3Definitions Seizure Epilepsy The clinical manifestation of an abnormal and excessive synchronization of a population of cortical neuronsEpilepsyTendency toward recurrent seizuresUnprovoked by systemic or acute neurologic insultsSyncope secondary to arrhythmias or other cardiovascular abnormality
4Definitions Prodrome Aura Ictus Post ictus Longterm indication of seizurehours to days before seizuresAuraInitial sensation of seizure before observable signsseconds-minutes prior to seizureIctusSeizure itself, usually 1-3minutesPost ictusTransient abnormalities in brain functionSeveral hours to 1-2 days, 3-4 days (horses)
5Secondarily generalizes ClassificationseizuregeneralizedfocalNo impairmentof consciousnessTonic-clonicNo impairment of consciousness: simple: primarily abnormal motor neuron d/cTremors, head turning, facial mm twitching, salivation, mydriaasisImpairment of consciousness: complex-staring into space, tail chasing, fly/light biting, abn aggression/rage-brief episodes of loss of consciousnessSecondarily generalizes: most common, occurs in about 80-90% of dogs with IE (requires close observation to neote different staes)Tonic/clonic: most common generalized szTonic or clonicMyoclonic: repetitve brief myoclonic jerking of head, neck thxic limbsAtonicAbsence: very uncommon in animals, brief (sec), loss of consciousness, lacks motor activityAbsenceImpairment ofconsciousnessMyoclonicSecondarily generalizesTonic/clonic/atonic
6Decrease d inhibitory neurotran smitters (e.g. GABA, Glycine) ClassificationSeizureIntracranialExtracranialVascularInfect/inflTraumaAnomalyNeoplasiaCryptogenicStructuralAltered membran e function leading to excessive depolariza tion(e.g. alteration of Na/K pump; permeabili ty changes in the cell membran e secondary to hypoxia, inflammati on, or trauma, Channelo pathies)Decrease d inhibitory neurotran smitters (e.g. GABA, Glycine)Increased excitatory neurotran smitters (e.g. glutamate, aspartate, acetylcholi ne)Altered extracellul ar potassium and calcium concentrat ionToxicMetabolicFunctionalInherited/Idiopathic
7Differentials Syncope Narcolepsy/Cataplexy Vestibular episodes Movement disorders
11Lesion Localization Forebrain or Prosencephalon Includes Rostral to tentorium cerebelliIncludesCerebrum (telencephalon)Thalamus (diencephalon)Cerebrum important forBehaviorVisionHearingFine motor activityConscious perception of touch, pain (nociception), temperature, and body position (proprioception)DiencephalonPrimary sensory integrating system in CNS
12Forebrain dysfunction Altered mental status and behavior changesDepression/deliruim dementia/ stupor coma
13Gait and Posture Normal gait Postural reactions Pleurothotonus body turn toward lesionCircling (toward)Postural reactionsDeficits oncontralateral side
14Menace responseAbsent contralateral to lesionNormal PLR
15Sensory Facial hypoalgesia Hypoaesthesia on contralateral side of body HemineglectIgnore sensory input from one half of their bodyEat out of one half of bowlHemineglct:indicates forebrainlesion on contralateralside to the side ignored
17Idiopathic epilepsy Recurrent seizures with no identifiable cause Genetic predispositionCryptogenic epilepsyNo identifiable causeNo genetic predisposition
18IE: Signalment 6 months to 6 years of age Normal neurologic examinationNormal inter-ictal examinationPurebred dogJaggy: as early as three months, as late as 10 yearsAS: moderate to severe clinical course of sz activity; clusters and SE high frequency; poor control and a high initial frequency is associated with shorter survivalPoor sz control unrelated to ABCB1 mutations (MDR1)Mutations in ABCB1 gene is associated with drug responsiveness in BC: mutation was significantly more freq in epileptic BC resistant to PB tx than in epileptic BC responsive to PB treatment
19Diagnostics Minimum data base Advanced imaging?? CBC Chemistry Profile Urinalysis+/- Liver function testsAdvanced imaging??
20Who should be imaged? Asymmetrical neurologic examination Abnormal inter-ictal periodPatients > 6 years oldAll dogs??
21Treatment Goals? When to start? Maintain seizure control Limit unacceptable side effectsSeizure control ≠ eliminationWhen to start?
