1. General motor seizure: Better known as grand mal seizures, this
type of seizure is expressed by the entire body. There is an initial
activation of neurons throughout both hemispheres of the brain.
The convulsions are symmetric. Salivation, urination, defecation,
loss of consciousness are usually observed. Tonic and clonic movements
of the limbs and jaws occur. The cause of these seizures can be:
Only one area of the body is affected. There is an initial activation of
a limited number of neurons in part of one hemisphere of the brain.
This category of seizures is considered to be of acquired etiology and
has many causes as for generalized motor seizures. It is witnessed
in all species. The seizure can be:
- simple (isolated muscle groups). The consciousness is preserved
- complex (change in behavior, fly biting, tail chasing, chewing, licking,
Consciousness is not preserved.
Psychomotor seizure is a term often used to refer to this form of seizure
activity. This term has been dropped due to its allusion to psychiatric
problem. In this form of seizure, the patient is “unresponsive”
that is, does not respond to sound nor visual cues. Amnesia is often
described in humans. The behavior seen is automatic and lasts 30
seconds to 2 minutes or more. In human literature 3 types of psychomotor
seizures are identified:
Type I -motionless stare-behavioral arrest
Type II - behavioral arrest only
Type III - drop attack, confusion, amnesia, and gradual recomposure
Psychomotor seizures must be differentiated from psychogenic nonepileptic
seizures, and nonepileptic paroxysmal disorders which are episodic (sleep
walk, dizziness, head nodding, tics such as Tourette’s, head banging,
etc.) 3. Myoclonic seizures: A sudden brief shock-like contracture
occurs. The activity is general orconfined to face, trunk, or
one or more limbs. One must be careful to differentiate these
types of seizures from myoclonus originating from spinal cord disease.
This form of seizure is better described in humans and usually not mentioned
extensively in the veterinary literature.
3. Lapse attack: This
is the petit mal seizure, or absence seizure. Here, no motor
activity is seen. There is a brief loss in consciousness.
Absence seizures, characterized by a specific EEG pattern, have not been
reported in domestic animals yet.
B. Epilepsy: Recurring seizures of any type
arising from intracranial disease of either acquired or inherited origin.
Metabolic (liver disease, hypoglycemia, etc.) and toxic causes are
excluded from this definition. They are recurrent unprovoked seizures.
One seizure alone does not represent epilepsy. However, evidence suggest
that the occurrence of one seizure puts the patient more at risk to become
an epileptic than a patient without any seizures.
C. Status epilepticus: A condition
in which seizures rapidly repeat, with no intervening stage of consciousness.
It is a neurologic emergency. If uncontrolled, it may lead to cerebral
edema, brain damage and death. Pyrexia, hypotension, hypoxia, and
metabolic acidosis are often seen and complicating. See below.
II. The Pathophysiology of Epilepsy
The normal central nervous system (CNS) can be stimulated to elicit seizures.
¨ Numerous agents can provoke seizures.
The similarity of these seizures suggest common underlying mechanisms
¨ The CNS has intrinsic inhibitory
and excitatory capabilities that suppress or promote neuronal firing.
Seizures may result from an imbalance between these two systems.
Suggested mechanisms of seizure include:
1. A defect in the neuronal membrane and ion channels:
The principal cell of the brain is the neuron. It is surrounded
by numerous supporting cells. The neuron’s stability depends on the
inside of the cell being more negative than the outside of the cell.
The membrane function is responsible for maintaining this potential of
-70 mV. The contributing factors are the electrolyte channels.
a) The fast sodium channels contribute to depolarization
or activation of the neuron. They are self limiting. When the
sodium enters the cell, it takes water along causing cell swelling and
decreasing the water around the cell. This of course magnifies
the difference in electrolyte concentrations and increases the excitability
of the tissue.
b) The calcium channels (3 are recognized) are slower.
c) The potassium channels contribute to repolarization or return
2. A defect in the GABAergic inhibitory mechanisms - insufficient
A number of receptors exist on the neuronal membrane. The GABA receptor
is well known. When GABA binds to it, the cell is less likely to
discharge. GABA is an inhibitory neurotransmitter. Many anticonvulsants
bind GABA receptors.
3. A defect in the excitatory mechanisms - excess excitation
The NMDA receptors are the focus of recent research. They are sensitive
to voltage and magnesium amongst other things. Activation of these
receptors causes excitation. Calcium influx in the cell is mediated
by NMDA receptors. The cell death is subsequent to excess calcium influx
in the cell. Cell loss in the brain causes a circuitry reorganization.
