EpilepsEpilepsyy

ABDULAZIZ ALRUWAISHID, MDABDULAZIZ ALRUWAISHID, MD

الرحيم الرحمن الله الرحيم بسم الرحمن الله بسم

"َق" ل َخ" )ِذ&ي ال )ه& &ل ل +َح"م+ُد( "َق" ال ل َخ" )ِذ&ي ال )ه& &ل ل +َح"م+ُد( الَو"َج"َع"َل" ْر+َض"

" َو"اَأل م"اَو"اِت& َو"َج"َع"َل" الس) ْر+َض"" َو"اَأل م"اَو"اِت& الس)

)ِذ&ين" ال (م) ُث 9وْر" َو"الُّن (م"اِت& )ِذ&ين" الُّظ9ل ال (م) ُث 9وْر" َو"الُّن (م"اِت& الُّظ9ل(وَن" "َع+ُد&ل ي <ِه&م ب &ر" ب + َوا "َف"ر( (وَن" َك "َع+ُد&ل ي <ِه&م ب &ر" ب + َوا "َف"ر( َك

EpilepsyEpilepsy

►DefinitionDefinition►TypesTypes►CausesCauses►TreatmentsTreatments►EffectsEffects►Prognosis Prognosis

Treatment optionsTreatment options

►Medications:Medications: AEDAED Others (steroid, Acetazolamide)Others (steroid, Acetazolamide)

►Vagal nerve stimulationVagal nerve stimulation►Magnatic brain stimulation Magnatic brain stimulation ►Diet / fasting Diet / fasting ►SurgerySurgery

EpilepsyEpilepsy► incidence of epilepsy in children incidence of epilepsy in children

50-100/100,000 50-100/100,000 [[Hauser and Hesdorffer, 1980; Hauser and Hesdorffer, 1980; Hauser, 1994]. Hauser, 1994].

►AEDs are primary treatment modality AEDs are primary treatment modality ►30% of children with epilepsy have:30% of children with epilepsy have:

intractable seizures intractable seizures suffer adverse medication effects suffer adverse medication effects [Pellock, 1993, [Pellock, 1993,

1995, 1996; Heller et al., 1993; Pellock and Pippenger, 1993; Patsalos and 1995, 1996; Heller et al., 1993; Pellock and Pippenger, 1993; Patsalos and Duncan, 1993].Duncan, 1993].

► limited number of children benefit limited number of children benefit from surgical therapy.from surgical therapy.

NEUROTRANSMITTERSNEUROTRANSMITTERSSEROTONIN

GABA

DOPAMINE

NOREPINEPHRINE

EPINEPHRINE

Glutamate

Glycine

Endorphins

Risks of seizures to childrenRisks of seizures to children

► higher rates of mortality higher rates of mortality ► AccidentsAccidents► InjuriesInjuries► cognitive and psychiatric impairmentcognitive and psychiatric impairment► poorer self-esteem poorer self-esteem ► higher levels of anxiety and depression higher levels of anxiety and depression ► social stigmatization or isolation social stigmatization or isolation ► treatment is fundamental to improving treatment is fundamental to improving

overall outcome in childhood epilepsyoverall outcome in childhood epilepsy

Case ICase I

► Basem is an 8 year old boy with uncontrolled Basem is an 8 year old boy with uncontrolled seizureseizure

► Unremakable pernatal historyUnremakable pernatal history► Seizure started at 3 month of age Seizure started at 3 month of age ► Developmental history: global delay with Developmental history: global delay with

hyperactivity and poor verbal communicationhyperactivity and poor verbal communication► EEG: EEG:

slow background activityslow background activity generalized epileptiform discharges generalized epileptiform discharges

► AED used so far: Depakin, Tegretol, Topamax, AED used so far: Depakin, Tegretol, Topamax, Lamictal, keppra, Acetazolamide (Diamox)Lamictal, keppra, Acetazolamide (Diamox)

► MRI brain: normalMRI brain: normal

Case IICase II

► A 6-year-old girl was referred to epilepsy clinic A 6-year-old girl was referred to epilepsy clinic with a history of intractable complex partial with a history of intractable complex partial seizuresseizures

► Right hemiparesis was noticed in 1Right hemiparesis was noticed in 1stst year of life. year of life. ► Exam revealed right hemiparesis & mild Exam revealed right hemiparesis & mild

cognitive delaycognitive delay► tried on 6 AED without any benefit. tried on 6 AED without any benefit. ► After 4:1 ketogenic diet initiation, the patient After 4:1 ketogenic diet initiation, the patient

was able to stop all medications and remained was able to stop all medications and remained completely seizure-free for more than 2 years. completely seizure-free for more than 2 years.

