Emergency management of seizures (Proceedings)

Pathophysiology

Seizures represent an uncontrolled, paroxysmal discharge from the neurons in the brain. Any involuntary event that is brief and episodic should be considered a possible seizure. A typical seizure is characterized by 4 stages. The Prodrome stage is characterized by altered behavior preceding the seizure by hours to days. This stage is rarely recognized in animals. The Aura occurs minutes before the seizure and is characterized by restlessness, attention seeking, hiding, whining, salivating, or trembling. The Ictus refers to the actual seizure. It typically lasts seconds to a few minutes, though owners frequently overestimate the duration. The Postictal period generally lasts minutes to hours, and is characterized by disorientation, restlessness, temporary blindness, and occasionally aggression.

History Taking

Accurate description of the episode from start to finish helps to rule out other seizure-like conditions such as syncope, vestibular disease, tremors, pain, stereotypies, dreaming, or narcolepsy. It is important to ask about the presence of, and symptoms related to, auras, ictus, and post-ictal periods, as well as their approximate duration. The presence of salivation, urination, defecation, and chewing motions should be also be determined as these are frequently associated with seizures. Owners should be questioned about whether any localizing signs could be identified. Did it start with one leg, or on one particular side of the face? Questions should also be directed towards previous illnesses or injuries that could have resulted in seizures. For example, a history of vomiting or respiratory signs might suggest distemper as a possibility. A history of heart disease could suggest that syncope, rather than a seizure is the problem. Intoxications should be ruled out through careful history taking, particularly with regard to lead paints, home remodeling, and so on. Vaccination status should be confirmed, particularly if distemper is a possibility. Problems associated with littermates or related animals could suggest congenital or hereditary disease. Questions should also be asked about relationship of episodes to feeding, as patients with hepatic encephalopathy may have seizures in response to high protein meals. Finally, indoor/outdoor and free-roaming status should be ascertained to find out if the possibility exists for unknown toxin exposure or trauma.

Physical Examination

A complete physical exam is important and may help to differentiate systemic versus intracranial causes of seizuring. Skull conformation may suggest the presence of congenital diseases like hydrocephalus. Cardiac auscultation may reveal the presence of arrhythmias or murmurs, potentially associated with syncopal episodes. The presence of (or history of) respiratory signs could suggest the possibility of syncopal episodes secondary to hypoxia (eg. laryngeal paralysis) or canine distemper in the young dog. Gastrointestinal signs could go along with lead toxicity, distemper, or metabolic disease. Careful attention should be taken to evaluate for the possibility of trauma or toxin exposure, particularly in pets allowed to roam freely. Petechiation could suggest rickettsial diseases like RMSF, which has been associated with seizures secondary to vasculitis. Fundic exam should always be performed, as many systemic diseases such as neoplasia, FIP, toxoplasma, cryptococcus, distemper, and hydrocephalus are associated with ocular manifestations such as retinal plaques, papilledema, or anterior uveitis. Nasal discharge in the older pet may suggest the presence of a nasal tumor that has broken through the cribiform plate. Various endocrinopathies, such as hypo- or hyperthyroidism have also been associated with seizures, the former as a result of hyperlipidemia leading to hyperviscosity and atherosclerotic plaques, and the latter as a result of hypertension.

The neurological exam is a very important component to the diagnosis of seizure disorders, as it may help to identify focal or multifocal lesions indicative of structural or systemic disease. In animals with idiopathic epilepsy, the neurological exam is frequently normal, though abnormalities such as weakness, lethargy, or disorientation may be present during the post-ictal period, and transient blindness or aggression are occasionally seen. In animals with post-ictal abnormalities, neurological exam should be repeated interictally to see if abnormalities have resolved.

Signalment Clues

Dogs less than 1 year are most likely to have congenital anomalies (hydrocephalus), inflammatory disease, metabolic diseases (PSS, hypoglycemia), or intoxications. Hyperglycemia should always be one of the first ruleouts in a young dog and should be ruled out prior to proceeding with further testing. Dogs between 1-5 years are most likely to have idiopathic epilepsy, and dogs >5 yrs are most likely to have neoplastic, metabolic, or inflammatory diseases. Several breeds of dogs have been documented or suspected to have a higher incidence of epilepsy. Schnauzers and Yorkies have a genetic predisposition for portosystemic shunts. Breed related forms of encephalitis have been identified in Pugs and English bulldogs. Toy breeds are more prone to hypoglycemic seizures during their first year of life if concurrent illness results in anorexia or vomiting.

