Status Epilepticus in Dogs

Peer Reviewed OCTOBER 2005 VOL 7.9

STANDARDS of CARE® EMERGENCY AND CRITICAL CARE MEDICINE FROM THE PUBLISHER OF COMPENDIUM

STATUS EPILEPTICUS IN DOGS

J. D. Smith, DVM Small Animal Intern

T. W. Axlund, DVM, MS, DACVIM (Neurology) Associate Professor

Department of Clinical Sciences College of Veterinary Medicine Auburn University

tatus epilepticus (SE) refers to sustained focal or lying cause in young (<1 year) toy breeds. generalized seizure activity lasting longer than • Infectious inflammatory diseases can occur in dogs S5 minutes or cluster seizure activity (i.e., multiple of any age but are most common in dogs younger seizures characterized by lack of a defined interictal than 1 year. period). SE is a life-threatening emergency that requires • Idiopathic epilepsy should be considered as an immediate medical treatment. Initial management is underlying cause in dogs 1 to 5 years of age. focused on stopping seizure activity, most commonly • Intracranial neoplasia and metabolic diseases are with a benzodiazepine (e.g., diazepam, midazolam). most common in dogs older than 5 years. Untreated generalized seizure activity can result in seri- ous metabolic, cardiovascular, and respiratory dysfunc- • Toxic, metabolic, and noninfectious inflammatory tion; permanent brain damage; and/or death. disorders can occur at any age. Most dogs presenting with SE exhibit generalized Breed Predisposition: Breeds with a proven or highly motor seizure activity. Data gathered from limited epi- suspected genetic predisposition for idiopathic epilepsy demiologic studies regarding populations of dogs pre- include beagles, German shepherds, Labrador retriev- senting for SE indicate that the majority of dogs have ers, golden retrievers, vizslas, Belgian Tervurens, and primary (idiopathic) or secondary (acquired) epilepsy English springer spaniels, but the condition can occur (i.e., epilepsy secondary to intra- or extracranial dis- in any dog. ease). Gathering a thorough history from the client is imperative in determining the potential cause of SE in a Owner Observations given patient and will aid in formulating appropriate • Clients may observe either one continuous pro- diagnostic and therapeutic plans and in establishing the longed seizure episode (lasting longer than 5 min- prognosis. The longer SE remains untreated, the less the utes) or multiple seizures between which the dog chance for response to initial seizure control and the does not regain full consciousness. poorer the prognosis for a positive clinical outcome. • Seizure activity may consist of generalized convul- DIAGNOSTIC CRITERIA sive or focal seizures. Historical Information Other Historical Considerations/Predispositions • History of idiopathic (primary) epilepsy. Gender Predisposition: None. Age Predisposition Also in this issue: • Congenital abnormalities (e.g., portosystemic shunt, hydrocephalus) should be considered as an under- 7 Electrocution and Electrical Cord Injury

1 Questions? Comments? Email [email protected], fax 800-556-3288, or post on the Feedback page at www.SOCNewsletter.com. OCTOBER 2005 VOL 7.9

• History of known intracranial disease (e.g., previously diagnosed space- STANDARDS CARE® occupying lesion, meningoencephalitis). EMERGENCY AND CRITICALof CARE MEDICINE • Past history of SE. Editorial Mission: • Known toxin ingestion. To provide busy practitioners with concise, • Head trauma. peer-reviewed recommendations on current treatment standards drawn from published • Known metabolic disorder. veterinary medical literature.

