Epilepsy and seizures

Question 1

Seizure

Answer 1

Any sudden attack or dramatic paroxysmal event.

Non-specific but is often used to describe a seizure of neurological origin (an ‘epileptic seizure’).

Other non-specific terms for epileptic seizures (often used by owners) include fits and convulsions.

Question 2

Epileptic seizure

Answer 2

A clinical manifestation of excessive activity of neurons in the cerebral cortex.

Question 3

Epilepsy

Answer 3

A disease characterised by recurrent seizures.

Question 4

Excitatory neurotransmitters

Answer 4

Glutamate
Aspartate
Acetyl choline

Question 5

Inhibitory neurotransmitters

Answer 5

GABA
Glycine
Tairine
Norepinephrine

Question 6

Seizure threshold can be affected by:

Answer 6

Structure of dendritic zones and synapses - oedema, neoplasia, inflammation

Neuronal lipoprotein cell membrane and ion channels - influenced by neurotransmitters + enzymes

Ionic environment - availability of Na, K, Ca, and Cl

Concentration of neurotransmitters

Question 7

When do focal seizures occur?

Answer 7

When the abnormal neuronal activity is restricted to an isolated region of the brain.

Question 8

Clinical signs of focal seizures

Answer 8

Usually results in lateralised and localising clinical signs such as twitching of one side of the face or flexion of a single limb (contralateral to the side of the seizure focus).

May be non-clinical, only identifiable with EEG, or observed clinically.

Question 9

Generalisation of focal seizures

Answer 9

May secondarily generalise to involve both cerebral hemispheres if the abnormal neuronal activity spreads across the midline.

Generalisation of a focal seizure may be seen in some forms of idiopathic epilepsy, such as that reported in Belgium Shepherd Dogs.

Question 10

Simple focal seizures

Answer 10

Motor signs only
e.g. episodic tremor, head turning, limb flexion, facial muscle twitch

Lateralised signs often imply contralateral forebrain lesion

Question 11

Complex focal lesions

Answer 11

Some involvement of sensory system

Examples - staring into space, fly-catching, tail chasing, aggression, manic activity

Also called automotor or psychomotor seizures

Suggest involvement of the limbic system

May progress to generalised seizure

Question 12

Generalised seizures

Answer 12

The most common type of seizure observed, especially in dogs.

Question 13

What causes generalised seizures?

Answer 13

They are caused by abnormal neuronal activity in both cerebral hemispheres

Question 14

Clinical signs of generalised seizures

Answer 14

Loss of consciousness

Bilaterally symmetric tonic/clonic skeletal muscle activity

Recumbency

+/- Jaw clenching, mydriasis, urination/defaecation, sialosis

Question 15

How long do generalised seizures usually last?

Answer 15

Most generalised seizures last for between 30 seconds and 3 minutes, and are fortunately self-limiting

Question 16

Cluster seizures

Answer 16

Defined as two or more individual seizures within a 24-hour period, with a complete recovery between events.

Question 17

Status epilepticus

Answer 17

Used to describe a seizure that is not self-limiting and is specifically used for a single seizure of greater than 5 minutes in length, or if there are two or more seizures without a complete recovery between them lasting for more than 30 minutes.

Question 18

Features of epileptic seizures

Answer 18

Prodrome

Aura

Ictus

Post-ictal signs

Question 19

Prodrome

Answer 19

A period of abnormal behaviour (such as restlessness) hours/days before a seizure.

Question 20

Aura

Answer 20

The initial focal sensory signs that occur seconds/minutes before a seizure.

In humans this often involves an unusual metallic taste or hallucinations, which may be difficult to determine in our veterinary patients.

Dogs will often appear agitated, and either hide away or seek their owner.

Question 21

Ictus

Answer 21

the seizure event itself. Seconds to minutes.

Question 22

Post-ictal signs

Answer 22

these may last for several hours (up to several days) and include disorientation, ataxia, proprioceptive deficits, blindness, pacing and polyphagia.

