Seizure: management

• Guidelines have been established to aid the clinician as to when antiepileptic medication should be initiated.
• In general antiepileptic drugs may either raise the seizure threshold or prevent the spread of the electrical activity.
• The aim of any antiepileptic treatment is to “control” the seizures by reducing their frequency, intensity and severity with minimum side effects while maximizing the owner’s and dog's quality of life.
• Owners should be appropriately advised to ensure that their expectations are realistic from the outset.
• Unless idiopathic epilepsy is considered to be the primary differential diagnosis for the seizure activity, specific treatment of the underlying cause is essential and the success of this will determine the need for symptomatic seizure therapy.
• The decision of when to start antiepileptic treatment is still a subject of controversy:
  • Dogs with a single seizure or isolated seizures separated by long periods of time (more than one month) do not require treatment.
  • Treatment is indicated when:
    • The animal has a very severe seizure or clusters of seizures, irrespective of the frequency of the seizures or seizure clusters
    • Seizures occur more than once a month and/or the owner objects to their frequency.
    • Seizures are becoming more frequent or more severe.
    • An underlying progressive intracranial disorder has been identified as the cause of the seizures.
    • Post-ictal signs are objectionable (eg aggression).

Phenobarbital

• The standard first line antiepileptic therapy is phenobarbital Phenobarbital at 3 mg/kg PO BID.
• It a barbiturate-derivative.
• Most commonly used antiepileptic drug.
• Dogs should be dosed orally, starting with a dose of 2-3 mg/kg PO BID.
• Steady state serum concentrations are not achieved until 1-2 weeks after treatment is initiated.
• The full effect of the medication therefore does not appear for 2 weeks and doses should not be increased during this time.
• If seizures are not being controlled at this stage, the dosage may be increased by 20% at a time, with associated monitoring of serum phenobarbital concentration.
• In dogs, repeated phenobarbital administration is known to alter the estimated steady state serum concentration as a consequence of enzyme induction (cytochrome P450 induction):
  • This results in the need to regularly monitor serum phenobartital concentrations and progressively increase the oral dosage with time in order to maintain steady state therapeutic levels.
• The recommended therapeutic range in dogs is 20-35 mg/l:
  • This therapeutic range is only an indication for the adaptation of the oral dosage.
  • Most dogs will “respond” (ie achieving a reduction in the frequency, intensity and severity of the seizures with minimal side effects) with serum concentrations within this range.
  • However, some dogs might need to be in the upper limit of this range while others may respond to concentrations below the lower limit.
• Determination of serum phenobarbital levels is indicated when:
  • Steady state blood levels are achieved after starting treatment (10-15 days in dogs). This provides a baseline to further guide changes in dose according to clinical circumstances.
  • When the seizure frequency increases or the patient becomes refractory to the phenobarbital therapy.
  • Every 3-6 months to verify that the blood concentration has not drifted out of the intended range.
  • When drug-related side effects are suspected.
• It does not matter when the serum concentration is measured in relation to the timing of the pill as long as the measurement is taken at the same time consistently in each individual patient.
• There is no magic dose of phenobarbital that is needed or that is toxic to individual dogs. Therefore, assessing phenobarbital concentration Phenobarbital assay before deciding that a dog is getting too much or too little is extremely important.

Pharmacokinetics

• Half-life = 46-88 hours in most dogs.
• High bioavailability (86-97%).
• Absorbed within 2 hours after oral administration.
• Maximal plasma concentration achieved 4hours after oral administration.
• 45% is protein bound in serum.
• Chronic administration reduces elimination half-life.

Metabolism

• Primarily metabolised by hepatic microsomal enzymes, although up to 25% is excreted unchanged renally.
• Metabolism increases with chronic administration (autoinduction) due to the drug being a potent inducer of hepatic microsomal cytochrome P450); thus increased clearance of phenobarbital is seen along with other endogenous compounds (eg thyroid hormones).
• Metabolism is also affected by diet and urine pH - low protein diets can increase elimination of phenobarbital.

Mechanism of action

• Phenobarbital increases seizure threshold and decreases the spread of electrically induced discharges.
• Primary mechanism of action - binds GABA_A receptor activating BAGA receptor-gated chloride channels and increase the affinity of GABA for its own receptor.
• This results in greater influx of chloride ions resulting in hyperpolarization of the resting membrane potential of the post-synaptic neuron and preventing further action potentials.
• Secondary mechanisms of action include interaction with glutamate receptors to decrease neuronal excitatory postsynaptic currents and blocking presynaptic entry of calcium ions into nerve terminals.