Physical Examination Findings This publication acknowledges that standards The presentation of SE and the associated physical examination findings may may vary according to individual experience and practices or regional differences. The differ from case to case because of the variable etiology and clinical behav- publisher is not responsible for author errors. ior of SE. • Continuous generalized or focal seizure activity may be observed on Compendium’s Standards of Care: presentation. Emergency and Critical Care Medicine® • In cases of prolonged SE in which cerebral autoregulation has failed, the is published 11 times yearly (January/February is a combined issue) patient may present in a comatose state and only occasional muscle by Veterinary Learning Systems, twitching may be observed. 780 Township Line Road, Yardley, PA 19067. • Focal or multifocal neurologic deficits may be present and may be attrib- The annual subscription rate is $83. utable to either the underlying cause of the seizures (especially with For subscription information, call 800-426-9119, fax 800-589-0036, intracranial disease) or to postictal neurologic impairment (cortical blind- email [email protected], or visit ness, disorientation, lethargy). www.SOCNewsletter.com. Copyright • An elevated rectal temperature may be present in cases of prolonged con- © 2005, Veterinary Learning Systems. vulsive seizures. Editor-in-Chief • External signs of cranial trauma, such as soft tissue injury, broken teeth, or Douglass K. Macintire, DVM, MS, palpable skull fractures, may be detected. DACVIM, DACVECC • It is important to note that in rare situations, mechanically “quiet” seizures Editorial, Design, and Production (nonconvulsive epilepsy) can occur, in which an animal shows no outward Lilliane Anstee, Vice President, signs of seizure (e.g., tonus, urination, defecation, clonus) but is still expe- Editorial and Design riencing the cerebral overactivity associated with a seizure. Thorough neu- Maureen McKinney, Editorial Director rologic examination may reveal neurologic deficits or other abnormalities Cheryl Hobbs, Senior Editor (e.g., pupil asymmetry or abnormal pupillary light reflex, abnormal oculo- Michelle Taylor, Senior Art Director cephalic reflex, subtle focal muscle twitching) in a nonresponsive patient, which may lead one to suspect this form of seizure is occurring. This type Bethany L. Wakeley, Studio Manager of seizure is as damaging to the cerebral cortex as the more common gen- Chris Reilly, Assistant Editor eralized (systemic) seizure and needs to be treated as aggressively. Unfor- Kristin Sevick, Editorial Assistant tunately, this electromechanical dissociation is impossible to diagnose Andrea Vardaro, Editorial Assistant without an electroencephalogram (EEG). Editorial Review Board Mark Bohling, DVM Laboratory Findings University of Tennessee Initial diagnostics should include a complete blood count, serum chemistry Harry W. Boothe, DVM, DACVS profile, urinalysis, electrocardiography (ECG), blood pressure measurement, Auburn University arterial or venous blood gas analysis, partial or complete coagulation profile Derek Burney, DVM, PhD, DACVIM (especially if the patient is significantly hyperthermic or signs of disseminated Houston, TX intravascular coagulation [DIC] are present), and measurement of antiepilep- Joan R. Coates, DVM, MS, DACVIM tic drug (AED) levels if the patient is receiving phenobarbital or potassium University of Missouri bromide (KBr). Depending on the underlying cause of SE, the following Curtis Dewey, DVM, DACVIM, DACVS abnormalities may be present on clinical laboratory testing: Plainview, NY Nishi Dhupa, DVM, DACVECC Cornell University D. Michael Tillson, DVM, MS, DACVS KEY TO COSTS Auburn University $ 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