Hence the research on NMDA antagonists such as MK-801.
4. A defect in the modulatory
mechanisms that govern excitatory and inhibitory function
In epilepsy, a large population of sensoronously active neurons exists.The
seizures can occur due to hyperexcitability of multiple neurons or hypersynchrony
of neurons, even in the absence of hyperexcitability (petit mal seizures)
The progressive evolution of seizures induced by repeated electrical
or chemical activation of a variety of neural pathways. Repeated
activation by subconvulsive stimuli over a period of days to weeks causes
a gradual evolution of increasingly complex behavioral and electroencephalographic
seizures. Secondary generalized seizures eventually ensue.
Once this stage of kindling has been achieved, the susceptibility to seizures
is essentially permanent. Secondary epileptogenesis The phenomenon
of a second epileptogenic site distant from the original site that has
intrinsic epileptogenic capabilities of its own, even when the primary
focus is removed. The mechanism is not well understood. Repeated
bombardement of normal neurons by an epileptogenic focus may perhaps cause
the development of kindling or secondary epileptogenesis in the recipient
neurons. This mechanism may play a role in the gradual worsening of some
epileptics. Thus, treatment of seizures may be indicated even in cases
where clinical seizures may be considered too infrequent to bother treating.
The breed, sex, age, history of vaccines, diet, geographical location, history
of seizures in the lineage, past trauma, medical history are all crucial.
(Tables 5-8) The type of seizure witnessed also helps narrow down
the etiology (seizure history form).
Inherited epilepsy has been confirmed in only 5 breeds: Beagle, German
Shepherd Dog, Tervuren Shepherd, Horak’s dogs (research dogs), and Dachshunds.
A number of breeds are suspected to have familial epilepsy but extensive
research is still required to confirm inheritance. Most recently,
the Golden Retriever is being added to the inherited epilepsy list.
The work required to demonstrate inheritance and the mode of inheritance
is extensive and large number of dogs and breedings are necessary.
Males seen to be about 5 times more often affected than females.
One report on seizure classification examined 50 dogs and states that “44%
of dogs had primary epilepsy (idiopathic or without identifiable cause),
46% had secondary epilepsy (identifiable intracranial cause), and 10% had
reactive epilepsy (metabolic or transient noxious cause).” It appears
that “the diagnosis of secondary epilepsy was statistically more probable
when the dog was less than 1 or more than 7 years old at the first seizure,
when the first seizure was a partial seizure, or when the first seizure
occurred between midnight and 8 AM. A diagnosis of reactive epilepsy
was statistically more probable only when the interval between the first
and second seizure was brief (<= 4 weeks). A diagnosis of primary
epilepsy was statistically more probable when the dog was between 1 and
5 years of age at the first seizure, when the dog was a large breed (>15
kg), when the seizure occurred between 8 AM and midnight, or when
the interval between the first and second seizure was long (> 4 weeks).”
(Podell et. al. JAVMA Vol 206(11) 1995: 1721-1728)
physical and neurologic examinations
assistance here is the video of the patients seizure events.
seizures are caused by metabolic disturbances. A complete blood count
(CBC), and chemistry panel with electrolytes will help rule out some causes
of seizures. The blood glucose level at the time of seizure is important.
Urinalysis is also needed for the metabolic work up. If a metabolic
problem is detected, it is addressed and dealt with promptly. If the
work up is normal, then the suspicion for epilepsy arises. Examples
of metabolic disorders are listed in the Table.
These may be required depending on the most likely cause of the seizure.
For example, a puppy with normal blood work and seizures should be tested
for canine Distemper virus.
E. Electroencephalography (EEG)
This test in not readily accessible. It is difficult to run and
requires the expertise of a well trained neurologist to interpret it.
The test takes about a hour to run and necessitates patient cooperation
as movement will interfere with the recording. The EEG assists the
clinician is confirming seizure occurrence, localizing them to focal vs
multifocal vs generalized and thus being able to decide on the most appropriate
test. EEG may also rule out the possibility of seizure activity.
The equipment is expensive and requires technical help. The University
of Wisconsin in Madison has an EEG and we are currently training for its
Magnetic Resonance Imaging (MRI) or Computer Aided Tomography (CAT) scans
are available to image the brain and rule out some of the causes of epilepsy
such as cancer, granulomatous meningoencephalomyelitis (GME-an immune meningitis),
trauma, congenital anomalies, and so on.
