the shake down: an in-depth look at epilepsy
TRANSCRIPT
The shake down: An in depth look at epilepsy
Chelsie Estey, MSc, DVM Neurology/Neurosurgery service Upstate Veterinary Specialties
Seizures Seizures are the most common neurologic problem
in small-animal medicine
Incidence of idiopathic epilepsy is between 0.5% - 5%
Some breeds have much higher incidence
Treatment dependent on underlying cause
What causes a seizure? An epileptic seizure: clinical manifestation of
excessive and/or hypersynchronous electrical activity in the cortex
Altered excitability of a group of neurons can lead to marked and prolonged depolarization
Can involve neurons in a specific region of the brain focal seizure
Entire cerebrum generalized seizure
http://vanat.cvm.umn.edu/brainAtlas/
Pathophysiology Inadequate neuronal inhibition—major inhibitory
NTs include GABA and glycine
Excessive neuronal excitation—major excitatory NTs include aspartate and glutamate
A combination of 1 & 2
http://thebark.com/content/vet-advice-seizures-dogs-and-canine-epilepsy
Resting membrane potential is normally set so neurons are not constantly firing
Close enough to threshold that they can discharge
AP generation is essential to CNS function
The control of resting potential is critical to prevent excessive discharge associated with seizures
https://primalcanine.wordpress.com/tag/infographic/
Normally a high [K+] inside a neuron and there is a high EC [Na+]
If the balance is upset (e.g. if K+ is elevated in the EC space), this can lead to depolarization that promotes abnormal activity
Primary generalized seizures
The initial clinical signs reflect involvement of both hemispheres
Impairment of consciousness is common
Motor manifestations are bilateral
Generalized tonic-clonic seizures are the most common
http://www.labrador-retriever-pet.com/seizures-in-dogs.html
Seizure classification Generalized tonic-clonic seizures
The 1st part of the seizure = tonic phase sustained contraction of all muscles
Loss of consciousness and falling
Breathing irregular or absent, and cyanosis
Salivation, urination, or defecation The tonic phase lasts for ~1 min and leads to clonic
phase paddling or rhythmic jerking of the limbs and chewing
movements
The clonic phase is usually < 1-2 min
Consciousness can be maintained
Seizure classification Tonic seizures
Consists of generalized muscle rigidity w/o clonus
Clonic seizures Paddling and jerking with no tonic component
Atonic seizures Sudden, often brief losses of muscle tone
May be a brief drop of the head, or sudden collapse
Seizure classification Myoclonic seizures
Brief contractions that may be generalized or confined to individual muscle groups
Not all myoclonic jerks are seizures
Absence seizures In people defined as abrupt, brief losses of
consciousness
Not recognized in vet med Characterized by brief episodes of unresponsiveness,
sometimes w/ facial twitching & mild limb jerking
Types of seizures: focal Initial clinical signs indicate abnormal activity in
one region of a cerebral hemisphere
Simple focal seizures do not impair consciousness
When consciousness is impaired classified as complex focal
Motor signs, autonomic signs, and behavior signs are most common
Focal seizures Focal seizures with motor signs
Rhythmic contractions of facial or masticatory muscles, abnormal movements of one limb, and turning the head to one side
Focal seizures with autonomic signs Autonomic signs include hypersalivation, vomiting,
gagging, diarrhea, and apparent abdominal pain
Focal seizures Focal seizures with abnormal behaviour
In people can cause sensory symptoms: e.g. abnormal skin or vision sensations
Seizures manifested as licking or chewing and “fly-biting” may be similar
Complex focal seizures may be manifested as impaired consciousness and bizarre behaviour, e.g. aggression or extreme, irrational fear
http://www.vetneurochesapeake.com/index.php?page=questions-about-dog-seizures
Stages of a seizure
Prodrome
A long-term indication of a forthcoming seizure
May exhibit abnormal behaviour restlessness, clinginess, and vocalizing (hours to days
before a seizure)
Not always seen
Aura
The initial sensation of a seizure before observable signs
Last seconds to minutes