2 OCTOBER 2005 VOLUME 7.9 • Hypoglycemia: Generally accepted as glucose levels • Magnetic resonance imaging: Indicated in patients below 60 mg/dl (reference range, 80–100 mg/dl), suspected of having a structural intracranial abnor- although clinical signs may not be evident until mality and is preferred for visualization of parenchy- concentrations become extremely low (< 30 mg/dl). mal changes, such as soft tissue masses, vasogenic Also, the severity of central nervous system (CNS) edema, and potential focal or multifocal inflamma- signs is generally a result of the rapidity of the drop in tory lesions. Changes may also be evident due to the blood glucose rather than the actual concentration. seizure activity itself. Disadvantages include cost • Hypocalcemia (serum ionized calcium [iCa2+] < 0.8 and need for general anesthesia. $$$–$$$$ mg/dl; reference range, 1.34 ± 0.05 mg/dl). • EEG monitoring: This is generally performed in a spe- • Polycythemia (packed cell volume > 55%; reference cialized hospital setting and can be used to diagnose range, 37% to 55%) and hyperproteinemia (>7.5 nonconvulsive epilepsy and to monitor response to g/dl; reference range, 5.1–7.3 g/dl) may be present treatment in patients being treated for SE. $$–$$$ and indicate dehydration. • Elevated creatine kinase activity (>368 U/L; refer- Summary of Diagnostic Criteria ence range, 92–367 U/L) due to skeletal muscle dam- • Continuous focal or generalized seizure activity age secondary to prolonged generalized seizures. lasting longer than 5 minutes or a history of cluster Muscle damage may also result in myoglobinuria. seizures without return to full consciousness be- • Metabolic acidosis (blood pH < 7.31; reference tween episodes. range, 7.31–7.42; bicarbonate < 17 mEq/L; refer- • History of known primary or secondary epilepsy ence range, 17–24 mEq/L; or total carbon dioxide < (intracranial versus extracranial disease) or known 14 mEq/L; reference range, 14–26 mEq/L), espe- toxin ingestion. cially in cases of ethylene glycol toxicosis. • Clinical pathology findings consistent with meta- • In severe cases of SE, prolonged coagulation times bolic diseases that may induce seizures; alterna- (prothrombin time > 10.1 sec; reference range, tively, CSF or diagnostic imaging findings consistent 6.1–10.1 sec; activated partial thromboplastin time with CNS disease. > 14.4 sec; reference range, 8–14.4 sec) accompa- nied by thrombocytopenia (< 200 x103/µl; reference Differential Diagnosis range, 200–500 x103/µl), decreased fibrinogen (< • Idiopathic epilepsy. 100 mg/dl; reference range, 100–300 mg/dl), and • Intracranial disease: Neoplastic, cerebrovascular, elevated fibrin degradation products (>10 µg/ml; infectious inflammatory (e.g., distemper, toxoplas- reference range, 0–10 µg/ml) may be present and mosis), or noninfectious inflammatory (e.g., granu- indicate DIC is occurring. lomatous meningoencephalitis). • A variety of other laboratory abnormalities indicat- • Toxin ingestion: Ethylene glycol, organophosphates, ing disease of a major organ system (e.g., liver, kid- carbamates, strychnine, lead, metaldehyde, pyre- neys) may be present depending on the etiology. thrins, pyrethroids, or rodenticides are commonly incriminated toxins. Other Diagnostic Findings • Cranial trauma or cerebral anoxia. • Cerebrospinal fluid (CSF) analysis: Requires general • Hypoglycemia. anesthesia. Nonspecific findings are common, but • Hypocalcemia. inflammatory CNS disease can quickly be ruled in. • Hepatic encephalopathy. Total nucleated cell count, cytology, protein analysis, and possible infectious disease titers are indi- • Uremic encephalopathy. cated. There is a risk of cerebral or cerebellar • Tetanus. herniation after CSF collection in animals with increased intracranial pressure (ICP). This risk is TREATMENT higher in older animals in which an intracranial RECOMMENDATIONS space-occupying lesion is suspected. $ • Skull radiography: Indicated if cranial trauma is Initial Treatment suspected. $ • In any emergency situation, the ABCs (airway, • Computed tomography: Indicated in patients sus- breathing, and circulation) should be assessed and pected of having a structural intracranial abnormal- appropriate action initiated. ity or skull trauma and is optimal for visualization of • An intravenous (IV) catheter should be placed. bony changes. Disadvantages include cost, the • If the patient is hypoglycemic (blood glucose < 60 need for general anesthesia, and suboptimal visual- mg/dl), an IV bolus of dextrose and an IM dose of $$–$$$ $ ization of parenchymal lesions. thiamine (vitamin B1) can be administered. 