Daniel J. Fletcher, PhD, DVM, DACVECC Cornell University College of Veterinary Medicine, Ithaca, NY
Seizures are initiated by a high frequency burst of action potentials within a hypersynchronized population of neurons. Hypersynchronization of a large enough population of neurons leads to the characteristic “spike” seen in the electroencephalogram (EEG), measured via electrodes placed on the scalp surface. Individual neurons within the population experience a sequence of events including: (1) a burst of action potentials (700-1000 per second) mediated by an influx of calcium and sodium, (2) a sustained depolarization, and finally (3) rapid repolarization and hyperpolarization mediated by GABA receptors, which promote either chloride influx or potassium efflux. Many areas of the brain, including the subcortical nuclei, thalamus, cerebrum and brainstem, can participate in seizuregenesis and propogation. Individual, infrequent, and short-duration seizures may not require therapy, but severe, acute seizures are life threatening emergencies, and aggressive therapy is warranted. Cluster seizures and status epilepticus are the two most
life-threatening types of seizures. A cluster of seizures is clinically defined as more than 2 or 3 (depending upon the
author) seizures within a 24 hour period. Between the individual seizures, the patient returns to normal mentation and
activity. Status epilepticus is seizure activity that continues unabated for more than 5 minutes, or multiple seizures
between which the patient does not return to normal mentation. In addition to direct neuronal damage, systemic
sequelae of severe seizures include traumatic injury to other parts of the body, hyperthermia leading to disseminated
intravascular coagulation (DIC), aspiration pneumonia, and non-cardiogenic pulmonary edema. In addition, there is a
risk of permanent brain damage and expansion of the seizure focus in the brain. Aggressive management of cluster
seizures and status epilepticus is essential, and both intracranial and extracranial priorities must be addressed.
Differential Diagnoses
Causes of seizures can be divided into two main categories: extracranial diseases and intracranial diseases. Determining the definitive cause an individual patient’s seizures can require an extensive diagnostic workup. 1. Extracranial Diseases: Metabolic disturbances and systemic disease can lead to alterations in the electrophysiology of the brain, causing paroxysmal neuronal discharges and seizures. In general, these types of diseases are likely to cause widespread disturbances affecting both hemispheres. Therefore, generalized seizures are more common than focal seizures. a. Endogenous toxins accumulating due to hepatic or renal disease can lead to seizures b. Metabolic disturbances such as hypoglycemia, hyperlipidemia, and hypocalcaemia, as well as endocrine diseases such as hypothyroidism and diabetes mellitus (hyperosmolar non-ketotic) can also lead to seizures. c. Many toxicoses, including bromethalin, theobromine, caffeine, lead or organophosphate poisoning 2. Intracranial Diseases: There are many, primary intracranial causes of seizures. A classification scheme, such as DAMNIT-V, can be helpful for organizing this large list. a. Degenerative: Storage diseases b. Anomalous: Hydrocephalus, lissencephaly c. Metabolic: See extracranial diseases above d. Neoplastic: Primary brain tumors as well as metastatic disease e. Infectious: Viral (rabies, distemper, FIP), Bacterial, Fungal (Cryptococcus), Protozoal (Toxoplasma, Neospora), Rikketsial (Rocky Mountain Spotted Fever) Inflammatory: Granulomatous meningoencephalomyelitis (GME), sterile meningitis, necrotizing encephalitis g. Trauma: Head trauma h. Toxin: See extracranial diseases above i. Vascular: Thromboembolic disease, intracranial hemorrhage 1. Extracranial Stabilization: Rapid identification and treatment of life-threatening extracranial sequelae of seizures is key to successful case management and good patient outcome. i. Sustained seizure activity can result in dramatically elevated body temperature. Body temperature should be measured as soon after presentation as possible. Any patient presenting with a core body temperature > 105˚F (40.6˚C) should be actively cooled. 1. Room temperature intravenous fluids, wetting the fur, and cooling with fans are recommended. 