Initial abnormal electrical activity in the brain
Hide, clinginess, agitation
Difference between a prodrome and an aura is that prodromes are longer and not associated with abnormal EEG
Auras are short and caused by abnormal EEG
www.canine-epilepsy.net
Ictus
The seizure itself
Postictal stage
Transient abnormalities in brain function that are caused by the ictus and appear when the ictus has ended
Disorientation, restlessness, ataxia, blindness, and deafness
Often resolve after several mins, but may last for days
http://blogs.biomedcentral.com/bmcseriesblog/2014/10/22/bmc-veterinary-research-authors-discuss-how-poor-study-design-inhibits-progress/
Reactive Seizures Reactive seizures are the reaction of a normal brain
to a systemic problem Metabolic Nutritional Toxic disorder
Structural Epilepsy
Caused by a known and identifiable structural forebrain disorder vascular, inflammatory, traumatic, anomalous/
developmental, neoplastic and degenerative diseases
Reported prevalence of structural epilepsy in dogs and cats varies 25–38% in dogs 34–87% in cats
Idiopathic epilepsy Recurrent seizures and no identifiable brain
abnormality
May have a genetic basis
Normal interictal exam
Diagnosis of exclusion
Signalment
Onset: 1st seizure between 6 mos and 6 yrs
http://newsnetwork.mayoclinic.org/discussion/epilepsy-symptoms-causes-complications-and-what-you-can-do/
Genetic basis in some breeds
Prevalence of epilepsy in certain breeds of dog has been documented to be much higher than the estimated 0.5 to 6% in the general population
Belgian shepherd Tervueren and Groenendael variants: prevalence estimated in one study to be 9.5%, and as high as 33% in one extended Belgian shepherd family (Berendt et al., 2008, 2009)
Prevalence of 18.3% was documented in Irish wolfhounds with IE
Study of Petit Basset Griffon Vendeen dogs with IE revealed a prevalence of 8.9% (Casal et al., 2006; Gullov et al., 2011).
Lifespan and epilepsy MST after the initial seizure is 2.07 yrs in Border
collies and 2.3 years in a population of different purebred and mixed-breed dogs (Proschowsky et al., 2003; Berendt et al., 2007; Hulsmeyer et al., 2010)
The life expectancy for Irish wolfhounds is shortened by ~2 yrs in IE dogs compared with seizure-free relatives > 60% of the total number of deaths in the
population were related to epilepsy (Casal et al., 2006)
Lifespan and epilepsy Study of survival in Belgian shepherds with IE
showed that the lifespan of epileptic dogs was not significantly shortened by the presence of epilepsy Epilepsy was the predominant cause of death in the
population (Gullov et al., 2012)
Feline seizures The prevalence of feline seizures has been reported
as 2.1-14%
http://pets.thenest.com/tremors-seizures-cats-8114.html
Disorders mistaken for seizures
Syncope is characterized by partial or complete loss of consciousness, lack of violent motor activity, short duration and lack of post-ictal signs
Often associated with exercise and caused by cardiac or respiratory disease
Disorders mistaken for seizures
Narcolepsy is usually manifested as episodes of flaccid paralysis or loss of consciousness precipitated by excitement such as feeding, greeting, or play
http://www.tomopop.com/dog-narcolepsy-the-growing-epidemic-11787.phtml
Disorders mistaken for seizures
Myasthenia gravis can cause stiffness, tremor, or weakness with normal consciousness
Clinical signs of MG may be induced by exercise
Some myopathies can cause similar clinical signs
Disorders mistaken for seizures
Peripheral vestibular dysfunction is characterized by ataxia, head tilt, and abnormal nystagmus with no impairment of consciousness.
Disorders mistaken for seizures
Episodes of encephalopathy can cause disorientation, ataxia, blindness, and abnormal behavior
E.g Hepatic encephalopathy
Disorders mistaken for seizures
Normal or abnormal movements during sleep consist of twitching, paddling, or vocalizing while the patient is asleep
Waking the animal can interrupt these, and there are no postictal signs
Disorders mistaken for seizures
Behavior disorders, such as stereotypy, can cause specific patterns of unusual behavior
These episodes can usually be interrupted, and there are no postictal signs.
