the shake down: an in depth look at epilepsy

The shake down: An in depth look at epilepsy

Chelsie Estey, MSc, DVM Neurology/Neurosurgery service Upstate Veterinary Specialties

Outline   Seizure definition

  Types of seizures

  Causes

  Mimics

  Treatment

  Emergency management

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

Generalized tonic-clonic seizures

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

Focal seizure

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

Handbook of Veterinary Neurology 5th Ed

  From: Veterinary Neuroanatomy and Clinical Neurology 3rd Ed

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

Structural Epilepsy

Handbook of Veterinary Neurology 5th Ed

  From A Practical guide to canine and feline neurology 2nd Ed

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).

  From Canine and Feline epilepsy

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

From Canine and Feline Epilepsy

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


  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

Narcolepsy


  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

Myasthenia gravis


  Peripheral vestibular dysfunction is characterized by ataxia, head tilt, and abnormal nystagmus with no impairment of consciousness.

Vestibular disease


  Episodes of encephalopathy can cause disorientation, ataxia, blindness, and abnormal behavior

  E.g Hepatic encephalopathy


  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


  Behavior disorders, such as stereotypy, can cause specific patterns of unusual behavior

  These episodes can usually be interrupted, and there are no postictal signs.


  Pain, especially neck pain, can cause episodes of muscle rigidity or stiffness and crying

  Consciousness is not impaired

Seizure Mimic

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

www.pinterest.com

When to start therapy?   ≥ 2 seizures in 2-3 mo

  SE or cluster seizures

  Post-ictal behaviour

  Intracranial dz, trauma

From: Canine and Feline epilepsy

Seizure Medications

MOA


v


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


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


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


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

Keppra


  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/

Gabapentin/Pregabalin


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

Diazepam   0.5 mg/kg IV

  1.0 mg/kg if given rectally

Adjunctive AEDs   When monotherapy fails

  Drug level   Side effects

  Poor control

  Pulse therapy   Cluster   Prodrome

www.pinterest.com

Doses for dogs


Doses for cats

From Canine and Feline epilepsy

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

Seizure emergencies

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

  From Canine and Feline Epilepsy 2014

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

From Canine and Feline epilepsy

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the shake down: an in depth look at epilepsy

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