Diagnosis of Seizure Disorders

Initial diagnostics should include the following:

1. History and complete physical exam

2. Neurologic exam- assessment of generalized vs. focal seizures

3. Differentiate intracranial disease from systemic illness

a. CBC, chemistry, UA

b. Bile acids, thyroid panel, tick panel (if indicated)

c. Viral screening (± protozoal, fungal) in cats and young dogs

d. Testing for toxins if indicated

Note: Laboratory testing is very helpful for ruling out systemic illness as a cause of seizures, but is rarely useful in differentiating types of intracranial disease.

In a dog of a typical epilepsy breed (such as Beagle, Lab, Keeshond, Shepherd) that has onset of seizures between the ages of 1-4 years, there is not necessarily a need to perform advanced neurodiagnostics. Once laboratory testing is performed to rule out the various systemic diseases, treatment may then be aimed at seizure management. However, any time a pet does not fit the typical picture of epilepsy, further workup is indicated.

Advanced modalities used in the diagnosis of seizure disorders include CT, MRI, CSF tap, and possibly EEGs. CT scanning is extremely helpful for diagnosing bony lesions and skull fractures. Masses can also be well visualized, particularly when contrast enhancement is used. MRIs are better at differentiating soft tissue abnormalities such as vascular infarcts, encephalitic diseases, and tumors. CSF tap is typically used in the diagnosis of inflammatory disorders. CSF analysis includes cell counts, cytology, protein quantification, and possibly culture. Titers or PCR may also be performed for distemper, FIP, toxoplasma, and cryptococcus.

Anticonvulsant Therapy

There is a great deal of debate as to when seizure prophylaxis should be started. Some feel that because of concepts like the "kindling effect" and "mirror focus", seizure pathways become more established with each seizure and early intervention is therefore warranted. Others feel that anticonvulsants should not be started until there has been time to establish a baseline for seizure frequency so that effectiveness of therapy can be determined. I personally tend to start anticonvulsant therapy as some as it becomes established that a patient has a recurrent seizure disorder (ie. by the second seizure). Pets with infrequent or less severe seizures might prompt the use of a drug like bromide with fewer side effects.

Everyone agrees that dogs with severe seizures, cluster seizures, or status epilepticus should be started on anticonvulsants immediately because of the life-threatening nature of these problems. Additionally, in older dogs or dogs where tumors are suspected, or in animals in whom a progressive disease like a brain tumor is confirmed, early intervention is warranted.

Benzodiazepines are the treatment of choice for immediate termination of seizures, as they penetrate rapidly into the brain, where they exert potent GABA effects, resulting in local inhibition of signal transmission. However, diazepam is not a good medication for seizure prophylaxis, as it is very lipophilic, and therefore redistributes very rapidly from the plasma into the tissues. Because of this, the anticonvulsant duration of action is very brief following IV administration. Additionally, diazepam is metabolized by the liver into intermediates with only 15-20% of the GABA activity of the parent compound. Because plasma elimination of these intermediates proceeds more slowly, prolonged sedative effects may be seen following large doses, despite very brief seizure control.

Phenobarbital has long been the mainstay of anticonvulsant therapy as it is the cheapest and most effective of the drugs currently available. It is estimated that seizures can be controlled in between 60-80% of epileptics with phenobarbital alone. The mechanism of action again relates to its GABA binding, leading to neuroinhibition, but phenobarbital may also inhibit glutamate activity (excitatory neurotransmitter). Phenobarbital is effective relatively quickly following IV administration (or loading), but may take as long as 14 days to reach steady state levels in the blood if started orally at normal maintenance dosing. Common side effects include increased appetite, thirst, weight gain, and sedation. Dogs and cats typically develop a tolerance to the sedative effects over the course of 10-14 days.

Potassium bromide is another anticonvulsant that has experienced a resurgence of popularity in recent years. It has typically been used as an adjunct drug to control seizures in patients with poor response to phenobarbital alone, but many clinicians employ it as a first line of defense because of its minimal side effects. Mechanism of action is believed to relate to replacement of negatively charged chloride ions with bromide, hyperpolarizing the neurons. Bromide is not liver metabolized, making it a good choice for patients with liver disease or poor phenobarbital tolerance. The major side effects include gastrointestinal upset (think seawater) and ataxia at high doses. Because it has an extremely long half life (>25 days), it takes a long time to achieve steady state (up to 3 months).

Levetiracetam (Keppra) is a newer anticonvulsant used in people for focal and generalized seizures. It is currently under investigation for use as an adjunct anticonvulsant in dogs. Mechanism of action has not been well described at this time. Half-life in the dog is 3.3 hours, necessitating TID dosing. It is excreted primarily in the urine with no hepatic metabolism, making it useful as an adjunctive therapy in animals with liver disease or animals refractory to phenobarbital and KBr. The primary side effect noted is drowsiness, though GI signs have been reported at higher doses.

