Susan M. Cochrane, DACVIM (Neurology)
Status epilepticus (SE) is a relatively common, potentially life-threatening emergency in small animal veterinary medicine that requires immediate and aggressive treatment. Like many emergencies in veterinary medicine, it is best approached with a standardized treatment protocol in order to achieve rapid and effective cessation of the seizures and a successful recovery.
SE is defined as continuous seizure activity of greater than 5 minutes in duration or more than one discrete seizure without regaining normal level of consciousness between the seizures. Potential causes of SE include primary and idiopathic epilepsy, metabolic disturbances (e.g., hypoglycemia), heat stroke, head trauma, intracranial neoplasia, vascular event, post hepatic shunt ligation and inflammatory CNS diseases. Cluster seizures (CS), defined as greater than one seizure within 24 hours with return to normal consciousness between the seizures, is also a relatively common presenting problem, especially in dogs that have been previously diagnosed with primary or idiopathic epilepsy. CS often require similar treatment to SE although the CS patients are usually more metabolically stable.
Understanding the pathophysiology of SE is important in order to establish an effective treatment plan. During the initial 30 minutes of SE (compensatory phase), the brain tries to compensate for increased oxygen and glucose demands by increasing cerebral blood flow. The activated sympathetic nervous system contributes to elevation in body temperature, bronchial secretions and salivation. As the SE proceeds, lactic acidosis can develop secondary to increased anaerobic metabolism along with hypoglycemia and electrolyte imbalances.
After approximately 30 minutes, the patient enters the decompensatory phase where cerebral regulatory mechanisms start to fail, resulting in disruption of the blood brain barrier and subsequent cerebral edema. Cerebral blood flow then starts to decrease resulting ultimately in neuronal cell death. Cardiac arrhythmias, pulmonary hypertension and myoglobinuria have been documented during this phase of SE. After approximately 60 minutes, increased intracranial pressure along with multiple organ failure occurs and death of the patient usually follows.
The initial goal of treatment for SE is to immediately stop the seizure activity to protect the brain from further insult and to maximize the chance for complete recovery. Intravenous diazepam (DZ) is the initial drug of choice. This drug is highly lipid soluble which allows it to penetrate the CNS rapidly (i.e., within approximately one minute after intravenous administration). DZ also has pharmacologically active metabolites. Unfortunately, the antiepileptic effect of DZ decreases rapidly so the seizure activity may recur quickly especially in the dog. While the t ½ of DZ in the dog is 2-4 hours, the t ½ in the cat is considerably longer at 15 to 20 hours when considering both DZ and its active metabolites.
For the initial treatment of SE, diazepam should be administered as an intravenous bolus at 0.25-1 mg/kg in the dog and 0.5 mg/kg in the cat. This dose can be repeated 3-4 times at 5 to 20 minute intervals while monitoring for cardiopulmonary depression. If IV access cannot be achieved initially, then DZ can be administered rectally at 0.5-1 mg/kg to allow for an IV access to be established. If the patient is already receiving oral phenobarbital therapy, then the dose of rectal DZ can be increased to 2 mg/kg.
As seizure activity decreases, initial assessment of the patient should include ensuring a patent upper airway and adequate oxygenation along with heart and respiratory rate, body temperature, ECG, blood pressure and if possible blood gas values. Stat blood work including PCV and blood glucose, total protein, electrolyte and calcium levels should be performed. Initial historical information should be gathered from the owner to help direct specific care (e.g., possible toxin exposure and medications such as insulin).
In cases of seizure -induced hyperthermia, remember that body temperature will usually correct itself rapidly with cessation of the gross motor seizure activity. At body temperatures greater than approximately 40.5 degrees C, cooling methods can be considered including cool surface to lie on, fan and cold water-soaked towels. Cold water enemas will make evaluation of body temperature difficult and cooling of IV fluids is often impractical. Cooling methods should be discontinued at approximately 39.5 degrees C to avoid rebound hypothermia. Glucose supplementation should only be added if hypoglycemia is documented since glucose may contribute to lactic acidosis. Lactic acidosis rarely requires specific treatment (e.g., bicarbonate) since it usually corrects rapidly with cessation of the seizures. If SE is severe and cerebral edema is suspected, then mannitol at 0.25-1.0 g/kg should be administered slowly intravenously over approximately15-20 minutes. Although the use of steroid is controversial in CNS disorders, dexamethasone phosphate at 0.25 mg/kg IV or methylprednisilone succinate at 30 mg/kg IV can be considered.
Once the initial crisis of SE is controlled, then further evaluation such as physical and neurologic examinations, samples for CBC, clinical chemistries, urinalysis and antiepileptic drug (AED) levels if applicable can proceed. Samples for AED levels should not be collected in serum separator tubes. Depending on the individual patient, investigation of the cause of the SE could include brain imaging (e.g., CT scan or MRI), CSF analysis, abdominal ultrasound and thoracic and abdominal radiographs to assess for neurogenic pulmonary edema, neoplasia and infection.
Neurologic examination during the post-ictal period can be abnormal as a result of neuronal disturbance secondary to the SE. These deficits should be symmetric in nature and often include blindness, disorientation, behaviour changes, generalized weakness and incoordination. The deficits present during the post-ictal period usually resolve within a few hours or rarely a few days following resolution of the SE. Asymmetric deficits on neurologic examination such as asymmetric menace deficit, nasal septum sensation and/or postural reaction deficits are considered significant indicators of structural cerebrocortical disease as the cause of the SE. Poor prognostic indicators include opisthotonus and decerebrate rigidity (i.e., rigid extension all limbs) which are suggestive of brain herniation.