G. Spinal tap
analysis of the spinal fluid can assist in the diagnosis of brain disease
and causes of epilepsy. The cell count and amount of protein are
measured. The type of cells seen also is of value.
IV. Treating Seizures When to start treatment?
DIAGNOSIS = PROPER TREATMENT
- Acquired epilepsy should be treated based on the diagnosis
- brain cancer - surgery and/or radiation, steroids
- GME - radiation and/or steroids
- infections - treat with appropriate antibacterial or antifungal, +/-
- congenital or anomalies - surgery or appropriate drug therapy (diuretics,
- trauma - surgery, diuretics, steroids
Inherited epilepsy is very difficult to confirm in most breeds as discussed
above. Hence, once the blood work, imaging and spinal fluid analysis
are normal, the best a clinician can do is diagnosis idiopathic epilepsy.
The term “idiopathic” basically means that no specific cause can be identified
for the seizures. But anticonvulsant therapy is now necessary to
manage them. Most large dogs tend to kindle and hence require therapy
if they seizure more often than once every 4 months. Smaller dogs
are often allowed to seizure once a month before therapy is started.
The true deciding factors are the owners, the progression of the seizures’
severity and frequency and the postictal phase.
Independent of the diagnosis, almost all patients with epilepsy need
some form of anticonvulsant therapy at some point in time. The next
section will discuss the drugs available and how they work. Just remember
that NO DRUG IS EFFECTIVE IN ALL CASES.
Many drugs act on GABA (phenobarbital, benzodiazepines). These drugs
are particularly useful for general tonic-clonic seizures, partial
seizures, and partial complex seizures.
Principles of anticonvulsant therapy:
- Thorough work up
- Knowledge of pharmacokinetics of the drugs used
- Trough drug levels
- Therapeutic ranges
- Multiple drug usage - paradoxical intoxication
- Elderly or pregnant patients - decrease proteins can affect effect
of drug The more rapidly serum drug concentration are reached, the better
the success. Thus it is best to start with higher dosages or a
Problems with anticonvulsant therapy:
- The medication is changed too quickly, before therapeutic range is
reached. Therefore change therapy only after the highest possible
level is reached.
- Monotherapy is superior to polytherapy
- Poor record keeping
- Drug interactions (antibiotics, antacids, cardiac drugs, steroids,
- Renal or hepatic diseases
1. Mechanism of action: PB
binds to GABA receptor at a specific barbituate binding site. In
the presence of GABA, the chloride channels are open for longer
period of time and hyperpolarization occurs (the inside of the cell
becomes more negative). PB also decreased the effects of glutamate,
an excitatory neurotransmitter, and blocks the response to NMDA.
2. Steady state of the drug is reached
in about 10 to 14 days.
3. The therapeutic range in the dog
is 15-45 ug/ml. The dose is adjusted based on the serum levels. There
exists a linear correlation between the dose and the level.
4. The major side effects are sedation,
drinking too much (polydypsea), urinating excessively (polyuria), and
eating too much (polyphagia). PB is suspected to be hepatotoxic.
Even though elevations of liver enzymes are frequent, hepatotoxicity is
not yet proven. To monitor the drug therapy, serum levels of PB
and chemistry panel are performed 2 weeks after every dose adjustment
and once a year once maintenance is achieved. Libido is reported
to be affected in humans.
5. Drug interactions can be encountered.
Some drugs potentiate the effects of PB
6. Therapy is terminated once the
patient has had no seizure within 6-12 months. Decreasing the drug
by 20% every 2-4 weeks is recommended.
1. Mechanism of action is the same
as PB. Primidone is metabolized to PB and phenylethylmalonamide
(PEMA), and primidone. 85% of the anticonvulsant activity is due
to PB. PEMA is a very weak anticonvulsant.
2. The half life is shorter than
that of PB. It takes 5 and 1/2 half lives for a drug to stabilize.
3. Monitoring is done by assessing
PB serum levels.
4. Primidone has been proven to be
hepatotoxic and it is sometimes necessary to switch to PB. When
this is the case, one must know that the ratio primidone to PB is 5:1.
C. Potassium Bromide
1. The mechanism of action depends
on the small size of bromide (Br-) compared to chloride (Cl-). The bromide
ion replaces the chloride and enters the cell faster, making the inside
of the cell more negative and less likely to discharge. The half
life is 25 days in the dog. Hence, levels are not stable for about
4 to 5 months. But because toxic levels can be reached sooner, the
first check should be performed 6 weeks after initiating therapy.