22Seizure therapy PRINCIPLES Life-long daily treatment Frequent reevaluations are necessaryPotentials for emergency situationsInherent risks of the drugs
23Seizure therapy When to start? Intracranial disease Status epilepticus Cluster seizures2 or > isolated events in wk period
24Phenobarbital “Broad spectrum” Increases seizure threshold Decreases spread of seizuresGood first line drugControls ~ 80% of IE dogsBinds to GABAAprolongs the duration chloride channel is openInhibits AMPA receptor (glutamate)Blocks voltage gated calcium channelsAt high concentration: can slow sodium conductance
25Phenobarbital Dose (a) Dog - 2 - 4 mg/kg every 12 hours (b) Cat – mg/kg every 12 hoursTherapeutic serum concentration(a) Dog µg / ml(b) Cats µg / mlIncreases seizure threshold and decreases spread of seizures.“Broad spectrum”Binds to GABAAprolongs the duration chloride channel is openInhibits AMPA receptor (glutamate)Blocks voltage gated calcium channelsAt high concentration: can slow sodium conductance
26How to use PB ? 45 15 2-4 mg/kg twice daily Dosing interval << T1/2 (accumulation)5.5 time T1/2 = 10 to 14 days
27Phenobarbital T1/2; Steady State (SS) Dog – 32-90 hours; 10-18 days Cat – hours; daysHorse – hours; 3-6 days90-100% BioavailablePeak conc. 4-8hrsPrimarily Hepatic metabolismUp to 25% excreted unchanged by kidneysMicrosomal enzyme action - oxidative hydroxylation to form hydroxyphenobarbital – metabolite has weak anticonvulsant activity (does not contribute). Up to 25% is excreted unchanged in the urine.
28Loading Dose Loading Total Phenobarbital loading dose: 10 to 14 daysTotal Phenobarbital loading dose:18 to 24 mg/kg intravenously over 24 hr
29Phenobarbital: adverse effects Idiosyncratic(1) Hyperexcitability(2) Acute toxic hepatopathy in dogs(3) Immune-mediated bone marrow suppression(4) Lymphadenopathy in cats (pseudolymphoma)(5) Superficial necrotizing dermatitis(6) Facial pruritus and limb edema (cat)
30Phenobarbital: adverse effects Dose-related / transient(1) Sedation(2) Polydipsia & polyuria(3) Polyphagia(less common in cats)(4) Pelvic limb weakness
31Phenobarbital: adverse effects Laboratory changes(1) Elevation of serum ALP(2) Depression of serum albumin(3) Serum T4 and fT4 significantly depressed in % dogs (minimal fluctuation in TT3)(4) Serum TSH may even be elevated in <7% dogs (slow, compensatory)(5) Cholesterol high normalPhenobarb has no effect on adrenal function testing (acth, LDDS), it will start to influence thyroid function after 3 weeks of use, and this is manifested as a low T4, low free T4, and a normal to slightly increased TSH. Some dogs do become hypertriglyceridemic. Liver values will become elevated with mild to marked increases in ALKP, ALT should be normal/high end, AST, TBILI should not be elevated with phenobarb. Liver values will usually return to normal within 6-8weeks after lowering/discontinuing medications. Cytopenias are reported and usually resolve with discontinuation, it has been reported to cause myelofibrosis, does not appear to be autoimmune.
32Potassium Bromide No biotransformation Competes with Cl- HyperpolarizationSynergistic effectsControls 80% of refractory casesEntirely excreted by kidneysHyperpolarization after traversing cl- ion channel
33Potassium Bromide 30 mg/kg/day orally T1/2 (dog): 25 to 46 days (cat 10 days)Steady state (dog): 3 to 6 monthsSerum concentration: µg/mLAdministrationOral, rectal 30mg/kg Q24hrIV (sodium bromide, reduce dose 15%)
34Potassium Bromide Loading dose : Total dose = 600 mg/kg Divided over 4 days = 150 mg/kg/dayRisks = vomiting / extreme sedation
35Potassium Bromide PuPd, Polyphagia, Pruritus Hyperactivity/ behavioral changePancreatitis (with PB)?Asthma in catsAllergic Pneumonitis 35-42%IdiosyncraticResolves over 1-2 months
36Bromism Dose-dependant Ataxia, Sedation Pelvic limb stiffness and weakness
37Benzodiazepines Mechanism of Action Increase the frequency of the chloride channel openingHyperpolarizes cell
38Diazepam Half-life: Develop tolerance to medication Dogs ~ 3hrsCat ~ 8-10hrsDevelop tolerance to medicationRapid withdrawal may induce seizures
39Diazepam Emergency management of seizures Limited use in dogs 0.5-1 mg/kg divided bid - tidSteady state in daysMonitor liver enzymes after 5 days due to risk of hepatic necrosis
40Adjunctive Medication Clorazepate Metabolized to nordiazepamTolerance develops but slower than to diazepam0.5 mg/kg q8-12 hrsUseful for ‘breakthroughs’ as only effective for 2 months
41Gabapentin / PREGABALIN Structural analogue of GABABinds to the a2-d sub-unit of high voltage pre-synaptic calcium channelsDecreases NT releaseHalf-life 3-4 hrs30% metabolized in liverrest unchanged in urinePregabalin – increased affinity for alpha2 subunit of voltage gated calcium channels and in some dogs can be used Q12hrsliver (n-methylgabapentin)
42Gabapentin (Neurontin) Metabolized in liverT1/2 3-4 hrs10-20 mg/kg TID PO50% improved controlDo not use liquid formulation!