3 STANDARDS of CARE: EMERGENCY AND CRITICAL CARE MEDICINE — The dose of diazepam may need to be increased CHECKPOINTS in dogs that have received phenobarbital long- — Cerebral edema secondary to sustained term (related to enhanced hepatic clearance of neuronal activity associated with SE is diazepam). generally cytotoxic rather than vasogenic in — If an IV route is not available, 1.0 mg/kg of nature, although there are likely contributions from both. The use of osmotic diuretics such either drug may be administered per rectum as mannitol and hypertonic saline for the (PR). Dogs that have been on long-term pheno- treatment of increased ICP secondary to SE is barbital therapy may require higher doses of controversial, as these agents may be more diazepam (up to 2 mg/kg PR). Intranasal admin- effective in the face of vasogenic edema than istration of diazepam (0.5 mg/kg) has been cytotoxic edema. However, if signs of shown to result in therapeutic plasma drug con- increased ICP are present, symptomatic centrations as well. treatment with osmotic diuretics may be • Supplemental oxygen should be provided by flow- attempted. Steps should be taken to ensure by, nasal insufflation, or intubation as needed. the patient is adequately hydrated. • Rectal temperature should be monitored; if it • Mannitol (1 g/kg IV over 10–20 min): If exceeds 103.5˚F, the patient should be cooled: signs of increased ICP persist, a dose of — IV fluid administration and seizure control are 0.5 g/kg IV over 10–20 minutes may be generally sufficient. repeated q8h for up to three treatments. — Placing ice packs or other cooling devices • Hypertonic saline (7.5% NaCl; 4–6 ml/kg directly onto the patient should be avoided as IV over 20 min). the resulting peripheral vasoconstriction can — Some veterinarians recommend using impede total body cooling. pentobarbital over phenobarbital in the — Cooling measures should be discontinued initial management of refractory patients. when the patient’s temperature has reached We prefer using injectable phenobarbital to 102˚F. effect rather than pentobarbital because of the potential for confusing true seizure • Known toxin exposure/ingestion should be treated activity with the activity an animal may accordingly. Contact your regional poison control exhibit when recovering from pentobarbital center for more information. anesthesia. Alternative/Optional — IV or PR loading of sodium bromide (NaBr) Treatments/Therapy has been attempted in limited studies, but $ this is difficult to do and has resulted in Phenobarbital patient death. We do not recommend this If seizures persist despite a 1.0 to 2.0 mg/kg cumula- treatment. tive dose of diazepam or midazolam, an attempt should be made to initiate phenobarbital therapy. • In an animal not already receiving phenobarbital, a cumulative dose of 20 to 25 mg/kg IV is divided into — 50% dextrose: 1.0 ml/kg IV (diluted 1:2 in IV three or four increments, with a wait time of 15 to 30 fluids) over 10 minutes. This dose can be minutes between administration of each dosage repeated as necessary, ideally guided by serial increment. Diazepam or midazolam boluses (0.5 blood glucose determinations. mg/kg IV) can be given as needed to control seizure — Thiamine: 50 mg IM once after dextrose admin- activity that may occur between administrations of istration in patients suspected of having thiamine phenobarbital dosage increments. Diazepam and deficiency. However, any patient receiving glu- midazolam are relatively safe drugs (reported LD50 of cose supplementation may be given this water- 720 mg/kg PO in mice for diazepam; reported LD50 soluble cofactor as a preventive measure against of 86 mg/kg IV in mice for midazolam), but signifi- inducing acute thiamine deficiency secondary to cant CNS depression can occur with overdosage. dextrose infusion. Thiamine is an important Alternatively, a loading dose of phenobarbital can cofactor in neuronal glucose metabolism and be given with the goal of rapidly establishing a ther- has the potential to become rapidly depleted apeutic drug level in serum: Loading Dose (mg) = with an acute increase in glycolysis. Body Weight (kg) × 0.8 × Desired Serum Concentra- • An attempt should be made to control seizures with tion (µg/ml). diazepam or midazolam (0.5 mg/kg IV bolus). $ • In animals already receiving phenobarbital, it is — Bolus can be repeated once or twice if the imperative that the dose of phenobarbital be patient does not respond. decreased. The following formula can be used in