Question 23

Causes of epileptic seizures

Answer 23

Extracranial
- response of a normal brain to insults from inside the body (metabolic disease) or outside the body (toxins)
- reactive seizures
- generalised seizures with symmetrical neurological deficits

Intracranial
- result of structureal brain lesions or a functional inrtacranial disorder

Question 24

Metabolic causes of extracranial epileptic seizures

Answer 24

Hypoglycaemia,
Hepatic encephalopathy,
Uraemic encephalopathy,
Electrolyte abnormalities,
Hypoxia,
Hypertension,
Polycythaemia

Question 25

Toxic causes of extracranial epileptic seizures

Answer 25

Lead,
Ethylene glycol,
Organophosphates,
Metaldehyde (found in slug pellets),
Chocolate,
Strychnine,
Illegal drugs,
permethrin (cats)

Question 26

Differential diagnoses for intracranial epileptic seizures

Answer 26

V – Vascular e.g. haemorrhage or infarction

I – Infectious/Inflammatory diseases e.g. bacterial meningitis, meningoencephalitis of unknown origin (MUO), infection e.g. toxoplasmosis/neosporosis

T – Trauma – seizures may occur at the time of head trauma, or the onset of seizure activity can be delayed, often occurring at 3-6 months after trauma. Post-traumatic epilepsy has been reported in 6-10% of dogs following significant head trauma.

T - Toxic e.g. mouldy food poisoning, recreational drugs, lead

A – Anomalies e.g. malformation, hydrocephalus

M - Metabolic e.g. Hypocalcaemia, hypoglycaemia, hypo/hypernatraemia, hepatic encephalopathy

I - Idiopathic epilepsy

N – Neoplastic disease e.g. glioma, meningioma, lymphoma, metastatic disease

D – Degenerative e.g. lysosomal storage diseases (rare)

Question 27

Idiopathic epilepsy (IE)

Answer 27

A functional intracranial disorder where the lowered seizure threshold is likely to be influenced by genetic, environmental and developmental factors, and is reported to be inherited in certain breeds of dog, including Border Collies, Labradors and German Shepherds.

It is the most common cause of seizures seen in dogs but is possibly less common in cats due to their more diverse genetic background.

Question 28

Is it a seizure?

Answer 28

Clinical history from the owner

Owner description and videos of the event

Diary of dates, times, possible predisposing factors

Toxin exposure

Behaviour between and before/after the event – seizures are often followed by a post-ictal phase which is absent in many other forms of paroxysmal event (e.g. syncope).

Travel, vaccination status, antiparasitic treatment

Previous possible trauma

Other signs of metabolic disease

Muscle tone during the event – usually increased in seizures and decreased (‘floppy’) in events such as syncope.

Presence of autonomic signs – absent during most movement disorders and other paroxysmal episodes

Can the animal be distracted by their owner during an episode

Electroencephalography (EEG) during an episode – only definitive test

Response to anti-epileptic medications

Question 29

Seizure mimics

Answer 29

Syncope or cardiorespiratory disease

Pain or orthopaedic disease e.g. cervical disc disease resulting in marked cervical muscle spasms and apparent poor response to owner interaction secondary to pain

Acute vestibular attack

Collapse/weakness e.g. Addison’s disease, Hypoglycaemia

Narcolepsy/cataplexy

Stereotypical behaviours or obsessive compulsive behaviour disorders

Fulminant myasthenia gravis

Neuromuscular causes for collapse, involuntary muscle tremors or contractions (tetanus, myoclonus, myotonia)

‘Movement disorders’ or ‘paroxysmal dyskinesias’– these are a poorly characterised group of disorders associated with episodic involuntary movements but with retained consciousness / normal mentation. Whether these represent a form of focal seizure disorder remains controversial for some conditions!

