SEIZURESWorkup and treatment of

Topic Rounds, 8/21/12Dharshan Neravanda, DVM, Diplomate ACVIM (Neurology)

Definition

Excessive or hypersynchronous activity in the cerebrum

Focal/partial seizures involve a select group of neurons

Generalized seizures involve the entire cerebrum

Neurons are Excitable Cells A seizure focus is a hyperexcitable

area Inhibitory neurotransmitters

GABA (gamma aminobutyric acid) Glycine

Excitatory neurotransmitters Glutamate Aspartate

Generalized Seizure

Tonic: sustained muscle contraction Loss of consciousness (usually) Opisthotonus and extensor rigidity Salivation, urination, defecation Breathing is affected

Clonic: paddling, jerking, chewing

Focal Seizures (simple) Rhythmic contraction of

facial muscles Fly biting, tail chasing

(sensory SZ) Licking or chewing at body

part Autonomic signs (salivation,

vomit, diarrhea, abdominal pain)

Focal Seizure (complex)

Impaired consciousness Bizarre behavior (limbic system)

Aggression Extreme fear

Not a Seizure

Narcolepsy/cataplexy Syncope

Not a Seizure

Vestibular event Head-bobbers Involuntary

movement disorders

What is a Seizure?

Stereotypical Involuntary Abnormal EEG during the event

Stages of a Seizure

Prodrome: hours to days prior Restlessness, vocalizing

Aura: seconds to minutes prior (the start of the SZ) Hide, clingy, agitated, vomit

Ictus Postictus: minutes to days after

Disoriented, restless, ataxic, blind, deaf

Causes of Seizures

Vascular

Stroke- a sudden interruption of blood supply Hemorrhagic Ischemic

Infectious

Bacterial Viral Rickettsial Fungal Protozoal Parasitic

Inflammatory (autoimmune)

Small breed dogs Poodle, Maltese, Pug, Yorkie, Shih-Tzu,

Lhasa 1-7 years old Can be multifocal localization

Seizures Vestibular

Inflammatory (autoimmune)

Diagnosis based on CSF tap Diagnosis can be masked by steroids Evidence usually persists on MRI

Inflammatory (autoimmune)

GME Pug dog encephalitis Necrotizing encephalitis of Yorkshire

Terriers

Trauma

Current trauma can cause seizures by direct concussive damage

Can cause hemorrhage Can set up a focus for seizures in the

future

Toxins

Lead Ethylene glycol Metaldehyde

Anomalous

Consider age Hydrocephalus Lissencephaly Cortical dysplasia Cyst Many other oddball malformations

Metabolic

Hypoglycemia 1. 2. 3. 4. 5. 6. 7.

Metabolic

Hypoglycemia 1.Paraneoplastic

1. 2. 3. 4.

Metabolic

Hypoglycemia 1.Paraneoplastic

1. Insulinoma 2. Leiomyosarcoma 3. Giant hepatoma 4. Lymphoma

Metabolic

Hypoglycemia 1. Paraneoplastic 2. 3. 4. 5. 6. 7.

Metabolic

Hypoglycemia 1. Paraneoplastic 2. Insulin overdose 3. Young anorexic toy breed 4. Liver failure 5. Addisons 6. Hunting dog 7. Sepsis

Metabolic

Hypoglycemia Hepatic encephalopathy Hyper/hypo- natremia Hyper/hypo- calcemia Uremia Increased viscosity (triglycerides,

RBC)

Idiopathic

Age at onset: Breed: Neuro exam: Type of SZ:

Idiopathic criteria

Age at onset: 1 to 6 years Breed: Purebreed (genetic) Neuro exam: Normal interictal

exam Type of SZ: Generalized or Partial

Idiopathic criteria

No medical history (toxin, travel, systemic health, medications)

Greater than 6 months of SZ as the only clinical sign

Younger dogs with severe seizures Older dogs with mild seizures

Neoplasia

Diagnostics

CBC Chemistry panel Urinalysis Chest radiographs MRI CSF analysis

Goals of Treatment

Stop seizures Decrease seizure frequency Decrease seizure severity

When to start treatment?

Any episode of status epilepticus SZ > 5minutes 2 or more SZ without full recovery of

consciousness between them Many seizures in a short period of

time Underlying progressive disorder

causing seizures

When NOT to start treatment? Single seizure Infrequent seizures Provoked seizure?

Status epilepticus

Increased autonomic discharge Tachycardia, hypertension,

hyperglycemia Skeletal muscle contractions

Hypoxia, lactic acidosis, hyperthermia Physiologic deterioration after 30

minutes Hypotension, hypoglycemia,

hyperthermia, hypoxia, myocardial damage

Treatment of status epilepticus Stop the seizure Systemic support After the seizure stops…

Treatment of statusStop the Seizure

Diazepam 0.25 to 0.5 mg/kg IV or 1 to 2 mg/kg PR

Midazolam 0.2 to 0.4 mg/kg IV or IM Can be repeated up to 3 times Higher doses are needed for dogs on

Phenobarbital Propofol to effect (4 to 6mg/kg) slowly!