2. Core body temperature should be rechecked frequently. 3. Active cooling should be discontinued when the temperature drops to 103˚F (39.4˚C). 4. The use of ice packs or ice baths is not recommended, as these can lead to peripheral vasoconstriction, decreasing heat loss through the skin. ii. Hyperthermia can lead to many systemic sequelae, including DIC, hypoglycemia, acid-base disturbances, hypotension, and pulmonary edema. Perfusion deficits can develop in patients with severe, acute seizures due to vasodilation secondary to hyperthermia or neurogenic shock. i. Aggressive fluid therapy with isotonic crystalloids, hypertonic crystalloids, and/or synthetic colloids should be initiated early in the course of treatment to normalize blood pressure. ii. In patients with persistent, inappropriate vasodilation that remain hypotensive in the face of adequate volume resuscitation, pressor therapy (e.g., dopamine or norepinephrine) should be considered. The partial pressure of CO2 in the arterial blood (PaCO2) is a potent regulator of cerebrovascular tone. i. Normocapnea is essential to maintaining cerebral perfusion. 1. Some anticonvulsants can lead to sedation and hypoventilation (barbiturates, propofol), requiring intubation/tracheostomy and mechanical ventilation. 2. Acid-base disturbances and hyperthermia can lead to hyperventilation, and should be treated aggressively to minimize effects on cerebral blood flow. The brain has a high basal metabolic rate and is intolerant of decreases in oxygen delivery. i. Oxygen supplementation should be provided via mask, oxygen cage, nasal catheters, or intubation. ii. In cases of severe edema or pneumonia, mechanical ventilation may be required to address hypoxemia. iii. Oxygen carrying capacity of the blood is determined primarily by the amount of hemoglobin present. Anemic patients should receive transfusions. a. Hyperosmotic Therapy: Development of cerebral edema is common during and after severe, acute seizures. i. Mannitol is an effective therapy for patients with increased ICP, and has been shown to reduce cerebral edema, increase CPP and CBF, and improve neurologic outcome in patients with cerebral edema. It has a rapid onset of action, with clinical improvement occurring within minutes of administration, and these effects can last as long as 1.5-6 hours. Mannitol boluses of 0.5-1.5 g/kg have been recommended for treatment of increased ICP in dogs and cats. The diuretic effect of mannitol can be profound and can cause severe volume depletion. Therefore, treatment must be followed with isotonic crystalloid solutions and/or colloids to maintain intravascular volume. ii. Hypertonic saline (HTS) is a hyperosmotic solution that may be used as an alternative to mannitol in patients with cerebral edema. Because sodium does not freely cross the intact BBB, HTS has similar osmotic effects to mannitol. Other beneficial effects of HTS include improved hemodynamic status via volume expansion and positive inotropic effects, as well as beneficial vasoregulatory and immunomodulatory effects. Rebound hypotension is uncommon with HTS administration because unlike mannitol, sodium is actively reabsorbed in the kidneys, especially in hypovolemic patients. This makes it preferable to mannitol for treating patients with increased ICP and systemic hypotension due to hypovolemia. In euvolemic patients with evidence of intracranial hypertension, both mannitol and HTS can have beneficial effects. If an individual patient is not responding to one drug, the other may yield a beneficial response. 3. Acute Anticonvulsant Therapy: It is vital that seizure activity be stopped as soon as possible to prevent continued injury to the brain and to reduce the potential for systemic sequelae. a. Benzodiazepines: Intravenous diazepam (0.5 – 1.0 mg/kg) or midazolam (0.066 – 0.22 mg/kg) should be considered first line therapy for patients with severe, acute seizures. These drugs are GABA agnoists, leading to hyperpolarization of neurons and cessation of seizure activity. They are generally effective and safe in dogs and cats, and have a low likelihood of significant side effects. For patients in whom intravenous access is not readily available, diazepam at a dose of 1 – 2 mg/kg is rapidly absorbed intrarectally. If the patient responds to benzodiazepine therapy but rapidly