OCD behavioural changes
Sleep movements (e.g. REM sleep)

Question 30

Signalment for seizures

Answer 30

Age:
○ <1 year old – Portosystemic shunt, hydrocephalus, hypoglycaemia, infectious diseases such as canine distemper virus encephalitis
○ 1-6 years old – Idiopathic epilepsy is most likely
○ >6yrs old – brain neoplasia, hypoglycaemia due to insulinoma, inflammatory disease, (idiopathic)

Breed:
○ Purebred dogs in general more likely to suffer with idiopathic epilepsy.
○ Certain breeds known to be predisposed including: Beagle, Boxer, Cavalier King Charles, Dachshund, Labrador and Golden Retriever, Poodle, Hungarian Viszla, St Bernard, Border Collie
○ Cardiorespiratory disease; BOAS

Question 31

History of seizures

Answer 31

Onset and course – age at onset, relationship to exercise or feeding

Progression if more than one event (e.g. inflammatory diseases and neoplasia can progress rapidly) and frequency of the episodes

Post-ictal and inter-ictal behaviour/mental status/gait

Vaccination status

Travel history

Other animals affected? – contagious infections, toxin exposure, familial history

Diet – thiamine deficiency

Medical history – previous seizures, trauma, toxins, smoke inhalation, other neoplasms, behaviour changes, PUPD, concurrent medications etc.

Question 32

General clinical examination for seizure

Answer 32

vital to assess for signs of systemic disease that may cause seizures (extracranial disorders), mimic seizures (e.g. syncope) or that will affect prognosis and/or anaesthetic risk.

Cardiorespiratory disease, evidence of neoplasia, vomiting/regurgitation (myasthenia), evidence of coagulopathy, blood pressure.

Question 33

Full neurological examination for seizures

Answer 33

Should be performed in the inter-ictal period if possible to avoid overlap of post-ictal signs such as ataxia and depression.

Also note that anti-epileptic medications can cause sedation and ataxia and influence the neurological assessment.

Important tests include mentation, cranial nerves especially menace testing and postural reactions.

The neuroanatomical localisation for an animal that is having seizures should always be the forebrain.

Interictal neurological deficits that would also be consistent with a forebrain disorder include a contralateral menace deficit, contralateral proprioceptive deficits, contralateral reduced nasal septum nociception, central blindness (vision loss with normal pupillary light reflexes), head turn, circling, depression/obtundation, and possibly neck pain.

Question 34

Blood and urine tests for seizures

Answer 34

Haematology: evidence of inflammation, infection, coagulopathy

Serum biochemistry: electrolytes, glucose, urea, liver enzymes

Routine urinalysis: evidence of renal disease, possible predisposing factor for hypertension

Other tests that can be performed dependent on the case include:
§ thyroid assessment (T4/TSH),
§ bile acid stimulation testing +/- serum ammonia (especially in young animals suspected of having a portosystemic shunt),
§ fructosamine and insulin levels if insulinoma is suspected,
§ clotting times,
§ urine protein:creatinine ratio,
§ serum serology or PCR for infectious diseases (Toxoplasma, Neospora, Distemper, FeLV/FIV etc).

Question 35

Blood pressure test for seizure

Answer 35

hypertension can be a cause of seizures, especially in older cats.

Question 36

Abdominal and thoracic radiographs and/or abdominal ultrasound for seizures

Answer 36

if neoplasia or an extracranial cause is suspected or supported by clinical examination and blood/urine results.

Thoracic radiographs - metastatic neoplasia, cardiac disease

Abdominal ultrasound - portosystemic shunt, neoplasia

Brain MRI or CT; MRI is gold standard, CT usually adequate for gross abnormalities

Question 37

Advanced imaging - CT/MRI for seizures

Answer 37

Specific indications include:
○ Seizures starting <6 months or >6 years,
○ Cluster seizures or status epilepticus,
○ Inter-ictal neurological deficits consistent with a forebrain lesion,
○ Refractory to drug therapy despite adequate serum drug levels.