Disorders mistaken for seizures
Pain, especially neck pain, can cause episodes of muscle rigidity or stiffness and crying
Consciousness is not impaired
Testing A CBC/chem to screen for metabolic causes of
seizures (e.g. hypoglycemia)
Serum BAs are tested in young animals to identify PSS
Blood lead with hx of possible exposure
Thyroid function is evaluated in adult dogs hypothyroidism may complicate seizures and
phenobarbital can affect thyroid testing
Testing MRI +/- CSF are indicated in dogs with:
interictal neurologic deficits seizures refractory to therapy onset of seizures <1 year or >5 years of age any cat with seizures
Patients with IE often have normal MRIs, transient MRI brain lesions secondary to seizure activity are occasionally seen
These lesions tend to be hyperintense on T2, do not distort surrounding brain parenchyma, and tend to occur in several brain regions (e.g., pyriform, temporal, and frontal lobes, and the hippocampus)
Therapy The goal of tx is to the frequency and severity of
the seizures QOL (pet and family)
Tx: seizures vs mimic
Therapeutic trial: seizure vs movement disorder
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When to start therapy? ≥ 2 seizures in 2-3 mo
SE or cluster seizures
Post-ictal behaviour
Intracranial dz, trauma
Phenobarbital The elimination t½ is 40-90 hr in the dog and
~40-50 hr in the cat after PO admin
10-15 days needed to reach steady-state
Potent inducer of hepatic microsomal enzyme activity and can lead to accelerated administration of itself as well as other hepatically metabolized drugs.
Phenobarbital The initial dose is 3-5 mg/kg orally q 12 hr in dogs
Similar range in cats Lower initial dose of 2.5 mg/kg orally q 12 hr
http://www.actavis.com.mt/en/products/Phenobarbital+-+Actavis.htm
Phenobarbital Serum levels should be checked 2 wks after
initiating therapy or changing the dose
The target range is 20-30 ug/ml
There is no clinically significant impact of the timing of blood collection (e.g trough versus peak level) in most dogs
Zonisamide ZNS is metabolized primarily by hepatic
microsomal enzymes and the t½ of elimination in dogs is ~ 15 h
The elimination t½ of ZNS is shorter in patients already receiving drugs that stimulate hepatic microsomal enzymes (e.g. phenobarbital)
http://www.heartlandvetsupply.com/p-4681-zonisamide-capsules.aspx
Zonisamide When used as add-on therapy for dogs already
receiving phenobarbital, the recommended dose regimen is 10 mg/kg PO q12 hr
Has been shown to maintain canine serum [ZNS] within the therapeutic range when used as add-on therapy
For dogs not receiving phenobarbital, it is recommended to start at 5 mg/kg PO q12 hr
Check trough serum ZNS concentrations after ~2 wks
Bromide Administered as KBr or NaBr
KBr is preferred when Na+ intake must be restricted (for example, CHF)
NaBr is preferred when K+ intake must be restricted (for example, hypoadrenocorticism)
http://www.petdoctorsofamerica.com/pharmacy/index.php/k-brovet-potassium-bromide-rx-required.html
Bromide The elimination t½ is 24 d in dogs, 11 d in cats
It takes ~ 80-120 days to reach steady-state kinetics in dogs, 6 weeks in cats
The initial maintenance dose for KBr is 20-35 mg/kg, PO SID, or divided BID
If NaBr is used, the dose should be decreased by 15% (i.e., 17-30 mg/kg) to account for the higher bromide content of the Na salt
KBr Loading 24-hour loading dose
(1) A total dose of 400-600 mg/kg of KBr is administered PO over 24 hours
(2) This is divided into doses of 100 mg/kg (the lower end of the range) q 6 hr, for a total of 4 doses
(3) If the patient appears obtunded prior to a dose, skip it and resume when the patient is alert again
(4) After loading, begin the regular dose the next day
(5) This schedule is used in patients that need adequate seizure protection immediately
(6) The patient should be hospitalized for this loading procedure
KBr Loading 5 d loading dose
(1) Administer 450 mg/kg of potassium bromide over 5 days
(2) The daily loading dose (90 mg/kg) is added to the maintenance daily dose (35 mg/kg) for a total PO dose for each of the 5 days of 125 mg/kg/day. This dose should be divided BID to avoid GI irritation
(3) On day 6, the maintenance dose is started
Bromide A serum bromide level is checked within 1 week
after loading or 3 months after starting a maintenance dose
Timing of sample collection is unimportant because of the long half-life
The target range is 1-3 mg/ml for patients taking bromide alone
1-2 mg/ml for those taking bromide and phenobarbital
Bromide Bromide competes with chloride for renal
elimination
High chloride intake increases bromide elimination, which increases the dose requirement
The chloride content of the diet should not be drastically altered during treatment
Levetiracetam (Keppra) The t½ of elimination for levetiracetam in dogs is
~4 hours
Drug is nearly 100% bioavailable following PO dose
~70%-90% of the drug is eliminated unchanged in the urine, the remainder being hydrolyzed in the serum and other organs
There is no hepatic metabolism of levetiracetam, and it is very safe in dogs
Administered IV, can be administered IM
IV administration is good in ER situations
20-30 mg/kg, PO q8 hours
Gabapentin Despite undergoing some hepatic metabolism in
dogs, there does not appear to be any appreciable induction of hepatic microsomal enzymes in this species
The elimination t½ for gabapentin in dogs is 3-4 hours
http://www.gaba-supplement.com/
Gabapentin Initial dose regimen of 10 mg/kg body weight q 8 hr,
titrate
Side effects appear to be uncommon and are typically limited to mild sedation, pelvic limb ataxia, and increased appetite with attendant weight gain
Pregabalin Canine dosage of 2-4 mg/kg body weight, q 8 hrs
Dosing should start at the low end (2 mg/kg) and be increased weekly, as needed, in order to avoid obvious side effects (e.g., sedation, ataxia).
