobarbital: In a naïve patient, up to 18 mg/kg IV (divided into single 5 mg/kg IV boluses) can be given, or the following formula can be used to target a 25 mg/ml blood level: body weight (kg) 0.8 L/kg 25 mg/dl = loading dose. Note: For each 3 mg/kg of phenobarbital given IV, serum concentration increases approximately 5 µg/ml. Drug distribution of phenobarbital into the central nervous system may take 15 to 30 minutes. If diazepam is ineffective at controlling seizures, propofol (4 6 mg/kg as a bolus followed by an infusion of 6 12 mg/kg/hr) can be given. Patients should be monitored closely; some may require intubation. Hydration should be maintained with IV fluids in patients that cannot eat or drink. Patients should be monitored for metabolic or electrolyte abnormalities. Nonambulatory patients should be rotated. Patient Monitoring First-Line AED Monitoring Phenobarbital Therapeutic range: µg/ml. Serum drug levels should be checked according to the following schedule: Two to 3 weeks after initiating therapy or changing the dose. Three months after initiating therapy. Every 6 to 12 months once the dose is stabilized. Following a breakthrough seizure. Liver function tests (serum chemistries ± bile acids) should be measured at the same time as drug levels. ON THE NEWS FRONT Vagal nerve stimulation by an implantable pulse generator has been described as an effective therapeutic modality in human patients with refractory epilepsy. This technique has been effective in inhibiting experimentally induced seizures However, no large-scale studies have been performed to evaluate its clinical efficacy in veterinary patients. Drugs that address epileptogenesis are being developed. Conventional anticonvulsants decrease seizure frequency and severity but do not stop or slow the progression of the disease. Bromide Therapeutic range: 1 3 mg/ml. Serum drug levels should be checked according to the following schedule: One week after administering the loading dose. One and 3 months after starting a maintenance dose. Every 6 to 12 months once the dose is stabilized. Following a breakthrough seizure. Second-Line AED Monitoring Felbamate: Therapeutic range (extrapolated from humans): µg/ml. Measurement of serum drug levels is not necessary Because of the risk of hepatotoxicity, serum chemistry profiles should be performed every 6 to 12 months. Gabapentin: Therapeutic range: 4 16 mg/ml. Measurement of serum drug levels is not necessary Zonisamide: Therapeutic range (extrapolated from humans): µg/ml. Trough levels should be checked 1 week after instituting therapy. Topiramate: Therapeutic range: 2 25 mg/l. Measurement of serum drug levels is not necessary Levetiracetam: Therapeutic range (extrapolated from humans): 5 45 µg/ml. Measurement of serum drug levels is not routinely performed. STANDARDS of CARE: EMERGENCY AND CRITICAL CARE MEDICINE 5

6 Home Management Owners must appreciate the importance of regular administration of the prescribed AED and understand what to do if a dose is missed. Anticonvulsant levels must be monitored regularly. Owners should maintain a seizure log, which should include the following information: Time, date, characteristics of seizure, duration of seizure, any changes in environment or routine just before the seizure, and a description of the postictal period. When possible, owners should videotape the seizure and the immediate postictal period. Owners should understand that changes in the pet s environment and routine (and diet for patients on bromide therapy) may precipitate a seizure. Some dogs suffer cluster seizures or status epilepticus requiring emergency treatment. To decrease the emotional and financial hardship of frequent emergency visits, diazepam may be given rectally by owners. Milestones/Recovery Time Frames The ultimate goal of therapy is to restore good quality of life for the patient by decreasing the frequency and severity of seizures. Complete control of seizures is uncommon; however, the target frequency is no more than one seizure every 4 to 6 weeks. The AED dose should be individualized to the patient with regard to efficacy, serum concentrations, and side effects. Patients may become refractory to the current therapy, and adjustments may be required. Treatment Contraindications Use of phenobarbital with concurrent hepatic disease. Use of bromide with concurrent renal disease and cardiac disease. Use of phenothiazines, ketamine, or xylazine; these drugs may precipitate seizure activity. Phenytoin, carbamazepine, valproic acid, and ethosuximide are used as AEDs in human patients, but the short half-life of these agents makes them ineffective PROGNOSIS Favorable Criteria Seizures are well controlled. Patient tolerates AEDs well. Good owner compliance. Seizures started later in life. Unfavorable Criteria Patient becomes refractory to available AEDs. Occurrence of frequent clusters or status epilepticus. Significant untoward side effects from AEDs. Seizures started at younger age. RECOMMENDED READING Boothe DM: Anticonvulsant therapy in small animals. Vet Clin North Am Small Anim Pract 28(2): , Dewey CW, Guiliano R, Boothe DM, et al: Zonisamide therapy for refractory idiopathic epilepsy JAAHA 40: , Dewey CW, Barone G, Smith K, Kortz G: Alternative anticonvulsant drugs for dogs with seizure disorders. Vet Med 99(9): , Munana KR, Vitek SM, Tarver WB, et al: Use of vagal nerve stimulation as a treatment for refractory epilepsy JAVMA 221: , Patterson EE, Armstrong PJ, O Brien DP, et al: Clinical description and mode of inheritance of idiopathic epilepsy in English springer spaniels. JAVMA 226(1):54 58, Ruehlmann D, Podell M, March P: Treatment of partial seizures and seizure-like activity with felbamate in six dogs. J Small Anim Pract 42(8): , Thomas WB: Idiopathic epilepsy Vet Clin North Am Small Anim Pract 30(1): , J A N U A R Y / F E B R U A R Y V O L U M E 8. 1

CANINE EPILEPSY. Types of epilepsy: Types of seizures:

CANINE EPILEPSY. Types of epilepsy: Types of seizures: CANINE EPILEPSY Epilepsy is found in all breeds and mixed breeds of dogs. The prevalence of epilepsy in the general dog population has been estimated at 0.5 to 5.7%. Seizures can be severe and frequent