recrudesces, an intravenous constant rate infusion (CRI) is a good option. Diazepam at 0.5 – 2.0 mg/kg/hr is often effective. b. Barbiturates: For patients refractory to benzodiazepine therapy, barbiturates (pentobarbital, Phenobarbital) can sometimes be effective. Pentobarbital (2 - 15 mg/kg IV) can effectively terminate the physical manifestations of seizure activity within several minutes, but it is not generally considered to be an effective anticonvulsant and is unlikely to stop seizure activity in the brain. Phenobarbital is an effective anticonvulsant (2 – 6 mg/kg IV), but can take 15-20 minutes to have an effect. If an effect is not noted within 15-30 minutes, the dose may be repeated to raise blood levels to the therapeutic range more rapidly (to a maximum loading dose of 16 mg/kg within the first 24 hours), but care must be taken to avoid overdose. c. Propofol: Propofol is a rapidly acting injectible anesthestic that is a centrally acting GABA agonist. It may be administered via slow IV injection at a dose of 1 – 6 mg/kg and has been shown to be effective for stopping seizure activity (cluster seizures and status epilepticus) in human and veterinary medicine. If the initial bolus dose is effective but seizures recur, a CRI at 0.1 – 0.6 mg/kg/min may be instituted. Apnea and cardiovascular depression are important side effects to consider, and it is the author’s opinion that any animal receiving a propofol infusion should be intubated to protect the airway, and ventilation should be closely monitored to avoid the sequelae of hypoventilation. d. Levetiracetam (Keppra): Levetiracetam is a piracetam anticonvulsant that has shown efficacy for treatment of seizures in peoples and experimental animals. The mechanism of action of this drug is not known, but it does not appear to have its effects via the more common neurotransmitter receptors or ion channels. It has a high bioavailability in dogs and is excreted unchanged in the urine without any significant hepatic metabolism. It has no sedative side effects. Intravenous administration is well tolerated in dogs, even at very high doses of 400 mg/kg (published oral dose = 20 mg/kg PO q 8hr). It is available in an intravenous formulation (also administered at 20mg/kg as a bolus). 4. Maintenance Anticonvulsant Therapy: Once life-threatening intracranial and extracranial sequelae of severe, acute seizures have been addressed and the seizures have been controlled with acute anticonvulsant therapy, options for chronic therapy can be considered. a. Phenobarbital: Phenobarbital is a barbiturate, and is still considered a first line anticonvulsant in both dogs and cats with seizure disorders. It is effective as a single agent in 60-80% of epileptic dogs and most cats. It has a long half life in both dogs and cats (40-90 hours), and therefore can take 10-15 days to reach steady state serum levels when administered at a maintenance dose (2 mg/kg PO q12hr). Serum levels should be checked 2-3 weeks after starting therapy, with normal levels ranging between 15 and 45 µg/ml. The most common side effects of Phenobarbital therapy include polyuria/polydipsia, polyphagia, weight gain, sedation, and ataxia. Uncommon, but more clinically relevant side effects include hepatic failure, blood dyscrasias and superficial necrolytic dermatitis. Cats occasionally develop facial pruritis, limb edema, and blood dyscrasias, but these usually resolve with discontinuation of therapy. Chemistry panels and Phenobarbital levels should be evaluated at least every 6 months during therapy. Elevations in ALP are common and are likely of no clinical consequence, but elevated ALT should be evaluated more thoroughly with bile acids testing. b. Bromide: Potassium Bromide (KBr) is often used as an add-on anticonvulsant (with Phenobarbital), and treating dogs with KBr in addition to Phenobarbital has been shown to reduce seizures by 50%. Side effects are similar to Phenobarbital with the exception of hepatic effects. Used as a sole agent, it is generally not as effective as Phenobarbital, but due to its renal excretion, is a good first-line anticonvulsant for dogs with underlying hepatic disease. Because of its long half life (24 days in dogs), it may take up to 120 days to reach steady state at maintenance doses. Therefore, a loading dose of 125mg/kg divided into two daily doses is