► Currently, the patient remains seizure-free on a 3 Currently, the patient remains seizure-free on a 3 to 1 ratio dietto 1 ratio diet

1910 –1980s

Advent of new anti-epileptic medications Phenobarbitone 1912 Phenytoin 1938 Carbamazepine 1972 Sodium valproate 1974 Clonazepam 1974 Clobazam 1979

KetogenKetogenic Dietic Diet

History

►Initiated in the 1920s

►1970s MCT diet introduced

►1990s resurgence of interest

Ketogenic DietKetogenic Diet

► is a high-fat, low carbohydrate diet is a high-fat, low carbohydrate diet ►mimicks metabolic state of fasting. mimicks metabolic state of fasting. ►During a prolonged fast, body energy During a prolonged fast, body energy

requirements are met by: requirements are met by: lipolysis lipolysis oxidation of fatty acids (no breakdown of oxidation of fatty acids (no breakdown of

carbohydrates)carbohydrates)

►misconception is that the brain can only use glucose for fuel

History of ketogenic dietHistory of ketogenic diet

►In 1920s: starvation resulted in decrease in seizure frequency

►KD became less popular after appearance of AED (diphenylhydantoin & phenobarbital)

►Research have proven the efficacy of KD in intractable epilepsy of adults and pediatric patients including infants

What are ketone bodies?

►3 ketone bodies: acetoacetate (AcAc) beta-hydroxybutyrate (BHB) acetone.

►AcAc & BHB are produced from condensation of acetyl-CoA (incomplete breakdown of FFA) in the liver

►1/3 of AcAc is converted to acetone, which is excreted in the breath and urine.

Functions of ketones in the body

►is to replace glucose as a fat-derived fuel for the brain brain can derive up to 75% of its total

energy requirements from ketone bodies Ketones decrease production of glucose in

the liver

What is ketosis?

►indicates an overall shift from a glucose based metabolism to a fat based metabolism.

►occurs in physiological states: fasting consumption of a high fat diet after exercise (called post-exercise

ketosis). ►2 potentially fatal metabolic states:

diabetic ketoacidosis and alcoholic ketoacidosis.

►FFA availability to the liver: dietary fat release of stored body fat.

►Normally, ketone bodies are present in bloodstream in minute amounts, approximately 0.1 mmol/dl

►Ketosis is defined clinically as a ketone concentration above 0.2 mmol/dl

►Mild ketosis: 2 mmol occurs following aerobic exercise

►Ketoacidosis is defined as ketone concentration above 7 mmol/dl.

►Diabetic and alcoholic ketoacidosis result in ketone concentrations up to 25 mmol

Comparison of ketone concentrations under different

conditionsMetabolic state Ketone body concentration

(mmol/dl)► Mixed diet 0.1► Ketosis 0.2► Fasting 2-3 days 1► Post-exercise Up to 2► Fasting 1 week 5► Ketogenic diet 5-6► Fasting 3-4 weeks 6-8► Ketoacidosis 8+► Diabetic ketoacidosis Up to 25

Efficacy of the Ketogenic DietEfficacy of the Ketogenic Diet► KD is an effective treatment for children with KD is an effective treatment for children with

epilepsyepilepsy [Wheless, 1995a, b; Lefever and Aronson, 2000; Levy and Cooper, [Wheless, 1995a, b; Lefever and Aronson, 2000; Levy and Cooper, 2003].2003].

► Nordli et al. :Nordli et al. : 32 infants, 32 infants, 17 of whom had infantile spasms 17 of whom had infantile spasms 71 % were able to maintain robust ketosis. 71 % were able to maintain robust ketosis. 19.4 % became seizure-free19.4 % became seizure-free 35.5 % (50 percent reduction)35.5 % (50 percent reduction) effective for children with infantile spasms. effective for children with infantile spasms.

► Kossoff et al. (infantile spasms) 4-year period Kossoff et al. (infantile spasms) 4-year period [Kossoff et al., 2002]. [Kossoff et al., 2002]. 23 children, (5 mon-2 yrs), 39 % had symptomatic 23 children, (5 mon-2 yrs), 39 % had symptomatic

infantile spasms infantile spasms 70 % hypsarrhythmia, were started on ketogenic diet.70 % hypsarrhythmia, were started on ketogenic diet.

How does the ketogenic diet How does the ketogenic diet workwork??

► Direct Anticonvulsant properties (BHB)► 2-Deoxy-D-glucose: a glucose analog that inhibits a glucose analog that inhibits

glycolysis by blocking phosphoglucose isomeraseglycolysis by blocking phosphoglucose isomerase

► BAD: Bcl-2associated death promotor Neuroprotective mechanism for induced cell death

► M-TOR:► Glutamate:

Direct inhibition of vesicular glutamate loading by ketone bodies

m-TOR pathwaym-TOR pathway

► is a protein kinase that integrates energy, nutrient, and GF signals to regulate cellular functions.

