Seizures and status epilepticus (Proceedings)

Definitions

    1. Seizure- transient self-limiting clinical manifestation of excessive hypersynchronous electrical activity in the CNS. Always indicates electrical dysfunction in the forebrain.

    2. Epilepsy- a chronic neurological condition characterized by recurrent seizures.

Classification

          a. Reactive: Secondary to a metabolic or toxic condition

          b. Symptomatic: Secondary to structural brain disease

          c. Idiopathic: No identifiable cause

          d. Cryptogenic: Epilepsy is thought to be symptomatic, but the etiology has not been determined.

    3. Cluster seizures- Two or more seizures within a 24 hour period

    4. Status Epilepticus- A neurological emergency, but no universally accepted definition. Practically- continuous seizure activity, or two or more seizures between which there is incomplete recovery of consciousness, lasting at least 5 minutes.

Pathophysiology of seizures

The pathophysiological mechanisms that cause seizures are poorly understood. Neurons are excitable tissue constantly held in check. Neurons have a seizure threshold and seizures result when the threshold is lowered and there is imbalance between excitatory and inhibitory mechanisms that favors excitation.

      • Excess excitation

          o Glutamate is the major excitatory neurotransmitter in the CNS, others include aspartate and acetylcholine. Glutamate can bind to NMDA or non-NMDA receptors resulting in sodium influx into a neuronal cell and neuronal excitation.

      • Insufficient inhibition

          o Gamma-aminobutryic acid (GABA) is the main inhibitory neurotransmitter in the CNS; others include glycine, taurine and norepinephrine. GABA binds to its receptor which leads to opening of a chloride channel leading to hyperpolarization and inhibition.

Seizure stages

      • Aura: initiation of abnormal electrical activity; occurs minutes prior to ictus; animal may hide, whine, appear anxious, salivate, or seek out owner.

      • Ictus: The actual seizure

      • Postictal phase: behavior changes, ataxia, lethargy, blindness or disorientation; may last minutes to a day or more

Types of seizures

    1. Generalized seizures – involves both sides of the forebrain simultaneously

      • Loss of consciousness, laterally recumbent

      • Tonic-clonic activity

      • Autonomic signs: salivation, urination, defecation

    2. Partial seizures – abnormal neuronal activity in one region of forebrain. Partial (focal) seizures may or may not progress to generalized seizures.

          a. Simple partial seizure: abnormal motor neuron discharge originating in contralateral cerebral hemisphere

      • Consciousness usually not impaired

      • Facial twitching and limb movement are common

          b. Complex partial seizure (psychomotor seizure) – behavioral abnormalities thought to originate from the limbic system or temporal lobe

      • Consciousness is usually impaired

      • Flybiting and tail chasing are common manifestations in dogs

      • Features in cats are more variable and might include drooling, growling, or skittish behavior

Antiepileptic drugs

    1. Benzodiazepines

      • Used to stop an active seizure. 0.5 mg/kg IV or 1-2 mg/kg per rectum. Effect only lasts 20-30 minutes.

      • Acts by enhancing the effect of GABA.

    2. Phenobarbital

      • Preferred anticonvulsant in cats & one of the first line drugs in dogs (sole agent in ~75% of dogs).

      • Acts via GABA-ergic properties by increasing chloride permeability hyperpolarizing the cell

      • Dose: 3-5 mg/kg bid in dogs, 2-4 mg/kg bid in cats. Approximately 2 weeks to reach steady state levels.

      • Monitoring includes serum Phenobarbital level after 2 weeks then every 6 months; CBC and serum chemistry profile every 6 months also. Phenobarbital is known hepatic enzyme inducer, however AST, Tbili, and SBA are not affected by Phenobarbital.

      • Side effects are common & include PU/PD, PP & weight gain, transient ataxia. Chronically animals may appear hypothyroid (↓TT4, ↓fT4, mildly ↑TSH levels) but it is debated if the animals are truly hypothyroid.

      • Uncommon severe side effects include hepatic failure and idiopathic bone marrow necrosis, superficial necrolytic dermatitis

    3. Bromide

      • KBr (PO) is used most frequently but NBr can be used IV if sterilized

      • Can be used as first line agent in dogs

      • Bromide ions compete with chloride transport across cell membranes resulting in membrane hyperpolarization. Renally excreted & preferred when concerns of liver dysfunction.

      • 40-60 mg/kg daily as monotherapy

          o Loading protocol of 100 mg/kg/day x 5 days is often utilized due to extensive half life (24 days)

      • 20-40 mg/kg daily when in conjunction with Phenobarbital

      • Br levels are checked 1-4 weeks after loading, or after 3 months of maintenance dosing

      • Side effects include PU/PD, polyphagia, typically transient sedation & ataxia, vomiting & anorexia when given without food, possibly pancreatitis, and bronchial asthma like conditions in cats

      • High salt diets increase Br excretion and will decrease plasma drug levels

    4. Zonisamide

      • Appears safe & effective as sole agent in dogs. Therapeutic levels in people are 10-40 mg/l.

      • Dose (K9): 10 mg/kg bid when dog is receiving phenobarbital, 5 mg/kg bid when not.

      • Phenobarbital enhances zonisamide clearance

      • Side effects reported thus far include sedation, ataxia, vomiting, mild increases in Alp & Alt. Limited experience in cats

    5. Gabapentin

      • Two small studies report responder rates of 45-63% for refractory idiopathic epilepsy.