2. The therapeutic range of bromide
in the serum is 1000 to 1500 ppm. This range is greater when the
patient is also on PB.
3. Side effects are rare. But
sedation and wobbliness are noted. In people, GI signs, rashes,
and emotional disturbances are noted. Whether or not KBr toxicity
or potentiation of PB exists is uncertain but some patients on both drugs
have shown more severe side effects. The idiosyncratic psychosis
reported in human is difficult to document in animals. Avoid in
4. KBr was the first anticonvulsant
used but went out of style with new drugs coming in the market.
Recently, it has been used more and more for refractory seizures in children.
In dogs, it is most commonly used as a combination therapy, added on to
the PB. Currently, studies are undergoing to evaluate
the effect of KBr in dogs as a sole anticonvulsant.
1. Mechanism of action is the same
for all. They bind to specific benzodiazepine receptors on the GABA
2. The half life in dogs is very
short and thus the drug is of little use for maintenance therapy.
3. Diazepam (Valium) is however the
first choice for status epilepticus treatment because it acts so fast
(very lipid soluble). Diazepam is now being investigated for rectal
use which would be an excellent method of administration for the owner.
Newer benzodiazepines are available on the market.
4. Clobazam is 8-10 times less sedative
than other benzodiazepines but this drug is not as potent as diazepam.
It is used mostly for clonic seizures in humans.
5. Clorazepate (Tranxene) may be
useful in dogs because they do not develop tolerance to the drug.
6. Clonazepam appears to act longer
in dogs and is not as sedative as Diazepam.
7. Side effects include tolerance
1. This drug is of questionable value
in dogs as the half life is very brief and extremely high doses are needed
to control seizures.
2. Avoid combining with primidone
as it enhances that drug’s hepatotoxicity.
3. Mephenytoin is a derivative of
phenytoin and has be used by some people. It is best used as an
adjunct drug. Reports of success could be anecdotal.
Similar to phenytoin in composition but not in action. It inhibits
calcium influx into the cell.
G. Newer Anticonvulsants Names to look for
in the near future are
¨ Clobazam - see above
¨ Felbamate - mechanism unknown;
less potent than other drugs in people but less side effects.
¨ Eterobarb - less sedative than
¨ Ralitoline - modifies membrane
¨ Flumarizine - reduces the influx
of calcium in the cell
¨ Levatiracetam (Keppra) – 250 mg
per day for 5 days, then 500 mg per day fior 5 days, then 500 mg BID.
Drugs working on the GABA system
- Vigabatrin - irreversibly inhibits GABA degradation
- Stiripentol - inhibits GABA uptake and degradation
- Progabide - GABA agonist
- Milacemide - is metabolized to an inhibitory neurotransmitter (glycine)
- Gabapentin - can cross the blood brain barrier very well
- Lamotrigine - inhibits the release of excitatory amino acids (glutamate)
H. Ketogenic Diet
This diet was first described in 1921 by Wilder. The recommendations
were high fat and low carbohydrate diet. This leads to ketosis and acidosis.
The basic principles of this diet were to imitate the effects of starvation
which were known to suppress seizures. The mechanism of the diet remains
unknown. A transient acidosis (increase acid) within the cell is suspected. This
decreased neuronal excitability. This diet has not been tried in dogs.
This diet is mostly used in children for refractory seizures, absence
seizures, myoclonic seizures, akinetic and atonic attacks. Here are
some of the guidelines.
1 gram/Kg of protein and the rest in fat.
Only small amount of carbohydrate
Fat to carbohydrate ratio should be 3:1.
This is called the Ketogenic potential to antiketogenic potential ratio.
0.9 (gram fat) + 0.46 (gram protein)
(gram carbohydrate) + 0.1 (gram fat) + 0.58 (gram protein)
The ketogenic diet: 87% of the calories come from fat, 6%
from carbohydrates, 7% from protein. The Medium Chain Triglyceride
diet is more palatable and does not increase cholesterol. This
diet requires 60% medium chain triglycerides, 11% other fats, 19% carbohydrates,
and 10% proteins.
I. Vagal Nerve Stimulation
Pacemaker device implanted in the neck to repetitively stimulate the
vagus nerve. Mechanism of action may be related to effects on the
noradrenergic neurons in the brainstem or release of inhibitory glycine
and GABA or stimulation of the RAS in the brainstem
J. Gold bead therapy and acupuncture
Control studies are lacking.