Interactions, side effects and toxicity

• Side effects of phenobarbital in dogs can be idiosyncratic or dose-related:
  • Idiosyncratic:
    • Severe hyperexcitability.
    • Acute hepatic necrosis.
    • Bone marrow dyscrasias (eg neutropenia, anemia and thrombocytopenia).
    • Superficial necrolytic dermatitis.
    • Dyskinesia.
  • Dose-related (often transient and resolve 1-2 weeks after starting treatment as tolerance develops):
    • Polyuria.
    • Polyphagia.
    • Ataxia.
    • Sedation.
    • Serious liver toxicity is less common and may be more likely when serum levels are maintained above 35 mg/l.
• Hepatotoxicity is rare. An increase in liver enzyme concentration is to be expected in all dogs receiving phenobarbital and so liver function tests are required to monitor the effects on the liver (eg bile acid stimulation testing and fasting urea, cholesterol, albumin and glucose concentrations).
• Hepatotoxicity may be reversible if detected early and phenobarbital withdrawn. There is an increased risk of pancreatitis in dogs receiving potassium bromide and phenobarbital.
• If toxic levels of phenobarbital are obtained, and seizure control is not adequate, then an additional antiepileptic is added (see below).

Summary

• Suppresses epileptogenic foci discharges and inhibits kindling; decreases neuronal excitability and increases the action potential threshold to electrical stimulus.

Dosage and monitoring

• Dosage: 2-4 mg/kg PO BID initial dose.
• Serum concentrations more closely correlated with therapeutic benefit than orally administered dose.
• Therapeutic levels of 20-35 mg/ml have been suggested to maximize seizure control while minimizing side effects.
• The timing of when to perform serum phenobarbital concentratins is not important provided you perform it consistently at the same time in each individual.
• Phenobarbital requires serum concentration testing. This is indicated:
  • Stready state blood levels are achieved after starting treatment (10-15 days in dogs). This provides a baseline to further guide changes in doses according to clinical circumstances.
  • When the seizure frequency increases or the patient becomes refractory to the phenobabrital therapy.
  • Every 3-6 months to verify that the blood concentration has not drifted out of the intended range.
  • When drug-related side-effects are suspected.

Emergency situations

• Status epilepticus Status epilepticus or cluster seizures.
• Phenobarbital naïve patients:
  • Intravenous phenobarbital in 4 mg/kg boluses every 10-20 minutes to a total dose of 24 mg/kg or until the seizures stop.
• Patients already receiving phenobarbital:
  • Intravenous phenobarbital 4 mg/kg intravenous bolus and initiating a new antiepileptic medication (eg potassium bromide or levetiracetam).
• Phenobarbital at 18 mg/kg IV in dog that has not been on phenobarbital.

Primidone

• 2-deoxybarbiturate Primidone.

Metabolism

• Rapidly oxidized to phenobarbital and phenylethylmalonamide (PEMA) by microsomal enzymes in liver.
• Phenobarbital contributes 85% of the antiepileptic activity due to its prolonged half life.
• Relative percentages of metabolites at steady state concentrations are:
  • Phenobarbital: 64.6 %.
  • PEMA: 33.6 %.
  • Primidone: 1.8 %.

Mechanism of action

• Effectiveness of primidone correlates better with serum phenobarbital concentration (correlation with primidone or PEMA and primidone dose is poor).
• T 1/2 of PEMA and primidone are 10-14 h.
• Only 1 in 15 dogs in one study that were refractory to phenobarbital benefitted from primidone.

Dosage and monitoring

• 30-55 mg/kg/day divided TID.
• Others have recommended somewhat lower dosages of 10-15 mg/kg/d and 15-30 mg/kg/d BID-TID.
• Adjustments in dose made on basis of serum phenobarbital levels.

Potassium bromide

• Halide salt Potassium bromide.

Metabolism

• Bromide salts are rapidly absorbed from small intestine.
• No protein binding.
• Exclusively excreted by the kidneys making it ideal for patients with hepatotoxicity.

Mechanism of action

• Mechanism of action is at the GABA receptor-gated chloride channels whereby bromide replaces negatively charged chloride ions through the chloride channels causing neuronal hyperpolarization.
• Bromide has synergistic effect with drugs that enhance chloride conduction, eg phenobarbital.