If the SE does not respond to initial intravenous bolus DZ therapy, or returns shortly after initial cessation of the seizure activity, then consider bolus phenobarbital (PB) therapy and/or constant rate infusion (CRI) of diazepam. Remember that this persisting seizure activity can be quite subtle such as twitching of an eyelid or lip. PB is slower than DZ to reach maximal effect at approximately 15 to 20 minutes after IV administration. PB does, however, have a longer duration of action than DZ. The IV bolus dose of PB administered slowly is 5 mg/kg to a maximum of 16 mg/kg in the dog that is currently not receiving oral PB therapy and 2 to 4 mg/kg if the patient is receiving PB therapy. In the cat, an IV bolus PB dose of 4 mg/kg has been suggested.
A CRI of DZ should then be started at an initial dose of 0.5-1 mg/kg/h for the dog and 0.5 mg/kg/h for the cat. The diazepam CRI should be administered by syringe pump or burette. Fluids that should be avoided for diazepam CRI include dextrose containing fluid and lactated ringer's solution since the DZ will precipitate and NaCl 0.9% which can increase renal clearance of bromide potentially lowering serum bromide levels. Since DZ binds to plastic and is inactivated by light, only a 1 to 2 hour quantity should be made up at a time and the container should be covered to avoid light exposure. The fluid requirements of the patient should be carefully calculated to avoid overhydration especially since brain edema is a potential complication of prolonged SE. If the seizures are controlled by these measures, then the diazepam CRI dose should be decreased in decrements of 25 % every 4 to 6 hours.
Repeat bolus dose DZ for the management of SE instead of a CRI should only be used if CRI diazepam administration is not possible. If intravenous bolus DZ therapy is the only option, then an IV dose of 0.5 mg/kg has been suggested every 20 minutes to a maximum of 4 to 5 doses.
If the seizures persist in spite of intravenous bolus PB and diazepam CRI, then increasing the diazepam CRI dose to 1.5 mg/kg/h in the dog and 1.0 mg/kg/h in the cat for approximately 4 to 6 hours can be considered. If the seizure activity stops, then the CRI dose of DZ is decreased in decrements of 25 % every 4-6 hours. Another option would be to add PB as a CRI at 0.25 mg/kg/h although some consider this a controversial step. If the seizures are controlled, then the CRI doses of PB and DZ are decreased in decrements of 25% every 4 to 6 hours.
In the most refractory cases of SE that are unresponsive to a CRI of diazepam and phenobarbital, these CRI's can be replaced with propofol. Propofol usually has antiseizure properties but in the rare case can have convulsant activity. Propofol CRI is preferred to pentobarbital anesthesia since propofol is less cardiovascular depressant and the recovery is faster and smoother (i.e., less seizure-like) than with pentobarbital. Propofol has also been documented to decrease the brain's consumption of oxygen and to decrease intracranial pressure. Blood pressure and oxygen saturation should be closely monitored since hypotension and respiratory depression can occur with propofol. Intubation and respiratory support may occasionally be required.
An IV bolus dose of propofol at 1-3.5 mg/kg up to 6 mg/kg should be administered followed by a CRI of 0.1 to 0.25 mg/kg/minute up to 0.6 mg/kg/minute administered by syringe pump. The propofol CRI should be continued for 6 to12 hours and then gradually decreased. The maximum duration of a propofol CRI in the dog is approximately 48 hours. Since propofol in the cat has been associated with Heinz body anemia and hemolytic anemia, the PVC and CBC should be closely monitored in this species and the CRI dose of propofol should be as low as possible and the duration of treatment should be as short as possible. Sterility is required in handling the propofol CRI.
Additional supportive care of the SE patient includes lubrication of the eyes, bladder catheterization, turning sides every 4 hours and limb physiotherapy, if appropriate for the specific patient. In cases where increased intracranial pressure is suspected such as trauma, the head, neck and shoulders should be elevated at approximately a 30 degree angle. Care should be taken in positioning of the patient being treated for SE to avoid compression of the jugular veins which can further increase intracranial pressure.
As soon as the patient can swallow, oral AED therapy should be initiated or, in the case of previously treated seizure patients, then dose adjustments and/or the addition of other AED(s) should be considered.
Some patents that suffer from recurrent episodes of SE or cluster seizure (CS) activity can potentially have their visits to the emergency clinic reduced by using rectal DZ at home. A dose in the dog of 0.5 to1.0 mg/kg administered every 20 to 40 minutes to a maximum of 4 to 5 doses within a 24 hour period should be initiated after the onset of SE or CS activity. The dose can be increased to 2 mg/kg in the dog that is receiving oral PB as an AED. The parenteral vials of DZ (10 mg/2 ml) should be opened at the time of the seizure activity rather than being preloaded in syringes in advance since the DZ is not stable in plastic and with exposure to light. A teat canula or soft rubber urinary catheter can be used to administer the DZ rectally. Oral clonazepam at a dose of 0.1 to 0.5 mg/kg PO q 8 hours for 1 to 2 days then every12 hours for 1 to 2 days can be used in dogs in addition to or instead of the rectal diazepam for CS activity if the seizures occur several hours apart.
Although status epilepticus and cluster seizure activity can be frustrating to treat, it is an extremely rewarding experience to have patients successfully recover from these potentially devastating situations.
References are available upon request.