The recommended dose is 20 mg/kg given every 8 hours (dogs)

Gabapentin (neurontin) is a structural analogue of GABA and exerts its effects though increased GABA action in the brain. It has been used in the past 5 years as an adjunct anticonvulsant in dogs and cats, though its efficacy in these species is unknown. It appears to be well tolerated, with minimal side effects. It is only minimally metabolized by the liver, making it useful as an adjunctive therapy in animals with liver disease or animals refractory to phenobarbital and KBr.

The recommended dose is 30-60 mg/kg/day divided into TID dosing for dogs and 100 mg TID in cats.

Notes on CRI Dosing

Valium CRI may be a useful adjunct therapy in the management of patients with severe cluster seizures or status epilepticus. The dose is 0.5-1 mg/kg/hour administered either by syringe pump or diluted in 5% dextrose solution.Poor solubility may lead to precipitation in solution however. Because valium is light sensitive, IV tubing should be covered to prevent degradation. Midazolam is more expensive but water soluble, and may therefore be more amenable to dilution.

Propofol has in recent years become a well established second-line of defense for the refractory seizure patient. After an initial loading dose of 2-4 mg/kg, a continuous infusion of 0.025-0.7 mg/kg/min may be given. The lower end of the dose range is used for seizure prophylaxis in cluster seizure patients, and the anesthetic range (0.2-0.7 mg/kg/min) for refractory SE or cluster seizures not responding to lower doses. Propofol has the advantages of rapid clearance and suppression of abnormal EEG activity at safer anesthetic planes than pentobarbital. The proconvulsant (myoclonic) effects of propofol seen occasionally during anesthesia are of unclear significance in the epileptic patient.

Pentobarbital was traditionally used to control status epilepticus and cluster seizures prior to the establishment of propofol as a safe alternative. Pentobarbital is a general anesthetic with minimal anticonvulsant effects. Predominantly controls physical manifestation of seizures, with some evidence that abnormal EEG activity may persist unless high doses are used. Hypotension and respiratory depression are potential concerns during high dose administration. The dose for pentobarbital is 3-15 mg/kg IV to effect, followed by 0.5-2 mg/kg/hr continuous rate infusion.

Therapy for Specific Conditions

Patients presenting with intermittent seizures

Initiate therapy with either phenobarbital 2.5 mg/kg BID (dogs and cats) or KBr 40 mg/kg/day (dogs). KBr is not often used in cats due to an unacceptably high incidence of adverse effects. Loading may not be needed if seizures are infrequent. However, a modified KBR loading protocol may be used to achieve therapeutic levels sooner, by giving the daily dose 3x daily for the first 3-5 days. Check trough phenobarbital levels in 2 weeks or KBr levels in 3 months. Have the owner keep a log of seizure frequency and duration so that efficacy of therapy may be objectively assessed. Increase doses as needed to maintain control, and consider dual therapy in refractory cases.

Patients presenting with cluster seizures

Do not wait to "establish frequency" before initiating therapy. Cluster seizuring tends to be a more severe form of epilepsy and early and aggressive control should be instituted. Phenobarbital is usually the initial treatment of choice because of its more rapid onset of action. You can transition to KBR long term if desired.

Consider phenobarbital loading if cluster continues (4 mg/kg IV q1h for 3 hours, or after each seizure until 12-18 mg/kg dose is reached). A benzodiazepine (diazepam 0.2-1 mg/kg) should be used to terminate individual seizures. It is unacceptable to allow seizures to continue, as each subsequent seizure lowers the seizure threshold and allows the cycle of cluster seizuring to continue. For this reason, if phenobarbital loading is ineffective in terminating the cluster seizuring, CRI drugs (propofol, pentobarbital, valium) should be considered if seizures continue in hospital.

Patients presenting with cluster seizures

Initially, boluses of diazepam (0.2-1 mg/kg) should be administered to terminate seizuring, followed by phenobarbital loading (4 mg/kg IV x 3-4 doses). If refractory, consider:

• Pentobarbital 3-15 mg/kg IV to effect, followed by 0.5-2 mg/kg/hr CRI or

• Propofol 4-6 mg/kg IV to effect, then 0.2-0.7 mg/kg/min CRI

Consider IV mannitol (0.5 gm/kg IV over 20 minutes) as prolonged seizuring may lead to the development of cerebral edema. If CRI anesthetic agents have been used and the patient is sedate enough to permit it, intubation should be performed to avoid adverse effects related to hypoventilation. Care should be taken to address hypotension, hypoglycemia, and hyperthermia that may result from prolonged seizuring or intervention with anesthetic drugs.