Dosage and monitoring

• Dosage of 20-60 mg/kg PO SID or BID (recommended dose 30 mg/kg daily best divided twice daily to limit side effects).
• Achieves a therapeutic blood level of 1-3 mg/ml.
• Requires 2-3 weeks before bromide blood levels will enter the therapeutic range and 9 weeks before steady state concentrations are approximated, therefore the timing of bromide assay Bromide assay is crucial.
• It has a long half-life of 25-46 days, steady state can be anticipated around 3 months after commencing the medication.
• If seizure control is needed more rapidly, can give loading dose of 400-600 mg/kg orally, which will achieve serum bromide levels of 1-1.5 mg/ml:

  • Give this dose over 4-5 consecutive days to avoid vomiting due to high osmolarity and potassium content.

  • The major limitation of loading is that there is no time for tolerance to the sedative effects of the drug to develop so this is best performed in a hospital setting on severely affected patients only.

• For a more rapid effect than that obtained with oral maintenance dosing regimes, a per rectum loading protocol has been devised. Intrarectal administration may be preferred in the patient that is heavily sedated from prior diazepam and phenobarbital administration. A loading dose for KBr (600 mg/kg) can be administered over a 24-hour period as 6 per rectum boluses (100 mg/kg, q4h). The side-effects seen with this regime may be transient but diarrhea and sedation.

Interactions, side-effects and toxicity

• Personality changes, eg aggression, irritability, hyperactivity.
• Erythematous dermatitis.
• Persistent cough.
• Pancreatitis.

Diazepam

• Benzodiazepine Diazepam.
• Crosses the blood-brain barrier faster than any other antiepileptic medication.
• Chronic oral administration of diazepam is not recommended in the dog due to its very short elimination half-life and functional tolerance.

Metabolism

• Major metabolites are nordiazepam (desmethyldiazepam) and oxazepam.
• Metabolites have 25-33 % of the antiepileptic activity of diazepam.
• Due to extensive first pass effect, oral systemic availability is only 1-3%.
• Rectal administration is preferable to avoid this first pass effect.
• Serum half-life is 3.2h.
• Serum protein binding is 96%.
• Tachyphylaxis is noted with repeated doses of benzodiazepines probably due to a feedback- regulated increase in benzodiazepine receptors or a decreased production of GABA.

Mechanism of action

• Binds to benzodiazepine receptors on the GABA receptors and facilitates binding of GABA to its receptor. 
• This opens chloride channel, allowing for Cl- influx and enhanced inhibition of the post-synaptic neuron.

Dosages and monitoring

• 0.5-1.0 mg/kg IV for acute seizure, up to a maximum dose of 20 mg.
• This dose can be repeated up to three times within 2 hours if required.
• Functional tolerance occurs within one week of dosing.
• Can be used as a continuous infusion at 2-5 mg/h in 5% dextrose in water IV. This takes 15-20 mins to penetrate the CNS but has a prolonged effect. Continuous use in prolonged seizures should be avoided as a diminished response is seen with repeated administration. If diazepam does not control the seizures, a phenobarbital bolus (4 mg/kg IV) should be considered.
• IV administration of diazepam may not be possible in some patients. It can be given IM, although absorption is not predictable. Rectal administration may be considered initially at a dose of 0.5-2.0 mg/kg body weight depending upon whether the animal was being treated with phenobarbital before onset of SE. It may be necessary to use the higher dose in dogs receiving long-term phenobarbital therapy. In previously untreated dogs, peak plasma concentrations of diazepam are seen 14 mins after a per rectum dose of 1 mg/kg.
• Adverse effects of IV benzodiazepines include respiratory depression, hypotension, and impaired consciousness.
• Rectal administration is probably only of benefit in the home environment with patients suffering cluster seizures/status epilepticus. The reason for this is this route is not as efficacious as intravenous dosing.

Imepitoin 

• Imidazoline with a chemical structure similar but distinct to benzodiazepines.