administered for 5 days before switching to maintenance therapy at 35mg/kg/day divided into 2 daily doses. In emergency situations, KBr loading can be done over 24 hours via rectum, or intravenously using Sodium Bromide (400-600 mg/kg loading dose over 24 hours). c. Gabapentin: Gabapentin is structurally related to GABA, and its anticonvulsant activity is likely via GABA receptors; however, there is evidence that it also exerts some of its effects via inhibition of cerebral voltage-gated calcium channels. Although virtually all orally administered gabapentin is excreted unchanged in the urine in people, approximately 30-40% is metabolized in the liver in dogs, but there is no induction of hepatic microsomal enzymes as with Phenobarbital. The published dose range in dogs is from 25-60mg/kg/day divided into 3-4 doses, due to its short half life. There are no published doses in cats, but a5-10 mg/g q8-12 hrs has been suggested. There is no data on the use of gabapentin as a sole anticonvulsant agent in dogs, but one clinical trial evaluating its use concurrently with Phenobarbital failed to show a reduction in seizure frequency in epileptic dogs. No efficacy data have been published in cats. In people, it has been used with greater success for management of focal seizures than for generalized seizures. d. Pregabalin (Lyrica): Pregabalin in structurally similar to gabapentin, but seems to have less GABA activity. Its mechanism of action is most likely mediated via inhibition of cerebral voltage-gated calcium channels, inhibiting excitatory neurotransmitter release at the synaptic junction. In animal models, pregabalin has been shown to be an effective anticonvulsant, and a recent meta-analysis incorporating several small clinical trials in people has shown it to be an effective adjunctive therapy for partial seizures as well as generalized seizures. The drug’s utility in dogs is currently being investigated at the author’s institution and preliminary results are encouraging. Like gabapentin, the drug is excreted unchanged in the urine. e. Zonisamide: Zonisamide is a sulfonamide approved for use as an anticonvulsant in people. It’s mechanism of action has not been definitively determined, but proposed mechanisms include antagonism of voltage gated sodium channels and T-type calcium channels in the brain, GABA agonism, glutamate antagonism, and dopaminergic and serotonergic effects. It is primarily metabolized by hepatic microsomal enzymes, and has a half life of approximately 15 hours in dogs. Recommended dosing for dogs is 5mg/kg q12hr, but dogs currently receiving drugs that induce hepatic microsomal enzyme activity (such as Phenobarbital) should be dosed at 10mg/kg q12hr. It can also be administered rectally in animals unable to take oral medications, but preliminary data suggests that the dose should be increased to 30mg/kg. The drug has a good safety profile. Zonisamide was shown to produce a 50% reduction in seizure activity in 7 of 12 dogs with refractory epilepsy currently receiving Phenobarbital therapy, and another study showed that 9 of 11 dogs with refractory epilepsy experienced a significant reduction in seizures with Zonisamide. Although no published studies have been done, there are reports that Zonisamide has been successfully used as a sole agent for treatment of epilepsy in dogs. There are no published studies on the use of zonisamide in cats, but there are anecdotal reports of successful management of epileptic cats with the drug. f. Levetiracetam (Keppra): The mechanism of action of Levetiracetam (as described above) is poorly understood, but there is some evidence that it may antagonize compounds that modulate the activity of GABA and glycine (inhibitory neurotransmitters) in the CNS. 70-90% of the orally administered drug is excreted unchanged in the urine in dogs, and there does not appear to be any significant hepatic metabolism. An initial dosing schedme of 20mg/kg q8hr has been recommended in the dog. The drug appears to be very safe in dogs, and toxicity studies showed no significant side effects in most dogs treated with up to 1200mg/kg daily for 1 year. A prospective trial evaluating Levetiracetam as an add-on therapy for dogs with refractory epilepsy showed a 54% decrease in seizures with no side effects.
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