      • Reported side effects include ataxia, mild increases in Alp, sedation

      • Pregabalin is considered the next generation gabapentin with higher oral bioavailability and longer half life in people. Pregabalin (dogs): 3-4 mg/kg q8h

      • Gabapentin- Dogs: 25-60 mg/kg/d divided q6-8h. Cats: 5-10 mg/kg q8h.

    6. Levetiracetam (Keppra)

      • Appears safe & well tolerated. Add-on of choice for dogs with hepatic dysfunction and cats' refractory to phenobarbital.

      • Side effects reported thus far include only mild sedation

      • 20 mg/kg q8h

      • An IV formulation is available

Emergency seizures

      • Status Epilepticus

          o Neuronal damage & brain injury occur after 30-45 minutes

      • Cluster Seizures

          o Considered an emergency with potential to lead to status epilepticus

Emergency Management of Seizures (status or cluster)

Treatment goal

When approaching the status patient, three goals are in mind: Stop the seizure, Stabilize the patient, begin the Work-up

    1. Stop the Seizure and protect brain from damage caused by status

      • Cytotoxicity occurs during status secondary to hypoxemia, ischemia, and excitotoxicity (excessive activation of glutamate receptors); if untreated, the result is cerebral edema and neuronal death

          a. Immediate anticonvulsant therapy

                  i. Midazolam or Diazepam 0.5 mg/kg IV or 1-2 mg/kg per rectum

                  ii. Still seizing- repeat twice

                        √ If effective a CRI of 0.25 to 5.0 mg/kg/hr can be initiated. Midazolam preferred for CRI as fewer drug interactions and does not adsorb to plastic.

                  iii. If no response to benzodiazepine & phenobarbital (8-12 mg/kg) is on board & glucose, Na, Ca are normal, consider next level:

                        √ Propofol: 2-4 mg/kg IV slowly followed by CRI 0.1-0.4 mg/kg/min. Antiepileptic properties are debated, and seizures have been associated with its use.

                        √ Pentobarbital anesthesia: 3-15 mg/kg IV slowly, CRI 0.5-2 mg/kg/hr IV. Does not have anticonvulsant properties.

                        √ Intubation and gas anesthesia

                        √ Regardless of which protocol the clinician uses, the commitment is typically for 12-24 hours of heavy sedation / anesthesia. Aggressive monitoring is indicated in all cases at this level.

          b. Begin maintenance anticonvulsant therapy

                  iv. Phenobarbital: initiate loading by administering 4-5 mg/kg IV every 2-8 hours to a total of 15-20 mg/kg

                  v. Sodium Bromide IV or Potassium Bromide PO: Loading dose of 400-500 mg/kg over 2 days.

                  vi. Keppra (Levetiracetam). IV formulation is available.

    2. Stabilize the patient

          a. Cases of status are often unstable and can deteriorate. An IV catheter should be placed and fluids administered as indicated for hypovolemia (20-25 ml/kg NormR bolus prn) or dehydration. Hypertonic saline (4 ml/kg over 10 minutes) is an excellent fluid for patients with head trauma, but should always be administered with a balanced crystalloid; patient's sodium must be reevaluated prior to repeating hypertonic saline. Mannitol (0.5 – 1.0 g/kg over 20 minutes) should be administered if there are signs of elevated intracranial pressure.

          b. Aggressive monitoring should be implemented including:

                  vii. Maintaining a patent airway, some patients will require intubation with concurrent immediate anesthesia. Others will be heavily sedated from medication that they cannot guard their upper airway.

                  viii. Ensuring good oxygenation as the patient may have noncardiogenic pulmonary edema & hypoxemia. Nasal oxygen should be avoided as sneezing will increase intracranial pressure; mask, flow by or hood oxygen supplementation are preferred.

                  ix. Hypoventilation can occur secondary to medications. Monitoring CO2 (end tidal or venous) is vital; if the patient is hypoventilating (CO2 > 45 mmHg) intubation & ventilation should be considered. If CO2 is > 60 mmHg, intubation & ventilation strongly indicated. Ventilation should target CO2 of 35-40 mmHg; hyperventilation and low CO2 induce cerebral vasoconstriction.

                  x. Hyperthermia is common in patients presenting in status. Actively cool with tepid water if T >107 F, and stop cooling once 103 F to avoid overshoot.

                  xi. EKG and blood pressure should be monitored

                  xii. Nursing care as needed: urinary catheterization, eye lubrication, oral chlorhexidine rinse, turning & soft padded bedding, heating pads as needed

    3. Begin work up by collecting blood samples for immediate PCV/TP, Glucose, calcium and sodium. Samples should be collected for a Complete Blood Count, Serum chemistry profile, and antiepileptic drug concentrations if the patient was on therapy prior to status. Other considerations include bile acids, blood ammonia, collection of gastric ingesta for toxin analysis (carbamate, organophospate, strychnine, etc).

As frightening as a case of status may seem, it tends to be a good thing. Dogs presenting with status epilepticus tend to be younger, are more likely to have a reactive or secondary cause (eg- toxin, hypoglycemia, hypocalcemia) and had more favorable outcomes than dogs with symptomatic epilepsy.

References available upon request.