Metabolism

• Imepitoin Imepitoin is metabolised va oxidative metabollism in the liver.
• It is broken down into 4 main inactive metabolites which are predominately excreted in the feces rather than in the urine.
• No major change in pharmacokinetics or accumulation of the drug is expected in dogs with concurrent renal disease.
• Due to the lack of data about the use of imepitoin in dogs with severe concomitant disease, the use of imepitoin in dogs with severe renal disorders is contraindicated.
• The cytochrome P450 system is not involved in imepitoin metabolism and therefore it does not induce liver enzymes with long-term administration of the drug. This means that imepitoin has a predictable metabolism without autoinduction and hence serial blood concentration monitoring is not necessary.
• Rapidly cleared from blood with elimination half-life of approximately 1.5-2 hours.
• Majority of imepitoin and its metabolites excreted via feces.
• The protein binding of imepitoin is low in dogs (60-70%) and therefore there is no expected interaction with highly protein bound compounds.

Mechanism of action

• Low-affinity partial agonist for the benzodiazepine (BZD) binding site of the GABA receptor:
  • Historically, drugs acting at the BZD-binding site have the potential for tolerance dependence and abuse liability, eg diazepam.
  • Imepitoin is known to be a partial agonist which is suggested to be an advantage over full agonists in respect of tolerance and abuse.
  • This is because it binds less strongly for a shorter period of time.
  • Diazepam has a high affinity for this receptor and hence serial administration can lead to a decreased efficacy over time, ie tolerance. Unlike diazepam, there is no evidence for the development of tolerance to imepitoin.
  • This also gives the added advantage that imepitoin is not a controlled medication and hence can be stored safely in a veterinary dispensary without being locked away.
• It is a centrally acting antiepileptic which crosses the blood brain barrier.
• Imepitoin also has a minor action of blocking calcium channels which may contribute to its antiepileptic properties.
• Imepitoin results in a less positively charged neuron which reduces the likelihood of an action potential developing.
• If a neuron cannot become excited then it cannot pass on any excitatory signals to neighboring neurons. These mechanisms contribute to prevent the spread of electrical activity within the brain, thereby reducing the potential for serizures.
• Imepitoin is described as having a targeted effect. This means that it will only bind to the BZD-binding site when the neurotransmitter GABA is present. In selectively binding only when GABA is present, imepitoin works to inhibit only those neurons that are firing. In essence it potentiates the action of GABA in neurons where GBA is struggling to provide enough inhibition. It therefore only exerts its effect in overactive neurons that are stimulated during a seizure.

Dosage and monitoring

• 10-30 mg imepitoin per kg bodyweight BID, approximately 12 hours apart (start at low end of dose range).
• Best given on an empty stomach.
• Required dose will vary between dogs and will depend on seizure control.
• If seizures are not adequately reduced following a minimum of 1 week of treatment at the current dose, the dog should be re-assessed. If imepitoin is well tolerated by the dog, the dose can be increased by 50-100% increments up to a maximum dosage of 30 mg per kg administered BID.
• There is no requirement for repeated blood tests to monitor therapeutic serum drug concentrations or liver enzymes.
• Biochemical screening forms an important part of initial investigations and on-going monitoring of general health and is considered good clinical pracice for a dog receiving chronic therapy.

Interactions, side effects and toxicity

• Mostly mild and generally transient.
• Polyphagia most common.
• Hyperactivity, polyuria, polydipsia and somnolence.
• In case of repeated overdose of up to 5 times the highest recommended dose, central nervous system (CNS) (loss of righting reflex, decreased activity, eyelid closure, dry eye and nystagmus), gastrointestinal-related effects and reversible prolongation of the QT interval have been noted. At such doses, the symptoms are not usually life-threatening and generally resolve within 24 hours if symptomatic treatment is given.

Clonazepam

• Klonopin™.
• Extremely potent benzodiazepine.
• Used for simple absence seizure, atonic seizures, and bilateral massive epileptic myoclonus.
• Generalized EEG abnormalities are better suppressing than focal abnormalities, possibly because clonazepam limits the spread of epileptogenic discharge rather than suppressing the focus.

Metabolism

• Nearly 100% bioavailable as an oral solution.
• Peak concentrations 1-3 h after PO dose.
• 82% protein bound.
• Hepatic clearance 10 times as efficient in dogs as compared to man.
• Metabolism becomes somewhat saturated at therapeutic doses in 10-25 % of dogs.
• Elimination T 1/2 increased from 1 h 25 min at start of therapy to 1 h 35 min to 2 h 55 min after 1 week of treatment.
• Elimination of clonazepam is increased by phenobarbital, an effect due to hepatic enzyme induction rather than an alteration in hepatic blood flow.