http://www.searchhomeremedy.com/drugs-and-medications-to-treat-fibromyalgia/
Diazepam Benzodiazepines are believed to exert anticonvulsant
activity by enhancing GABA effects in the brain
Benzodiazepines are metabolized primarily by the liver
The short t½ of diazepam in dogs (2-4 hours) and development of tolerance limits the use of this drug for maintenance therapy
Diazepam is used in dogs and cats IV or rectally for emergency treatment of seizures
Fatal hepatic necrosis has been associated with oral diazepam in cats
Adjunctive AEDs When monotherapy fails
Drug level Side effects
Poor control
Pulse therapy Cluster Prodrome
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Therapeutic Monitoring After starting treatment
Dose change
Loading dose
Poor seizure control
Dose-related toxicity occur, to determine if a dose decrease is necessary
Every 6-12 months to verify that changes in pharmacokinetics or compliance have not caused change in concentration
Cluster Seizures Cluster seizures (serial seizures, acute repetitive
seizures) ≥ 2 seizures occurring over a brief period with normal
consciousness between events
Occurrence of > 3 seizures in 24 hrs should be considered an emergency May evolve into SE and should be treated
Study of 407 dogs with IE found that 41% had CS at least once during their seizure history (Monteiro et al., 2012)
A study in Border collies with confirmed IE revealed that CS occurred in 94% of the cases and SE in 53% (Hulsmeyer et al., 2010)
Cluster seizures 48% of Australian shepherd dogs diagnosed with IE
< 5 years of age had both CS and SE, 12% SE only and 20% CS only (Weissl et al., 2012)
One study with 125 cats having primary and secondary causes of seizure activity found CS in 53% and 59% of cases, respectively (Pakozdy et al., 2010)
Status epilepticus Continuous seizure ≥ 5 minutes or ≥ 2 discrete
seizures w/o full recovery of consciousness between
Relatively frequent among dogs with IE, can occur with seizure disorders of any etiology
~59% of dogs with epilepsy of any cause will have one or more episodes of SE during their life (Saito et al., 2001)
Large breed dogs are at increased risk
Status is a life-threatening emergency
Status epilepticus Seizure activity >30 minutes may cause systemic
dysfunction, including hypoxia, altered BP, and hyperthermia and can lead to temporary or permanent brain lesions
The most common type of SE is generalized tonic-clonic status
With a prolonged seizure, the clinical manifestations can eventually become subtle, with only altered mentation and small twitching movements of the face or limbs. “electromechanical disassociation” and should be
treated
ER treatment of seizures
− O2 − Stat: BG, PCV/TS, lactate, platelet count,
BUN / crea, ECG, thoracic radiographs − Obtain blood sample for CBC/chem, UA,
[AED], sampling for toxicology and infectious disease titers
− IVF
ER treatment − Administer dextrose-IV bolus (1 to 5ml 50%
dextrose) ONLY in documented hypoglycemia − Hyperthermia should be rapidly corrected − Acidosis does not usually necessitate treatment − Marked metabolic acidosis often resolves w/
stabilization − Respiratory acidosis needs immediate treatment
Treatment Initiate AED to stop all gross motor seizure activity
or to rapidly reach therapeutic serum levels in the non seizuring dog Diazepam (DZ) IV bolus 0.5 mg/kg
Wait 5 minutes for effect / repeat Rectal DZ: reserved for patients where IV access
cannot be obtained / out-of-hospital treatment TREAT EARLY
Administer diazepam at 0.5-1.0 mg/kg, IV. Repeat for a total of 3 doses as necessary to stop the seizure
The duration of anti seizure effects is 30 min or less, so a longer-lasting AED drug should also be given