43Levetiracetam Binds to a synaptic vesicle (SVA2) Half-Life 2-4 hrs Modulates of neurotransmitter release, reuptake, recyclingHalf-Life 2-4 hrsExcreted primarily through kidneyHONEYMOON EFFECTDogs develop recurrence of seizure frequency – tolerance?
44Levetiracetam 20 mg/kg tid PO (Keppra XR?) Use higher dose when with PB50% improved controlIV use in emergenciesAtaxia & sedation
45Zonisamide Synthetic sulfonamide “Broad spectrum”/multi-modal Half-life 17 hrs (dog), ~35 hrs (cat)Liver metabolismMechanism of action (multi-modal)Blockade of voltage gated channels Sodium, T-Type calciumEnhancement of GABA functionModulation of serotonin, acetylcholine, serotoninMay have free radical properties
47Felbamate Mechanism of action Inhibits NMDA and kainate receptor activationInhibits voltage dependent Na+ channelsHigh bioavailabilityT ½ of 4-6 hours70% excreted in urine unchanged, 30% liverSide Effectsblood dyscrasias, hepatotoxicityMechanism of actionInhibits NMDA and kainate receptor activationInhibits voltage dependent Na+ channels
48Status epilepticus Definition: seizure activity > 5 min Cluster seizures: 2 or > seizures in a 12 to 24 hour periodAnticonvulsants: drug to stop seizure activityAntiepileptic: drug to prevent seizure activity
49Status epilepticus ADMISSION MANAGEMENT History Rectal temperature – cool if >104˚F/40˚CBlood work – Electrolytes/ Ca++ / Glucose / bile acids / Toxicity screen / PCV / TP+/- Dextrose 10% solution; 100 mg/kg IVOxygen administration+/- IV catheter
50Status epilepticus Treatment #1 Stop seizure activity1. Diazepammg/kg IV, mg/kg rectally or INMidazolam 0.2 mg/kg IV/IM/nasally2. Phenobarbital 2-4 mg/kg IV/IMOnset of action ~20 minq 30 min intervals if needed (20-24 mg/kg/24 hr)
51Status epilepticus Treatment #2 Valium/midazolam CRImg/kg/hour IV CRI in 0.9% salineRespiratory depression possibleReduce dose q3-6 hr to effect
52Status epilepticus Treatment #3 Levetiracetam (Keppra) IVAnticonvulsant and anti-epileptic20 to 60 mg/kg IV over 2 minutes lasts 8 hours (dilute)
53Status epilepticus Treatment #4 Barbituate comaPentobarbital mg/kg IV to effectProfound respiratory and cardiac depressionEspecially if toxin induced seizuresPropofol comaAnticonvulsant propertiesBolus 1-4 mg/kg IV to effectCRI ( mg/kg/min)Consider expense
54Status epilepticus Treatment #5 Last Ditch!!Inhalational Anesthesia vs. thiopentalKetamine – 5mg/kg IV then 5 mg/kg/hrPotassium bromide rectally – 100 mg/kg q4hrs 6 doses
55Status epilepticus Treatment #6 Cerebral edema?Oxygen and FluidsMethylprednisolone sodium succinate?Furosemide 1.0 mg/kg IM, IVMannitol 20% 0.5 g/kg IV
56Status epileptus Post seizure management Thoracic and Abdominal imagingUrinalysis / Indwelling urinary catheterECGCT / MRICSF+/-Gastric lavage