1. Workup and treatment of Topic Rounds, 8/21/12 Dharshan Neravanda, DVM, Diplomate ACVIM (Neurology)

2. Definition  Excessive or hypersynchronous activity in the cerebrum  Focal/partial seizures involve a select group of neurons  Generalized seizures involve the entire cerebrum

3. Neurons are Excitable Cells  A seizure focus is a hyperexcitable area  Inhibitory neurotransmitters  GABA (gamma aminobutyric acid)  Glycine  Excitatory neurotransmitters  Glutamate  Aspartate

4. Generalized Seizure  Tonic: sustained muscle contraction  Loss of consciousness (usually)  Opisthotonus and extensor rigidity  Salivation, urination, defecation  Breathing is affected  Clonic: paddling, jerking, chewing

5. 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)

6. Focal Seizure (complex)  Impaired consciousness  Bizarre behavior (limbic system)  Aggression  Extreme fear

7. Not a Seizure  Narcolepsy/cataplexy  Syncope

8. Not a Seizure  Vestibular event  Head-bobbers  Involuntary movement disorders

9. What is a Seizure?  Stereotypical  Involuntary  Abnormal EEG during the event

10. 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

11. Causes of Seizures VITAMIND

12. Intracranial Vascular Infectious inflammatory Anomaly Idiopathic Neoplasia Extracranial Toxic Metabolic

13. Vascular  Stroke- a sudden interruption of blood supply  Hemorrhagic  Ischemic

14. Infectious  Bacterial  Viral  Rickettsial  Fungal  Protozoal  Parasitic

15. Inflammatory (autoimmune)  Small breed dogs  Poodle, Maltese, Pug, Yorkie, Shih-Tzu, Lhasa  1-7 years old  Can be multifocal localization  Seizures  Vestibular

16. Inflammatory (autoimmune)  Diagnosis based on CSF tap  Diagnosis can be masked by steroids  Evidence usually persists on MRI

17. Inflammatory (autoimmune)  GME  Pug dog encephalitis  Necrotizing encephalitis of Yorkshire Terriers

18. Trauma  Current trauma can cause seizures by direct concussive damage  Can cause hemorrhage  Can set up a focus for seizures in the future

19. Toxins  Lead  Ethylene glycol  Metaldehyde

20. Anomalous  Consider age  Hydrocephalus  Lissencephaly  Cortical dysplasia  Cyst  Many other oddball malformations

21. Metabolic  Hypoglycemia  1.  2.  3.  4.  5.  6.  7.

22. Metabolic  Hypoglycemia  1.Paraneoplastic  1.  2.  3.  4.

23. Metabolic  Hypoglycemia  1.Paraneoplastic  1. Insulinoma  2. Leiomyosarcoma  3. Giant hepatoma  4. Lymphoma

24. Metabolic  Hypoglycemia  1. Paraneoplastic  2.  3.  4.  5.  6.  7.

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

26. Metabolic  Hypoglycemia  Hepatic encephalopathy  Hyper/hypo- natremia  Hyper/hypo- calcemia  Uremia  Increased viscosity (triglycerides, RBC)

27. Idiopathic  Age at onset:  Breed:  Neuro exam:  Type of SZ:

28. Idiopathic criteria  Age at onset: 1 to 6 years  Breed: Purebreed (genetic)  Neuro exam: Normal interictal exam  Type of SZ: Generalized or Partial

29. 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

30. Neoplasia Primary Meningioma Glioma Lymphoma Histiocytic sarcoma Choroid plexus tumor Metastatic Hemangiosarcoma Prostatic Mammary gland

31. Diagnostics  CBC  Chemistry panel  Urinalysis  Chest radiographs  MRI  CSF analysis

32. Goals of Treatment  Stop seizures  Decrease seizure frequency  Decrease seizure severity

33. 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

34. When NOT to start treatment?  Single seizure  Infrequent seizures  Provoked seizure?

35. 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

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

37. Treatment of status  Stop 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!

38. Treatment of status epilepticus  Systemic support  A-B-Cs  Flow-by oxygen  Treat hyperthermia down to 102 deg F

39. After the seizure stops…  Prevent the next ones:  Phenobarbital  Levetiracetam  Diazepam CRI

40. 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

41. 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.

42. 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

43. 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

44. Refractory Status Epilepticus  Phenobarbital infusion 2-4 mg/kg/hr  Maximum 24 mg/kg in 24 hours  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

45. 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

46. Causes of Status Epilepticus Idiopathic Extracranial Intracranial

47. Causes of Status Epilepticus  10% of idiopathic epileptics will have status epilepticus at some point in their life

48. Treatment of idiopathic epilepsy  Phenobarbital  Bromide  Levetiracetam  Zonisamide  Gabapentin  Pregabalin  Felbamate

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

50. Phenobarbital  80% success (n=15)  40% seizure free for at least 6 months  40% had at least 50% decreased SZ frequency  20% refractory

51. 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

52. Phenobarbital Side Effects Transient Ataxia and weakness Sedation if loaded Predictable PU/PD/PPPantingWeight gain Dose related SedationHepatotoxicity Idiosyncratic CytopeniasDyskinesia Superficial necrolytic dermatitis

53. 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  Dyskinesia 53

54. 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

55. 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

56. 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.

57. 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

58. 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

59. 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

60. 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)

61. 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

62. 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

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

64. Questions