► important regulator of cellular changes involved in epileptogenesis.

► is activated by signaling in presence of nutrients

► inhibited in energy deprivation

Dysregulated mTOR

►in genetic & acquired epilepsy TSC cortical malformations traumatic brain injury (Wong, 2010).

► Rapamycin (-) prevents development of epilepsy and mechanisms that cause epileptogenesis in animal models of TSC and KA-induced SE (Zeng et al., 2008, 2009).

► mTOR can be modulated by KD

►Rapamycin treatment after SE blocked hippocampal mTOR activation decreased mossy fiber sprouting in dentate

gyrus reduced spontaneous seizures

►KD inhibits mTOR pathway signaling in: brain and liver of healthy rats prevents late hippocampal mTOR activation

after KA-induced SE.Epilepsia, 52(3):e7–e11, 2011

m-TORm-TOR►mTORC1 is sensitive to rapamycin and mTORC1 is sensitive to rapamycin and

integrates inputs from at least 5 major integrates inputs from at least 5 major signals:signals: growth factorsgrowth factors genotoxic stressgenotoxic stress energy statusenergy status oxygenoxygen amino acidsamino acids

►to regulate cell growth and proliferationto regulate cell growth and proliferation

Bcl-2-associated death promoteBcl-2-associated death promote (BAD)(BAD) protein protein

►regulate apoptosis by controlling regulate apoptosis by controlling mitochondrial permeabilitymitochondrial permeability

► from cytosol: translocate to mitochondria from cytosol: translocate to mitochondria following death signaling & promote release following death signaling & promote release of cytochrome c of cytochrome c

► translocates to mitochondria & forms a translocates to mitochondria & forms a

pro-apoptotic complexpro-apoptotic complex► translocation is inhibited by survival factors translocation is inhibited by survival factors

that induce phosphorylation of Badthat induce phosphorylation of Bad

Ketogenic DietKetogenic Diet

► may protect against apoptosis via:

increased levels of protective protein calbindin

prevention of accumulation of pro–cell-death protein clusterin

Types of ketogenic dietsTypes of ketogenic diets

►Classic ketogenic dietClassic ketogenic diet►Medium-chain triglyceride (MCT) dietMedium-chain triglyceride (MCT) diet► Modified Atkin diet (MAD)Modified Atkin diet (MAD)► LOW GLYCEMIC INDEX LOW GLYCEMIC INDEX

Uses of Ketogenic Diet

►Epilepsy Intractable epilepsy Super-refractory status epilepticus Dravet syndrome Myoclonic astatic epilepsy

►Metabolic disorders Glucose transporter type 1 deficiency Pyruvate dehydrogenase complex

deficiency Phosphofructokinase deficiency McArdle disease

Uses of Ketogenic Diet

►Neurologic disorders Alzheimer disease Parkinson’s disease Amyotrophic lateral sclerosis Traumatic brain injury Autism Depression Migraine

Epileptic Epileptic syndromesyndrome

► Landau-Kleffner Landau-Kleffner syndromesyndrome

► Lennox-Gastaut Lennox-Gastaut syndromesyndrome

► Dravet syndromeDravet syndrome► Myoclonic astatic Myoclonic astatic

epilepsyepilepsy► Infantile spasms/West Infantile spasms/West

SyndromeSyndrome

Genetic Disorders

• Tuberous sclerosis• Lissencephaly• Rett syndrome• Mitochondrial disorders • Glucose transporter type 1 (GLUT-1)

Conditions Treated with Conditions Treated with Ketogenic DietKetogenic Diet

► Glucose transporter deficiency syndromeGlucose transporter deficiency syndrome► Pyruvate dehydrogenase complex deficiencyPyruvate dehydrogenase complex deficiency► Leigh's syndromeLeigh's syndrome► cerebral dysgenesiscerebral dysgenesis► Succinic semialdehyde dehydrogenase Succinic semialdehyde dehydrogenase

deficiencydeficiency► Phosphofructokinase deficiencyPhosphofructokinase deficiency► Mitochondrial respiratory chain complex Mitochondrial respiratory chain complex

defectsdefects► Ketotic hypoglycemiaKetotic hypoglycemia► Glycogenosis type V (McArdle's disease)Glycogenosis type V (McArdle's disease)► Rett's syndromeRett's syndrome

Contraindications of Ketogenic Contraindications of Ketogenic DietDiet

►Pyruvate carboxylase deficiencyPyruvate carboxylase deficiency►Organic aciduriasOrganic acidurias►PorphyriaPorphyria►Carnitine deficiency (primary)Carnitine deficiency (primary)►Carnitine palmitoyltransferase Carnitine palmitoyltransferase

deficiencydeficiency►Carnitine translocase deficiencyCarnitine translocase deficiency►Glutaric aciduria, type IIGlutaric aciduria, type II

Candidates for ketogenic Candidates for ketogenic dietdiet??

