Epilepsy Treatment Flashcards
Ketogenic Diet Mechanism
Uses long chain fatty acids > break down to acetyl-CoA –> ketone bodies (specifically acetoacetate) -> acetone + beta hydroxybutyrate
Ketone bodies cross BBB –> used for energy instead of glucose
Ratios of Ketogenic diet
3:1 or 4:1 (fat:protein +carb)
Medium Chain Triglyceride (MCT) diet
Uses MCT oil as source of MC FA
More effiecient in generating ketones
Can consume more protein and carbs
Cons: GI side effects, diarrhea, vomiting, and abdominal pain
Modified Atkins Diet
0.9:1 ratio
60-65% of calories from fat
30% from protein
10% carbs
Low Glycemic Index
allows high carbohydrates, but limits carbs to low glycemic index (foods that have lower postprandial index)
All carbs glycemic index <50
Indications for diet therapy
Strongly consider:
Failed 2-3 anticonvulsants
Symptomatic generalized epilepsies
Probable benefit:
MAE, Dravet sydnrome, TS, Retts, infantile sapasm
Possibly beneficial: LKS, Lafora body disease, SSPE, mitochondrial respiratory chain complex disorders, phosphofructokinase def, FIRES, LGS, HIE, focal malformations
Conditions where Keto diet is treatment of choice
GLUT1 deficiency
Pyruvate dehydrogenase deficiency (b/c pyruvate cannot be metabolized to acetyl-coA(
Contraindications for Keto Diet
Disorders of FA metabolism defects:
- Primary carnitine deficiency
- Carnitine translocase deficiency
- Beta oxidation defects (MCAD, LCAD, SCAD)
- Pyruvate Caroxylase deficiency
Relative contraindications: FTT, if surgical focus, noncompliance, lack of parental readiness
Labs to screen for contraindications for KD
CBC, Lytes, Mg, Phos, Zinc, Selenium, LFTs, UA, UCa/Cr, UOA, SAA, ACP
Duration of KD
Range of benefit 1 - 65 days, typically within 2 weeks
KD for 3 months
If seizure free x 2 years, can consider discontinuing
,
Complications of KD
Short term: vomiting, dehydration, hypoglycemia, and excessive acidosis
Long term: growth limitations, kidney stones, dyslipidemia, GERD
Monitoring labs evert 3 months:
Check weight/height Fasting Lipid Panel BMP, Ca, Mg, Phos, CBC, Free/total carnitine Zinc Selenium Vit D Urine Ketones, BHOB Bone density scan if on for >2 years
Efficacy for diet therapy:
KD: 38% experience 50% reduction rate at 3 months
MAD:
- 45-65% had at least >50% reduction of seizurse, 35-36% with >90% seizure reduction
- 45% with 50-90% seizure reduction, 28% with >90% seizure reduction
LGIT:
38% of pts >50% decreased seizures
-24% with >90% seizure decreased
Meds with extended release formulations
Gabapentin Lamotrigine Topiramate Levetiracetam Oxcarbazepine
Brivaracetam
Sodium blocking mechanism + SV2A binding
Similar SE profile, but higher potency
Cannabidiol
Indication for Dravet, LGS
Two main animal models in screening AED candidates:
- Maximal electroshock model (MES)
2. Subcutaneous pentylenetetrazole
Maximal electroshock model (MES)
Electrical stimulation applied through the cornea –> elicits hind limb extension
Subcutaneous Pentyenetetrazole Model
Description
PTZ is injected subcut at a dose to induce at least 5 s of clonic seizures activity in 97% animals.