4 OCTOBER 2005 VOLUME 7.9 such animals: Loading Dose (mg) = Body Weight therapy, the following should be performed (kg) × 0.8 × (Desired Serum Concentration – Current according to patient needs: Serum Concentration [µg/ml]). A pretreatment serum — Ensuring airway patency/stabilization, includ- sample should be saved for phenobarbital concen- ing intubation if necessary (especially in tration determination. patients without a gag reflex). • If phenobarbital is not available, a loading dose of — Providing well-padded bedding and rotating KBr (400 mg/kg PO or PR divided over 2–4 days) the patient from side to side every 4 hours. may be attempted. However, the long half-life of — Lubricating the eyes every 4 to 6 hours. KBr prevents acute seizure control. Some measure — Maintaining adequate patient hydration with of refractory seizure therapy (see below) may have isotonic IV fluids. to be employed while waiting for a therapeutic serum concentration to be established. $ — Providing adequate nutritional support, whether via oral feedings, feeding tube, or partial or total parenteral nutrition, in animals unable to volun- Refractory Seizure Therapy tarily eat within 48 hours. If seizure activity persists after phenobarbital loading, refractory seizure therapy should be initiated. Patient Monitoring • Diazepam or midazolam continuous-rate infusion • Patients that respond to initial pharmacotherapy (CRI) may be attempted first: 0.5 to 1.0 mg/kg IV and those receiving refractory therapy: cumulative loading dose to effect; if seizures — Serial neurologic evaluations to assess patient respond to the loading dose, a dosage of 0.5 to 1.0 progress and/or response to treatment. mg/kg/hr CRI is used initially but may be adjusted to — Regular evaluation of temperature, pulse, and fit individual patient needs. Isotonic saline should respiration. be used as the base fluid because diazepam may precipitate with other crystalloids. $ — Blood pressure or central venous pressure measurements • General anesthesia may be required for patients refractory to a diazepam or midazolam CRI. • Additional parameters to monitor in patients undergoing treatment for refractory seizures: — Propofol CRI: 2.0 to 8.0 mg/kg IV cumulative loading dose to effect; if seizures respond to the — Arterial blood gas analysis, with appropriate loading dose, a dose of 0.1 to 0.6 mg/kg/min adjustments in ventilation or oxygen therapy if CRI is used. $–$$ possible. — Pentobarbital: 3.0 to 15.0 mg/kg IV cumulative — Urine output. dose slowly to effect. This dose can be repeated — Coagulation status: A complete coagulation to induce full anesthesia in refractory patients. profile or individual tests of coagulation may There is a major caveat in using this drug to be performed periodically if DIC is suspected control seizures: Normal animals will often as a sequela to seizure-induced hyperthermia. paddle and vocalize when waking up from — Brain activity may be monitored with an EEG pentobarbital-induced anesthesia, which in a specialized hospital setting. allows for potential confusion between this • Patients receiving maintenance therapy (i.e., response and true seizure activity; thus, pento- patients with a history of epilepsy being managed barbital may be a difficult drug to use in cases with an AED): Serum drug concentrations of AEDs of SE. $–$$ should be evaluated to determine whether a ther- — Isoflurane anesthesia: The patient should be apeutic level existed before treatment of SE and/or intubated and minimum alveolar concentration whether a therapeutic level was established if phe- (MAC) adjusted accordingly. $–$$ nobarbital or bromide loading were attempted. — Therapeutic range of phenobarbital: 20 to 40 Supportive Treatment µg/ml; serum drug concentration should be • Patients that respond to initial treatment with checked after loading and 2 weeks after any diazepam or midazolam, or to phenobarbital load- dose alteration. ing, should be started on a maintenance AED, such — Therapeutic range of KBr: 1.0 to 3.0 mg/ml (if as phenobarbital or KBr, while the underlying cause used as the sole AED); serum drug concentra- for their seizures is determined. $ tion should be checked 2 to 3 days after • Patients requiring treatment for refractory seizures administering a loading dose and 3 months also require intensive monitoring and supportive after any dose alteration. The therapeutic care. Whether the patient responded to initial phar- range of KBr may be lower (0.8–2.4 mg/ml) in macotherapy or is undergoing refractory seizure animals concurrently receiving phenobarbital. 