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Seizures and status epilepticus in the dog and cat

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Category: Schede
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  • Disciplina: Medicina d'urgenza
  • Specie: Cane e Gatto

Seizures are a very common emergency in veterinary medicine,1,2 and occur because neurones in the cerebral cortex and other underlying areas develop paroxysmal, excessive, disordered, purposeless, often self-limiting activity which is associated with an enormous variety of clinical manifestations depending on the amount and area of the brain involved. Given that different areas of the central nervous system can be affected and that the clinical signs are, therefore, varied, it is difficult to give a uniform description of all seizures.3

 

PATHOPHYSIOLOGY

An area of the brain in which there is hypersynchronised activation of a group of neurones with high frequency action potentials is defined as an “epileptogenic focus”. The abnormal electrical activity of the area can give rise to various different clinical manifestations depending on the size of the area involved and the activity of the surrounding GABA-ergic inhibitory neurones, since these latter prevent the propagation of the electrical barrage and the manifestation of the symptoms. When the GABA-ergic neurones are able to inhibit the electrical impulses, the patient does not show evident seizures, but the abnormal electrical activity in the brain can be detected with an electroencephalogram (EEG). In some patients the balance between the epileptogenic focus and the inhibitory neurones can be lost following metabolic alterations, such as hypoglycaemia, hypoxia, electrolyte imbalances, and hyperthermia, and in these cases overt seizures may occur.

A series of events occurs in neurones that are hyperstimulated:

  • the initiation of numerous action potentials (about 700-1000 per second) mediated by calcium and sodium;
  • continuous depolarisation;
  • rapid repolarisation and hyperpolarisation mediated by GABA receptors that facilitate the entry of chloride into the cell, and the movement of potassium out of the cell, or both. Many areas of the brain, including the subcortical nuclei, the thalamic nuclei and the nuclei of the brain stem can participate in the generation and propagation of the impulse. During the clinical examination it is possible to see generalised muscle activity or contraction of a few muscle bundles; when the limbic neurones are activated there may also be changes in the state of consciousness and behavioural alterations.

Seizures can be classified as:

  • focal;
  • partial (simple or complex);
  • generalised.

Focal seizures are not clinically detectable and originate in a small area of the prosencephalon; the abnormal electrical activity can be detected by EEG.

Partial seizures are divided into simple or complex and are manifested by clinically detectable contractions of some muscle groups and sensorial changes with or without loss of consciousness due to activation of a small area of structurally altered prosencephalon or of idiopathic origin. Complex seizures can give rise to generalised convulsions. Both forms may affect only one side of the patient, thus indicating which area of the brain is involved. Simple seizures are responsible for paroxysmal contractions of skeletal muscles and can originate from the motor area of the cerebral hemispheres, while complex seizures, as well as causing contractions of skeletal muscle, are associated with alterations in behaviour or consciousness; the behavioural alterations depend on the limbic system, which can be involved in different ways.4

Generalised seizures are manifested as paroxysmal contractions of the antigravitational skeletal muscles, loss of posture, tonic-clonic contractions of all the skeletal muscles, pedalling movements, dilation of the pupils, loss of consciousness, jaw clenching, possible sialorrhoea, and evacuation of urine and faeces. The seizures can originate in one cerebral hemisphere, and extend to the other, or originate in the thalamus. These seizures, also known as gran mal seizures, can last a few seconds or minutes; when there is no recovery between seizures and these continue (for 5 minutes or more) the condition is defined status epilepticus which can cause neurological lesions and necrosis. Status epilepticus can also present as prolonged convulsions interspersed by periods of unconsciousness.5The so-called cluster seizures are multiple convulsions repeated in a period of 1-24 hours. Between one seizure and the next, the patient usually recovers a normal mental and motor state, with a post-ictal phase; in some cases, however, the patient can remain unconscious.

A patient with status epilepticus must be admitted to hospital and treated because the condition can compromise vital functions, preventing normal ventilation (respiratory acidosis) and tissue perfusion (metabolic acidosis). Seizures can be managed with domiciliary treatments. Seizures can be divided into a pre-crisis or pre-ictal phase which may not be manifested or recognized, an ictal phase and a post-ictal phase. During the pre-ictal phase, which can last from a few seconds to hours or even days, it may be possible to note behavioural changes: the animal is very often agitated and seeks its owner. The ictal phase corresponds to the true seizure, with the characteristic signs. The post-ictal phase lasts a very variable time, from a few minutes to some days, and the signs manifested during this period are also heterogeneous; they can include weakness, disorientation, fear, mydriasis, transitory blindness of central origin and polyphagia.