-Predictive of efficacy against generalized tonic-clonic activity and absences seizures
Genetic mice model DBA/2
Model for audiogenic seizures
GAERS mice models
Genetic model for absence seizures
6Hz psychomotor seizure model
6Hz pulse of 0.2ms duration through the cornia for 3 sec results in limbic seizures
Metylazoxymethanol acetate (MAM) model
Cortical dysplasia mouse model
MAM exposed in utero –> cortical dysplastic type lesions
Seizures inducted by kainate are drug resistant
Model for pharmacoresistant epilepsy
Catamenial Epilepsy
C1 = increased seizures just prior to menses
-> Responds to progesterone 200mg TID on days 14-28
C2 = increased seizures during ovulation
C3 = increased seizures with anovulatory cycles
Hormones in Catamenial Epilepsy
Estrogen –> proconvulsant
Progesterone –> Anticonvulsant
Seizures more likely to occur when ratio of progesterone to estrogen decreases (usually during menstruation or at ovulation)
ACTH used in treatment for
Infantile Spasm
Lennox Gastaut Syndrome
Landau Kleffner Sydnrome
IVIG/Steroids
Used in treatment for
Rassmussens
Limbic encephalitis
Faciobrachial dystonic seizures
Anti-LGI1 encephalitis (VGKC), anti GAD, anti thyroid, anti-NMDA
AED that REDUCE levels of OCPs
Phenytoin
Carbamazepine
Phenobarbital
Primidone
*Use alternative methods of contraception
AED that are affected by OCPs
Lamotrigine –> Estrogen reduces lamotrigine level
Teratogenicity and AED
Increased risk for major congenital malformations, 2-3x higher
Risk for lower IQ
VPA avoided in monotherapy or polytherapy in first trimester
Safest medications in Pregnancy
lamtorigine levetiracetam oxcarbazepine zonisamide Gabapentin
Less: CBZ, PHT
VNS Approval Indications
- Adjunctive therapy for pts >/= 12 years with refractory focal onset epilepsy
- Adjunctive therapy in pateints >/= 18 years with chronic or recurrent major depression episodes refractory to >4 adequate antidepressant
AED success rates in patients
Focal epilepsy 50%
Primary Generalized epilepsy 80%
Definition for refractory Epilepsy
Failure of adequate trials of two appropriate and tolerated doses of two appropriate and tolerated AED at maximum possible doses (in monotherapy or combination) for enough time
Enough time = f/u period of 3x longest interseizure interval
Clinical Indications for VNS
Refractory focal seizures not eligible for brain surgery Multifocal epilepsy Unclear seizure focus Overlapping eloquent cortex Opposed to surgery
Efficacy of VNS
18.75% of patients had >/= 50% reduction in in seizure frequency
VNS Lead placement
Lead must be placed below where the superior and inferior cervical cardiac branches separate from the Left vagus nerve.
- Stim of these nerves may cause bradycardia and/or asystole
Main vagus nerve is the largest of the three nerves
VNS electrode polarity
Bipolar lead transmit stim from the generator to the left vagus nerve
Lead consists of a pin that connects to the generator on one end and helices contain the stimulation and electrodes and anchor tether on the other end
VNS clinical trial
High group - signficant seizure reduction compared with baseline and LOW group
In High group - 31% of pts had >50% seizure reduction
In low group - 13% of pts had >50%
Side effects of VNS
In order of most common:
- Hoarseness -> due to device malfunction, nerve constriction, nerve fatigue
- Dyphagia/cough
- Dyspnea -esp with COPD/asthma
- OSA - esp during stim
- Nerve damage/pain
- Laryngeal irritation
- Lead break
- Trauma to VN
- SUDEP = not any difference than population
10: Twiddler syndrome - damage or disconnect
VNS parameters
Output current
Signal frequency
Pulse width
ON/OFF time
What VNS settings can cause degeneratve damage
High frequency (>50Hz) + ON time»_space; OFF time
Recommended starting parameters for VNS
Output current 0.25mA
On time 30s Off time 5min
Signal frequencies 20-30 Hz
Pulse width 250-500u
How do you optimize VNS?
Increase output current
Modifying on or off time
How do you manage side effects?
Decreasing signal frequencies 30 ->20 Hz
Decreasing output current (by 0.25mA)
If this doesnt achieve tolerability, lowering the pulse width 500 > 250uS.
MRI and VNS
VNS is MRI compatible
Before going to MRI –> need to set outptu current and magnet current to 0mA.
When MRI is done –> need to reprogram
Mechanism of Action of VNS
Unknown, but possibly
- Affect heart rated and respiratory rate
- Vagus-initiated activity in the brain has been localsed through fos1 immunoreactivity
- Regional brain glucose metabolism
Investigational neurostimulators
DBS and RNS
RNS
Responsive neurostimulation
-short trains of electrical stim can stop after discharges
Candidates:
- Focal seizures in eloquent cortex
- bilateral MTS
RNS Efficacy
Trials
12 weeks after: 37.9% had seizure reduction (compared to sham 17.3%
5 months postimplantation - 41.5% seizure reduction (compared 9.4%)
Open label:
50% responder rate seen in 55% of patients
44% responders at 1 year
53% at 2 years
SANTE Trial for DBS
DBS in focal epilepsy patients (with baseline 19.5 sz/month)
Implantation in the anterior nucleus of the thalamus
3months - 1/2 received stim vs no stim
Last month, simulated group had 29% greater seizure reduction compared to control