5 STANDARDS of CARE: EMERGENCY AND CRITICAL CARE MEDICINE • The underlying cause of the seizure activity should Favorable Criteria be investigated to facilitate appropriate treatment • Response to initial treatment with diazepam or planning and long-term prognosis. midazolam (e.g., significantly reduced or no seizure activity). Home Management • Rectal temperature not exceeding 105.0˚F. • Seizure control (a discussion of long-term seizure • No recurrence of seizure activity within a 24-hour management is beyond the scope of this article). period. • Removal of known toxicants from the home envi- • Return of complete neurologic function. ronment or closer observation (or confinement) to prevent the dog from consuming such items in the Unfavorable Criteria future. • Persistence of seizure activity despite initial treatment with diazepam/midazolam or phenobarbital. • If a potential episode of SE arising at home is a con- cern, clients may be instructed about how to • Loss of seizure control within 6 hours of initially administer diazepam PR (1.0 mg/kg PR; may repeat successful pharmacotherapy. once). Clients should be instructed to seek immedi- • Rectal temperature in excess of 105.0˚F. ate emergency care if seizure activity does not • Coagulation profile abnormalities. respond to this treatment. • Persistent neurologic deficits despite adequate seizure control. Milestones/Recovery Time Frames • Presence of underlying diseases such as neoplasia • Within the first 5 to 10 minutes of initial pharma- or granulomatous meningoencephalitis. cotherapy: Significant decrease or arrest of seizure • Nonconvulsive epilepsy. activity. • Within the first 24 to 48 hours: Improved neurologic RECOMMENDED READING function and nonrecurrence of seizure activity. Bateman SW, Parent JM: Clinical findings, treatment, and outcome of dogs with status epilepticus or cluster seizures: 156 cases Treatment Contraindications (1990–1995). JAVMA 215(10):1463–1468, 1999. • Anesthetic drugs that may increase ICP (e.g., keta- Marik PE, Varon J: The management of status epilepticus. Chest mine, halothane) should be avoided. 126:582–591, 2004. Parent J, Poma R: Single seizure, cluster seizures, and status epilepticus, in Wingfield WE, Raffe MR (eds): The Veterinary ICU PROGNOSIS Book. Jackson, WY, Teton NewMedia, 2002, pp 871–879. Platt SR, Haag M: Canine status epilepticus: A retrospective study Prognosis for return to normal neurologic function or of 50 cases. J Small Anim Pract 43:151–153, 2002. acceptable quality of life depends heavily on the expe- Platt SR, McDonnell JJ: Status epilepticus: Managing refractory cases and treating out-of-hospital patients. Compend Contin diency and aggressiveness of treatment, initial response Educ Pract Vet 22(8):732–745, 2000. to seizure control, and underlying etiology. As with Platt SR, McDonnell JJ: Status epilepticus: Patient management and other neurologic emergencies, the earlier SE is detected pharmacologic therapy. Compend Contin Educ Pract Vet 22(8): and stopped, the greater the chance of a positive clini- 722–731, 2000. cal outcome. Once the decompensated stage of SE is Saito M, Munana KR, Sharp NJH, Olby NJ: Risk factors for devel- reached (as generally occurs with SE lasting more than opment of status epilepticus in dogs with idiopathic epilepsy and effects of status epilepticus on outcome and survival time: 30 minutes), prognosis for a positive outcome decreases 32 cases (1990–1996). JAVMA 219(5):618–623, 2001. substantially. Prolonged SE can result in profound sys- Steffen F, Grasmueck S: Propofol for treatment of refractory seizures temic complications, permanent brain damage, and in dogs and a cat with intracranial disorders. J Small Anim Pract possibly death. 41:496–499, 2000.

Dr. Smith is currently an Adjunct Instructor in the Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University

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