Dosage and monitoring

• 0.5 mg/kg PO BID-TID.
• Achieves peak serum concentrations of 130-179 ng/ml and trough concentrations of 22-77 ng/ml; these concentrations are near the therapeutic range in people.

Interactions, side effects and toxicity

• Sedation.
• After prolonged treatment, abrupt cessation of therapy causes acute withdrawal signs including:
  • "Wet dog shakes".
  • Listlessness.
  • Weight loss.
  • Increased body temperature.
  • Dorsal recumbency.
• Signs are most severe 2 days after cessation, and will subside within 1 week of withdrawal. Therefore, gradually taper off of this medication.

Clorazepate 

• Tranxene™ Clorazepate.
• 15 times less potent than clonazepam.

Metabolism

• Rapidly and completely hydrolyzed in the stomach to nordiazepam.
• T 1/2 in people is 41 +/- 10 h after PO clorazepate.

Dosage and monitoring

• Preliminary evidence indicates the dosages of 2 mg/kg BID produce peak nordiazepam concentrations near 1 mg/ml with maximum concentration from 1-2 h after PO administration.
• Optimum seizure control in people is noted when serum nordiazepam concentrations are greater than 1 mg/ml.

Interactions, side effects and toxicity

• Clorazepate crosses the placenta slowly, but nordiazepam crosses very rapidly, and has been found in breast milk and the blood of nurslings.

Carbamazepine

• Causes much less CNS depression in people.
• Iminostilbene derivative.
• Used as an antiepileptic and also for relief of pain in trigeminal neuralgia.
• Structurally related to tricyclic antidepressants.

Mechanism of action

• Limits seizure propagation by reduction of post-tetanic potentiation of synaptic transmission.
• Sedative, anticholinergic, antidepressant, muscle relaxant, antiarrhythmic, antidiuretic, and neuromuscular transmission-inhibitory actions.

Metabolism

• Metabolized to carbamazepine 10,11-epoxide (liver).
• Further metabolism to inactive metabolites is self-induced during multiple dosing.
• When dogs have been switched to this drug from standard regimes, dogs have lapsed into status epilepticus, possibly due to the rapid elimination of carbamazepine.
• Concentration in CSF of humans is 15% serum concentration.

Felbamate 

• (2-phenyl-1.3-propanediol dicarbamate) Felbamate.

Metabolism

• Extensively metabolized by the liver via hydroxylation and conjugation.
• Well absorbed after oral administration.

Mechanism of action

• Not known; works on the NMDA receptor.
• Appears to increase seizure threshold and prevent seizure spread.

Dosage and monitoring

• Optimal dose not known.
• For dogs <10 kg, start at 200 mg PO TID with a 200 mg/week increase up to a maximum dose of 600 mg PO TID or until seizure control in obtained.
• For dogs >10 kg, start at 400 mg PO TID with a 400 mg/week increase up to a maximum dose of 1200 mg PO TID or until seizures are controlled.
• Doses of 60 mg/kg given in dogs for metabolism studies.

Interactions, side effects and toxicity

• Aplastic anemia and hepatic failure in humans.
• Side-effects in humans include:
  • Anorexia.
  • Insomnia.
  • Weight loss.
  • Nausea.
  • Dizziness.
  • Fatigue.
  • Ataxia.
  • Lethargy.

Levetiracetam

• An S-enantiomer of alpha-ethyl-2-oxo-1-prollidine acetamide and is structurally related to piracetam Levetiracetam.

Metabolism

• Minimal hepatic metabolism (>80% excreted in the urine).
• 20% hydrolyzed in the serum and other organs.
• Elimination half-life is 3-4 h in dogs.
• Steady state concentration at 48 h.

Mechanism of action

• Poorly understood but distinct to other antiepileptic medications and therefore potentially advantageous when polytherapy is required.
• Binds to the synaptic vesicle 2A (SV2A) protein on the presynaptic terminal modulating synaptic fusion and neurotransmitter release.
• Other modes of action include:
  • Inhibition of the sodium dependent chloride-bicarbonate exchanger.
  • Modulation of potassium and voltage-gated calcium channels.
  • Opposition of allosteric inhibition of GABA and glycine-gated currents.
  • Antagonism of neuronal hypersynchronization.

• Some evidence in cats suggests that this drug may be better than phenobarbital in the management of myoclonic seizures.