 

DIFFERENTIAL DIAGNOSIS

The causes of seizures can be divided into two broad classes: intracranial and extracranial. The extracranial causes are generally metabolic disorders or systemic diseases that produce alterations in the electrophysiological state of the brain tissue and are more frequently responsible for generalised seizures. They can be due to:

  • accumulation of toxins (e.g., hepatic and renal failure);
  • metabolic disorders (e.g., hypoglycaemia, hyperlipidaemia, hypocalcaemia, hypothyroidism);
  • hypoxia;
  • hyperthermia;
  • intoxication (e.g., theobromine, caffeine, organophosphates, lead, strychnine);
  • intestinal parasites.

The intracranial disorders identified as primary causes of seizures are:

  • congenital disorders (e.g., malformations);
  • cerebral neoplasms;
  • inflammation (e.g., encephalitis);
  • degeneration (e.g., due to ischaemia);
  • trauma.

 

TREATMENT OF STATUS EPILEPTICUS

The drugs of choice for the immediate treatment of status epilepticus are the benzodiazepines that rapidly enter the central nervous system, such as diazepam and midazolam. Both of these act by potentiating the inhibitory effect of GABA, facilitating the hyperpolarisation of neurones and interrupting the seizures. The dose of diazepam is 0.5-1 mg/kg as a slow intravenous bolus; if the patient is receiving long-term treatment with phenobarbital it may be necessary to increase the dose up to 2 mg/kg because of the induction of enzymes caused by the chronic metabolism of the barbiturate. The dose of midazolam is 0.3-0.5 mg/kg given intravenously or intramuscularly; this latter route of administration is possible by using an aqueous vehicle for the midazolam. When a vascular access cannot be obtained, benzodiazepines can be administered intranasally or via the rectal route at a dose of 1-2 mg/kg. If treatment with benzodiazepines is effective in controlling the seizures, but their duration of effect is too short, continuous infusions can be given at a rate of 0.5-2 mg/kg/hour for diazepam and at a rate of 0.05-0.3 mg/kg/hour for midazolam.

Patients refractory to treatment with benzodiazepines must be treated with barbiturates such as pentobarbital and phenobarbital; the former is administered at a dose of 2-15 mg/kg intravenously to reached the desired effect. Pentobarbital can arrest seizures, but, unlike phenobarbital, it is not considered an anticonvulsant. The dose of phenobarbital is 2-15 mg/kg intramuscularly.

An alternative to barbiturates is propofol, which has anticonvulsant GABA agonist activity. The dose of propofol is 1-8 mg/kg intravenously to reached the desired effect. If it is effective, but its duration of action is too short, it can be administered as a continuous infusion at a rate of 0.01-0.25 mg/kg/hour; when administered as a constant rate infusion, the respiratory function and haemodynamics of the animal must be monitored carefully.  Levetiracetam has also been used recently: the dose of this drug is 20 mg/kg administered as an intravenous bolus.5 The mechanism of action of this drug is not yet clear; it does not seem to act through the common neurotransmitters or ion channels. It is excreted in the urine, not metabolised by the liver and has been shown to reduce the frequency of seizures in the cat.6 It is a well-tolerated drug and can be used in association with phenobarbital in cats with idiopathic epilepsy.

Besides administering anticonvulsant drugs, the patient must be stabilised by controlling any hyperthermia, since convulsions can cause a dramatic increase in body temperature (to greater than 40.5°C). Hyperthermic patients must be given fluids at room temperature, bathed with cool water and, if necessary, cooled with a fan; these strategies should be used to bring the temperature to 39.5°C (if continued below this temperature there is a risk of causing hypothermia). The use of ice applied to the surface of the body is not recommended as this can cause local vasoconstriction which hampers the dispersion of heat. Hyperthermia can cause disseminated intravascular coagulation, hypoglycaemia, acid-base disorders, hypotension, pulmonary oedema and compromised cerebral function.

A perfusion defect may be the consequence of vasodilatation secondary to hyperthermia or due to volume distribution shock. Patients with inadequate perfusion must be given resuscitation treatment with fluids. Patients not  responding to fluid therapy should be given a vasoactive amine such as dopamine, dobutamine or noradrenaline. Patients receiving anticonvulsant treatment by continuous infusion, particularly with barbiturates or propofol, can develop hypoxia and hypercapnia which must be carefully monitored and treated with oxygen therapy or positive pressure ventilation. Cerebral oedema is a common consequence of a violent seizure and can be treated with mannitol, which reduces cerebral oedema and improves cerebral perfusion. Mannitol is administered at a dose of 0.5-1.5 g/kg in an intravenous bolus over 15-20 minutes and its effects last about 1.5-6 hours. It must only be administered to animals that are haemodynamically stable and, being an osmotic diuretic, can cause electrolyte imbalances (in particular, hyponatraemia and hypokalaemia) which must be managed in advance by administering balanced crystalloid solutions. Hypotensive patients with suspected cerebral oedema can also be given hypertonic saline solution 7% at a dose of 2-4 ml/kg intravenously.