Question 38

CSF analysis for seizures

Answer 38

Can be performed under general anaesthesia after imaging to assess for changes suggestive of inflammatory brain disease, such as elevated total protein and nucleated cell counts, or to look for neoplastic cells.

Beware of post-ictal changes.

Question 39

Diagnosis of idiopathic epilepsy

Answer 39

Tier I:
· 2 or more unprovoked seizures at least 24 hours apart
· Age at onset 6mth - 6yrs
· Normal inter-ictal physical and neurological examination
· No abnormalities on haematology, serum biochemistry and urinalysis.

Tier II: Tier I and unremarkable bile acid stimulation test, brain MRI, and CSF analysis

Tier III: Tier I and II and consistent EEG abnormalities

Question 40

Seizure management

Answer 40

Individual discussion with every client

Balance between seizures and medication

Quality of life of animal and owner to be considered

Goal of therapy - manageable seizure frequency and severity, with tolerable medication side-effects

Choice of drug - phenobarbitone/ imepitoin/ potassium bromide

Monitoring requirements

Seizure diary - times, dates, predisposing factors, behavioural changes

Dietary effects, changes

Question 41

Goals of seizure management

Answer 41

The overall quality of life for the animal is most important.

Whilst seizure-freedom is the ideal management goal, this is often not achieved in veterinary patients and as few as 15-25% of dogs may become seizure-free on medication.

A commonly used definition of a ‘responder’ is if a >50% reduction in seizure frequency is seen after starting treatment.

Whether this is a satisfactory result for an individual animal (and owner) obviously depends on the initial seizure frequency before starting treatment (i.e. once a day vs. once every 2 months).

A reasonable aim for an animal with idiopathic epilepsy would be to achieve a single, short, self-limiting seizure every 3 months.

Question 42

When to start seizure treatment

Answer 42

Depends on the underlying cause for the seizures, the seizure type and frequency, the effects of the seizures on the owner, the effects on both the animal’s quality of life and the animal’s brain, and also the adverse effects and costs associated with the medications used.

It has been suggested that long-term management of idiopathic epilepsy may be more successful if treatment is started early in the course of the disease, particularly in dogs with a high seizure density (short-time interval between seizures).

However, several questionnaire studies have also demonstrated that the adverse effects of medications can have a very large impact on owner-perceived quality of life for their pets.

This is important, as dogs with epilepsy have been reported to have an increased risk of premature death as a result of euthanasia, which can be driven by a combination of emotional stress for the owner associated with owning a pet with epilepsy and economic burden.

Question 43

Guidelines for commencement of anti-epileptic drug therapy

Answer 43

Two or more seizures in a 6 month period,

Increasing frequency/severity of seizures.

Cluster seizures or status epilepticus.

An underlying progressive disease resulting in the seizures (i.e. structural epilepsy).

Severe post-ictal signs (e.g. aggression or blindness).

Question 44

Anti-epileptic medications

Answer 44

Phenobarbitone

Potassium bromide

Imepitoin

Levetiracetam

Gabapentin, pregablin, zonisamide, felbamate, Na Valproate

Diazepam

Question 45

Phenobarbitone as anti-epilepsy medication

Answer 45

likely works by increasing the effects of GABA, reducing the effects of glutamate and decreasing calcium flow into neurons

takes 7-14 days to reach steady state.

The majority of dogs (70-85%) and most cats with idiopathic epilepsy will show a good response to phenobarbitone therapy.

It is currently the first line treatment of choice in cats with seizures.

Starting dose 2.5-3mg/kg BID (dogs) and 1-2mg/kg BID (cats).

Therapeutic range 15-35ug/ml.