Dosage and monitoring

• The recommended oral dose is 20 mg/kg every 8 h.
• There is no clear understanding of the relationship between serum drug concentration and efficacy; therefore, serum monitoring is not currently performed for this medication.

Interactions, side effects and toxicity

• Sedation, ataxia, decreased appetite and vomiting.

Gabapentin (Neurontin®) 

• Developed to be structurally similar to GABA, does not, however, work at the GABA receptor Gabapentin.

Metabolism

• Elimination T1/2 is 5-9 h in people and 2-4 h in dog.
• Peak serum levels in 2-4 h.
• Steady state concentration at 2-4 days.
• Not bound to plasma protein.
• The drug is primarily excreted by the kidneys although approximately one third is metabolised by the liver. Therefore dose reduction may be required in patients with renal insufficiency.

Mechanism of action

• Binds to neuronal voltage-gated calcium channels, inhibiting calcium flow.

Dosage and monitoring

• Optimal dose not known.
• An initial dose of 10 mg/kg every 8 hours has been suggested with a gradual increase up to 20 mg/kg PO TID over the next 4 weeks or until seizures are controlled.

Interactions, side effects and toxicity

• Sedation and ataxia are the only reported side-effects.

Zonisamde

• Synthetic sulphonamide-based antiepileptic medication Zonisamide.
• Elimination half-life is 15-20 h in dog.
• Steady state concentration at 3-4 days.
• Zonisamide is metabolised by hepatic microsomal enzymes; therefore, its half life is significantly shorter in patients that are receiving phenobarbital or any other drug that increases the hepatic microsomal enzyme cytochrome P450.

Mechanism of action

• It has a number of proposed mechanisms of action, including:
  • Reduction of presynaptic glutamate release via the blockade of sodium and calcium channels.
  • An increase in dopamine and serotonin levels in striatal and hippocampal.
  • Neuroprotection by free radical scavenging limiting neuronal damage following recurrent seizures.

Dosage and monitoring

• An initial dose of 5 mg/kg every 12 hours is suggested in a patient not receiving phenobarbital.
• If a patient is receiving phenobarbital then a dose of 10 mg/kg BID is recommended.
• Increase up to 20 mg/kg PO TID over the next 4 weeks or until seizures are controlled.

Interactions, side-effects and toxicity

• Teratogenic.
• Sedation, generalized ataxia, vomiting, inappetence.

Pregabalin

• A GABA analogue that is structurally similar to gabapentin Pregabalin.

Metabolism

• Limited information on its use and pharmacokinetics in dogs and cats.
• Elimination half-life is 7 h in dogs.

Mechanism of action

• Pregabalin may modulate calcium influx into neurons, therby reducing excessive neurotransmitter release.

Dosage and monitoring

• The recommended oral dose is 2-4 mg/kg every 8-12 h.

Interactions, side-effects and toxicity

• Sedation is the most commonly reported side-effect.

• Approximately 60-70% of idiopathic epileptic dogs will have their seizure frequency or severity decreased with the currently available anticonvulsant medications.
• Up to 30% of dogs with idiopathic epilepsy can develop drug-resistant epilepsy (pharmacoresistance), ie they are poorly controlled despite adequate doses and serum concentrations of antiepileptic medication.
• Begin treatment with phenobarbital Phenobarbital.
• The phenobarbital dosage is increased until:
  Either Significant side effects are noted.
  Or Seizure frequency or severity is unchanged when serum trough serum phenobarbital levels reach 40 mg/ml.
• Add potassium bromide Potassium bromide to the therapeutic regime.
• Monitor serum concentrations.
• If no benefit is seen at the high end of the therapeutic range for KBr, or significant side effects are noted, another anticonvulsant may be added. 

Alternative treatments for seizures

• If medical therapy is not effective, many owners will choose euthanasia rather than continue.
• Other options, while not whole-heartedly accepted by the medical community exist.
• Dietary trials with a hypoallergenic diet have been used with variable success.
• Surgical treatments, including seizure focus resection and corpus callosum division, have been used in similarly affected people to bring about seizure control.
• As the dog brain may be more able to endure these treatments than people, it would seem reasonable to begin critically examining surgical options.
• Seizure focus resection must await better intracranial seizure focus localization with EEG, and therefore, may take more time to perfect in veterinary medicine.
• Anecdotal information from some practitioners suggest that acupuncture may be helpful in seizure control.
• Vagal stimulation has been used experimentally in dogs to control some seizure activity.