Once the patient has been stabilised (both haemodynamically and neurologically), treatment with phenobarbital and potassium bromide can be planned. Phenobarbital is the barbiturate most widely used in seizures in both dogs and cat. It has a long half-life (from 40 to 90 hours) and 10-15 days are needed to reach the steady state serum concentration. The initial dose for maintenance therapy is 2-8 mg/kg bid per os. The levels of phenobarbital in the blood must be maintained in the therapeutic interval between 15 and 45 mg/ml. The dose of barbiturate may be reduced when the barbiturate is administered together with potassium bromide (KBr) since this latter, which is excreted through the kidneys, potentiates the effect of phenobarbital without affecting liver function. Potassium bromide has a long half-life (about 24 days) and 120 days are required for it to reach a steady state serum concentration. The loading dose to administer during status epilepticus is 100-150 mg/kg bid per os for 2 days.

Gabapentin and pregabalin are drugs that are structurally similar to GABA;30-40% of gabapentin is metabolised in the liver in dogs and this drug, unlike phenobarbital, does not cause enzymatic induction. The dose of gabapentin in the dog is 25-60 mg/kg/die divided into three or four doses, whereas the suggested dose in the cat is 5-10 mg/kg bid or tid. A combination of gabapentin, phenobarbital and potassium bromide can increase the inter-ictal period in epileptic dogs by reducing the frequency of the convulsions and shortening the post-ictal recovery period.9,10 Gabapentin is, however, little used because of its high cost. Pregabalin has anticonvulsant activity, is thought to act on synaptic calcium channels, inhibiting the release of excitatory neurotransmitters, and is the subject of study and evaluation.11

The mechanism of action of zonisamide, an anticonvulsant approved for use in humans, is not yet clear. It is thought that it can inhibit calcium channels in the brain, that it is a GABA agonist and glutamate antagonist, and that it has dopaminergic and serotoninergic actions. It is metabolised mainly by the liver. The suggested dose is 5 mg/kg every 12 hours but in subjects with microsomal enzyme induction, the dose can be increased up to 10 mg/kg every 12 hours. This drug can also be given rectally, at a dose of 30 mg/kg every 12 hours. It has been demonstrated to be able to reduce the frequency of seizures by as much as 50% in dogs with epilepsy refractory to phenobarbital.5 The limitations to its use are the induction of liver enzymes and its cost.12,13

 

References

  1. Podell M. Seizures in dogs. Vet Clin North Am Small Anim Pract 1996; 26:779.
  2. Quesnel AD, Parent JM, McDonell W. Clinical management and outcome of cats with seizure disorders:30 cases (1991-1993). J Am Vet Assoc 1997;210:72.
  3. Bernardini M. Neurologia del cane e del gatto. 1nd ed. Milano: Poletto editore; 2002, pp. 286-302.
  4. Crowell-Davis SL, Lappin M, Oliver JE. Stimulus-responsive psychomotor epilepsy in a doberman pinscher. J Am Anim Hosp Assoc 1989;25:57.
  5. Fletcher DJ. Seizures and anticonvulsant therapy. In: Sixteenth International Veterinary Emergency and Critical Care Symposium; 2010: San Antonio, Texas, pp. 325-328.
  6. Bailey KS, Dewey CW, Boothe DM, Barone G, Kortz GD. Levatiracetam a san adjunct to phenobarbital treatment in cat with suspected idiopathic epilepsy. J Am Vet Med Assoc 2008;232(6):867-872.
  7. March PA, Hillier A, Weisbrode SE, Mattoon JS, Johnson SE, Di Bartola SP, Brofman PJ. Superficial necrolytic dermatitis in 11 dogs with a history of phenobarbital administration (1995-2002). J Vet Intern Med 2004; 18(1):65-74.
  8. Bevier DE, Miller MA, Rohleder JJ, Wozniak AD. Pathology in practice. Superficial necrolytic dermatitis. Manca rivista 2010;237(4):365-367.
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  10. Platt SR, Adams V, Marosi LS, Abromson CJ, Pendersi J, De Stefani A, Matiasek L. Treatment with gabapentin of 11 dogs with refractory idiopathic epilepsy. Vet Rec 2006;159(26):881-884.
  11. Dewey CW, Cerda-Gonzalez S, Levine JM, Badgley BL, Ducotè JM, Silver GM, Cooper JJ, Packer RA, Lavely JA. Pregabalin a san adjunct to phenobarbital, potassium bromide, or a combination of phenobarbital and potassium bromide for treatment of dogs with suspected idiopathic epilepsy. J Am Vet Med Assoc 2009; 235(12):1442-1449.
  12. Dewey CW, Giuliano R, Boothe DM, Berg JM, Kortz GD, Joseph RJ, Budsberg SC. Zonisamide therapy for refractory idiopathic epilepsy in dogs. J Am Anim
  13. Von Klopmann T, Rambeck B, Tipold A. Prospective study of zonisamide therapy for refractory idiopathic epilepsy in dogs. Journal of Small Animal Practice 2007;48(3):134-138. Hosp Assoc 2004;40(4):285-291.