Treatment of status epilepticusSystemic support

A-B-Cs Flow-by oxygen Treat hyperthermia down to 102 deg F

After the seizure stops…

Prevent the next ones: Phenobarbital Levetiracetam Diazepam CRI

After the seizure stops…

Phenobarbital is the best bet for prolonged seizure prevention 3 to 4 mg/kg doses IV Loading dose is 12-16 mg/kg in 24 hours Considered background therapy

After the seizure stops…

Levetiracetam Single injection of 60mg/kg

Undiluted over 5 minutes Extravasation does not cause tissue

damage 56% of dogs will be seizure free for 24

hours

Hardy BT, Patterson EE, Cloyd JM, Hardy RM, Leppik IE. Double-masked, placebo-controlled study of intravenous levetiracetam for the treatment of status epilepticus and acute repetitive seizures in dogs. J Vet Intern Med 2012; 26(2): 334-40.

After the seizure stops…

Choose the dose that worked and set that as the hourly rate 0.5 to 2 mg/kg/hr diluted in D5W or 0.9%

NaCl Run for about 6 hours then reduce rate Can use midazolam with same

guidelines This is short-term prevention only

Refractory Status Epilepticus Repeat phenobarbital injections

Maximum 24 mg/kg in 24 hours May get respiratory depression

Propofol to effect (4 to 8 mg/kg slowly) Give through a 25 gauge needle

If seizures return when awake, it’s time for anesthesia

Anesthetizing the status patient Must be intubated! Propofol CRI (6 to 12 mg/kg/hr) Isoflurane (stay at or below 1% MAC

to minimize cerebral vasodilation) Taper dose q2h (to effect) Remember to continue background

phenobarbital

Causes of Status Epilepticus

Causes of Status Epilepticus 10% of idiopathic epileptics will have

status epilepticus at some point in their life

Treatment of idiopathic epilepsy Phenobarbital Bromide Levetiracetam Zonisamide Gabapentin Pregabalin Felbamate

49C. J. Landmark (2007). "Targets for antiepileptic drugs in the synapse." Med Sci Monit 13(1): RA1-7

--

KNaCl Ca

+

Phenobarbital

80% success (n=15) 40% seizure free for at least 6 months 40% had at least 50% decreased SZ

frequency 20% refractory

Phenobarbital

Starting dose 2-4 mg/kg BID Takes 2-3 weeks to reach steady

state Therapeutic blood levels 15- 45

mcg/ml (n=42) Keep below 35 to avoid toxicity

Phenobarbital Side Effects

Phenobarbital Side Effects

PU/PD, polyphagia Inhibit ADH release Suppress satiety ctr.

Sedation/ataxia 1-2 weeks Occasional

hyperexcitability Liver effects

Enzyme induction Functional disturbances Cirrhosis and failure

CNS depression likely when [PB]>40 mcg/ml Respiratory

depression

Liver damage likely when [PB]>35 mcg/ml

Cytopenias Superficial necrolytic

dermatitis Dyskinesia53

Phenobarbital Monitoring

CBC and chemistry 3 months after starting Every 6 months thereafter ALP will rise, don’t freak out Keep ALT < 200

If you are confused, a bile acids challenge is the most sensitive test for liver damage

Phenobarbital Monitoring

Serum levels Keep <30 to avoid sedation Keep <35 to avoid hepatotoxicity Not needed if well controlled and mild

side effects Useful if difficult to control and worry

about giving too much Check at least 2.5 weeks after a dose

increase Do not use serum-separator tubes Sample at same # of hours after dosing

each time

Bromide Efficacy as Add-on Dose of KBr: 22-40 mg/kg/d

Decrease dose by 15% to use NaBr Efficacy as add-on: ~70% of dogs Therapeutic range: 1000-3000

mcg/ml About 50% can or discontinue PB

Aim for [Br] > 2000 mcg/ml

56

Trepanier, L. A., A. Van Schoick, et al. (1998). "Therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide alone or in combination with other anticonvulsants: 122 cases (1992-1996)." J Am Vet Med Assoc 213(10): 1449-53.

Bromide

Very long half-life (25 days) 3 weeks to get clinical effect

More rapid effect with loading dose 5 months to reach steady state

Loading dose is 400 to 600mg/kg Give over 5 days Will cause sedation and ataxia

Cheap

Bromide Side Effects

Vomiting Very salty, squirt

in bread

Transient sedation

PU/PD/PP Ataxia and

sedation Usually the dose

limiting side effects

Can become stuporous or demented

58

Constipation Muscle pain and

anisocoria One report

Pancreatitis >30 times the

rate if on KBr+PB vs. PB alone

Zonisamide

80% response rate in difficult to control epileptics on phenobarbital 60 to 80% seizure reduction in

responders Possible loss of response long-term

Can use as a first line drug Dose:

5 to 10 mg/kg BID as first line drug 10 mg/kg BID if on phenobarbital

Zonisamide side effects

Mild ataxia or paraparesis Transient vomiting Lethargy Apathy Anxiety, panting, restless (n=1) KCS (n=1) Polyarthropathy (n=1) Hepatic necrosis (n=1; idiosyncratic)

Levetiracetam

50% response rate in resistant epileptic dogs 70% seizure reduction in responders Most responders lose benefit after 4 to 8

months Good adjunct to phenobarbital in

cats 70% response rate

Levetiracetam

Don’t use as a daily anticonvulsant in dogs Use instead to prevent additional

seizures in dogs known to cluster 20mg/kg TID for 3 days Give first dose after recovery from first

seizure May cause sedation

Can use similarly in dogs with a detectable prodromal period

Levetiracetam

Can be used as a first line drug in cats 10 to 30 mg/kg TID (BID is acceptable)

Questions