Initial symptomatic treatment

• As with any emergency patient, triage Triage is essential with initial focus of supportive care and systemic stablization being ‘ABC’:
  • Airway - ensure the patient has a patent airway and intubate as necessary.
  • Breathing - administration of 100% oxygen via face mask or flow-by. If the patient is unresponsive, not spontaneously breathing or not ventilating adequately then intubation and mechanical ventilation is necessary.
  • Circulation - placement of an intravenous catheter is then a priority to collect blood and administer intravenous fluid.
• It is important to monitor the blood pressure regularly to ensure adequate volumes of intravenous fluid to maintain cerebral blood flow and perfusion.
• It is recommended to achieve a mean arterial blood pressure of 80-100 mmHg. Hyperthermia is a big concern and so slow passive cooling is recommended if the body temperature increases above 40 degrees Celsius.
• Place intravenous catheter for laboratory sampling and antiepileptic therapy administration.

Standard treatment

• Status epilepticus (SE) describes continuous seizuring which persists for more than 5 minutes without return to consciousness.
• Although SE is primarily a central nervous system abnormality it results in significant systemic pathophysiological changes.
• In the early stages of SE there is increased autonomic discharge causing tachycardia, hypertension, and hyperglycemia. These changes help to compensate for the increased metabolic demands of the brain. However, after about 30 minutes decompensation and hypotension, hypoglycemia, hyperthermia, and hypoxia develop. Reduced cerebral blood flow results in ischemia and neuronal death.
• Skeletal muscle activity and impaired ventilation may lead to lactic acidosis, hyperkalemia, hypoxia, hypercarbia and hyperthermia. Severe muscle activity during seizure activity can result in muscle damage.
• Myoglobinuria may cause renal dysfunction (particularly when accompanied by systemic hypotension).

Initial management of status epilepticus – stop the seizures

• To obtain immediate control of the seizures a fast-acting short-duration antiepileptic medication can be administered. However, these fast-acting drugs are infrequently effective alone due to their short duration and subsequently longer-acting drugs may be required, potentially in combination with a continuous rate infusion.
• Diazepam is a fast-acting, potent GABA receptor agonist that increases the seizure threshold:
  • When the GABA receptor is open, chloride ions flow into the neuron making it less positively charged and reducing the likelihood of an action potential firing therefore inhibiting the spread of seizure.
  • Diazepam is fat-soluble and therefore rapidly crosses the blood brain barrie
  • The very short half-life of diazepam in the dog (approximately 3 hours) means that repeated doses can be safely administered but this makes it unsuitable for maintenance therapy  in cats, the half-life seems longer so tolerance does not develop as quickly.
  • With their effects only being temporary, a more long acting antiepileptic will be necessary following their use.
  • A bolus dose of 0.5-1 mg/kg intravenously or rectally if venous access is not available can be given up to three times in 24 hours. Time of onset of clinical effect is 2 -3 minutes and lasts for approximately 30 minutes. If using the rectal route then slightly higher doses may be required (1 to 2 mg/kg per bolus). If two doses of diazepam fail to control the seizure manifestation, addition of a longer-acting antiepileptic medication should be immediately considered (see below).
• Midazolam Midazolam is an ultra-short acting benzodiazepine and can be used as an alternative to diazepam or in combination with diazepam:
  • It is given as a bolus of 0.2 mg/kg intravenously and further boluses can be given to effect up to three times in 24 hours in the same manner as diazepam.
  • To obtain immediate control of the seizures a fast-acting short-duration antiepileptic medication can be administered. However, these fast-acting drugs are infrequently effective alone due to their short duration and subsequently longer-acting drugs may be required, potentially in combination with a continuous rate infusion.