Question 46

Adverse effects of phenobarbitone

Answer 46

Polydipsia/polyuria (PUPD),

Polyphagia and weight gain

sedation +/- ataxia (NB sedation and ataxia will often be self-limiting and resolve after 1-2 weeks),

less commonly: hepatotoxicity (either as an idiosyncratic reaction independent of dose, or associated with chronic therapy which is rare if serum levels are kept <35ug/ml), blood dyscrasias (anaemia, thrombocytopaenia, pancytopaenia – especially in the first 3 months following starting treatment) and superficial necrotising dermatitis.

Question 47

Potassium bromide (KBr)

Answer 47

MOA also poorly understood but likely enters with chloride ions causing hyperpolarisation of neuronal cell membranes.

It shows renal excretion with a very long half-life of 24-36 days, taking 2-3 months to reach steady blood levels.

It can be loaded at higher doses to achieve therapeutic serum levels more rapidly (over 2-5 days) but this approach may be associated with significant sedation and/or gastrointestinal signs.

Potassium bromide is often used as an add-on medication with phenobarbitone in dogs.

Starting dose 30-80 mg/kg SID (alone) or 30mg/kg SID (if used in combination with phenobarbitone).

Therapeutic range: 1 - 2.5 mg/ml

Adverse effects: Similar to those for phenobarbitone

Question 48

Why is prompt treatment necessary for status epilepticus?

Answer 48

Only 40% of SE will cease without treatment

Permanent cortical brain damage after 30-60 mins

Secondary epileptogenesis (new epileptic foci)

Avoid antiepileptic drug resistance

Increased mortality (25-38%)

Question 49

Does status epilepticus cause permanent brain damage in dogs?

Answer 49

Solid evidence is lacking

Case reports and case series show that dogs can suffer prolonged SE and apparently fully recover afterwards

Does prolonged SE lead to pharmaco-resistance in dogs? In humans this occurs with all drugs except NMDA receptor antagonists

How long to continue therapy in prolonged SE?

In one study, no dog presenting SE due to intoxication had further seizures once SE controlled

Do not give up trying to control seizures until all possible pharmacological options exhausted; even then the evidence for permanent neurological deficits post prolonged SE in dogs is limited

Question 50

How to stop the seizure in status epilepticus

Answer 50

Diazepam
- This can be repeated every 5-10 minutes if seizure activity persists (up to a maximum of 3 doses), and also as a cri if good response.

Phenobarbitone
- If seizures still persist after a further 15-20 minutes repeat boluses of 4-5mg/kg
Can be given slow IV every 20-30 minutes if required, up to a maximum loading dose of 16-20mg/kg.
If a chronic disease process is known or suspected, a long acting anti-epileptic such as phenobarbitone should always be started even if seizures are controlled with diazepam.

Levetiracetam
- requires diluting for slow iv injection. Can be given as alternative or before phenobarbitone, or as adjunct when seizures proving difficult to control before resorting to more general anaesthetic medication.

Propofol
- bolus given to effect (4-8mg/kg) followed by an intravenous constant rate infusion (6-12mg/kg/hr).

Ketamine
- 5mg/kg iv bolus, followed by 0.5mg/kg cri if responsive.

Medetomidine
- may be useful to control some of physical signs associated with seizure activity, although is not believed to have anti-epileptic properties.

Question 51

Underlying aetiology in status epilepticus

Answer 51

Reactive seizures (22%). Intoxication ; commonest cause acute SE in young dogs; Metabolic (hypoglycaemia, electrolyte imbalance – ↓Ca++)

Structural epilepsy (40%); Vascular, inflammatory/infectious, traumatic, anomalous, neoplastic (commonest cause acute SE old dogs)

Idiopathic epilepsy (38%); Border collie, Australian shepherd, German shepherd, Boxer

Question 52

Correction of metabolic disturbances in status epilepticus

Answer 52

Hypoglycaemia: cause or effect. Correct with 0.5-1mg/kg 50% dextrose diluted with 5% IV over 15min

Hypoglycaemia: correct if low (or if high index of suspicion e.g. nursing bitch) with 10% calcium gluconate (1-1.5ml/kg) over 10 minutes

Hyperthermia: active cooling