Long-term management - keeping the seizures away

• Longer-acting antiepileptic medication:
  • ​Phenobarbital is a longer acting barbiturate that also acts at the GABA receptor via a different mode of action to the benzodiazepines:
    • It can take up to 30 minutes to cross the blood brain barrier and exert its effect therefore this should usually be administered in combination with a fast-acting antiepileptic agent (as above)
    • Phenobarbital can be intravenously loaded to achieve a rapid steady state serum concentration. However, loading is associated with more adverse effects which most notably include sedation, ataxia, polyphagia and polyuria/polydipsia
    • ​A loading dose of phenobarbital should be given intravenously (or intramuscularly if IV access has not been obtained) in boluses of 4 mg/kg every 10-20 minutes up to a maximum of 24 mg/kg (in 24 hours) in a phenobarbital naïve patient. The boluses are given to effect and therefore care should be taken not to over-dose a patient, ie continued administration of phenobarbital despite having obtained seizure control. These loading doses should be followed with oral maintenance phenobarbital therapy (ie 2-3 mg/kg PO q12 hours) when SE has been controlled.
  • ​Levetiracetam  can be considered in patient in which phenobarbital is not appropriate (eg in patients with concurrent liver disease) or in which phenobarbital is already being administered
    • Levetiracetam has minimal hepatic metabolism in dogs, with almost 90% of the drug excreted in the urine and the remained being hydrolyzed in the serum and other organs.
    • The half-life in dogs is 3-4 hours giving the advantage of rapidly achieving steady state.
    • It is thought to act by modifying calcium-dependent exocytosis of neurotransmitters and may therefore be synergistic with phenobarbital or potentially effective where phenobarbital has not been.
    • Loading is not necessary for levetiracetam due to its short half-life. A bolus of 20-30 mg/kg can be administered intravenously every 8 hours. This should be followed with oral maintenance levetiracetam therapy (ie 20 to 30 mg/kg PO q8 hours) when SE has been controlled. A initial dosage of up to 60 mg/kg intravenously is reported.
  • Potassium bromide - Bromide is excreted by the liver and so makes it another useful choice in patients with hepatic insufficiency:
    • A big disadvantage of potassium bromide is its long elimination half-life (approximately 25 days).
    • Steady state is achieved only after 3-4 months of initiating therapy and this is important to remember when faced with a patient in the emergency setting.
    • This means administration of a loading dose is necessary although the major limitation of this is that there is not time for tolerance to the sedative effects of the drug to develop.
    • Lethargy and ataxia may be severe, vomiting may occur, and hospitalization during the loading period is mandatory.
    • If loading is performed a blood sample may be taken 24 hours later to assess the serum concentration.
  • Oral loading of 600 mg/kg divided over 5 days is recommended. However, in patients in which oral medication is not possible, rectal administration can be used instead. This should be followed with oral maintenance potassium bromide therapy (ie 20-30 mg/kg PO q24 hours) when SE has been controlled.
• Status epilepticus that does not respond to a benzodiazepine, phenobarbital or levetiracetam requires more aggressive therapy.
• Short-acting anesthetic drugs are the most commonly used agents given as continuous rate infusions (CRI) as they have a rapid onset of action, short half-lives, and cause reductions in cerebral metabolic rates.
• These drugs should be used only in an intensive care setting because of the need for regular monitoring and nursing care.
• Many of these drugs can cause severe sedation and apnoea therefore ventilator support should be considered if necessary.
• All CRI should be titrated to effect and decreased slowly to effect once longer-acting antiepileptic medications have been administered.
• Constant Rate Infusions:
  • Diazepam - a 0.2 to 0.5 mg/kg bolus should be given intravenously followed by a CRI of 0.2 mg/kg/hr given to effect.
  • Midazolam - a 0.2 mg/kg bolus should be given intravenously followed by a CRI of 0.3 mg/kg/min given to effect.
  • Propofol - a 1 to 2 mg/kg bolus should be given intravenously followed by a CRI of 0.1 to 0.2 mg/kg/min given to effect.
• Recovery from CRIs, in particular a propofol CRI, can result in paddling of the limbs and agitation. This can easily be mistaken for seizure activity but is a normal observation in cats recovering from anesthesia. It is advisable to place the patient in sternal recumbency to see if this stops these movements, giving confirmation this is an excitable phase of the drug rather than seizure activity. If seizure activity is considered unlikely then the use of dexmedetomidine Dexmedetomidine as a CRI can be started to help manage these patients.
• Inhalational anesthesia is also useful in severely affected patients. Agents such as isoflurane and sevoflurane are acceptable and should be given to maintain an adequate plane of anesthesia. Patient monitoring should be exactly the same as for any patient under inhalational general anesthesia, for example capnography, pulse oximetry and blood pressure monitoring. There are no specific guidelines on anesthetic reduction but it would be advisable to reduce the plane of anesthesia to effect with the aim of recovering the patient with no further seizure activity.