High-fat foodsHigh-fat foods

►butterbutter ►heavy creamheavy cream ►oiloil ►mayonnaisemayonnaise ►cream cheesecream cheese ►cheesecheese

High-carbohydrate foodsHigh-carbohydrate foods

► fruit and fruit juice fruit and fruit juice ►breads and cereals breads and cereals ►vegetables (corn, peas, and potatoes) vegetables (corn, peas, and potatoes) ►beans beans ►milk milk ►soda soda ►snack foods (chips, snack cakes, snack foods (chips, snack cakes,

crackers) crackers) ►sweets sweets

Sample ketogenic mealSample ketogenic meal

► 60 g heavy cream 60 g heavy cream ► 21 g strawberries 21 g strawberries ► 53 g eggs 53 g eggs ► 10 g cheddar cheese 10 g cheddar cheese ► 21 g butter 21 g butter

Sample ketogenic shake

500 g Ross Carbohydrate-free Formula (concentrate)

270 g heavy cream

13 g Egg Beaters

Initiation of the Ketogenic Initiation of the Ketogenic DietDiet

Day 1Day 1►     ▪▪       Maintenance fluidsMaintenance fluids

    ▪▪       Check urine ketones each void Check urine ketones each void    ▪▪       Check fingerstick blood glucose every Check fingerstick blood glucose every 6 hr6 hr    ▪▪       Initial EEG, laboratory tests Initial EEG, laboratory tests    ▪▪       Simplify antiepileptic drug (AED) Simplify antiepileptic drug (AED) regimen; regimen;

► change to low carbohydrate or change to low carbohydrate or carbohydrate-free formulationcarbohydrate-free formulation    ▪▪       Dietitian consultation Dietitian consultation    ▪▪       Education Education

Initiation of the Ketogenic Initiation of the Ketogenic DietDiet

Day 2Day 2►     ▪▪    4:1 ratio (3:1 infants) with 1/3 total 4:1 ratio (3:1 infants) with 1/3 total

calories calories     ▪▪    Then 2/3 total calories for 2Then 2/3 total calories for 2––3 meals3 meals    ▪▪    Stop fingerstick blood glucose checksStop fingerstick blood glucose checks

Day 3Day 3►     ▪▪       First regular meal on 4:1 ratioFirst regular meal on 4:1 ratio

    ▪▪       Discharge Discharge –– AED regimen AED regimen    ▪▪       B vitamins, sugar-free multivitamin B vitamins, sugar-free multivitamin    ▪▪       Calcium supplements Calcium supplements

Ketogenic Diet MaintenanceKetogenic Diet Maintenance

11    MonthMonth►     ▪▪    Neurologist, dietitian, nurse, social Neurologist, dietitian, nurse, social

workerworker    ▪▪    Adjust diet as neededAdjust diet as needed    ▪▪      CBC, platelets; AED; serum lipid, CBC, platelets; AED; serum lipid, carnitine carnitine     ▪▪       Urine calcium, creatinine Urine calcium, creatinine

3, 6, and 12 Months3, 6, and 12 Months►     ▪▪    Neurologist, dietitian, nurseNeurologist, dietitian, nurse

    ▪▪    CBC, platelets, serum lipid & carnitine CBC, platelets, serum lipid & carnitine profilesprofiles    ▪▪       AED level(s), urine calcium, creatinine AED level(s), urine calcium, creatinine    ▪▪       New meals New meals

Ketogenic Diet MaintenanceKetogenic Diet Maintenance

Maintain for 2 Years (Seizure-Free)Maintain for 2 Years (Seizure-Free)►     ▪▪  Shorter time interval for infantile Shorter time interval for infantile

spasms)spasms)

Wean over 1 YearWean over 1 Year►     ▪▪    3-5:13-5:1––3 months → 3:13 months → 3:1––3 months →3 months →

    ▪▪    2.5:12.5:1––3 months → 2:13 months → 2:1––3 mohths →3 mohths →    ▪▪    OffOff

Side Effects of the Ketogenic Side Effects of the Ketogenic DietDiet

► Hypovitaminosis and low calciumHypovitaminosis and low calcium► Metabolic acidosisMetabolic acidosis► Renal calculiRenal calculi► DehydrationDehydration► Nausea and vomitingNausea and vomiting► HypoglycemiaHypoglycemia► HypercholesterolemiaHypercholesterolemia► Poor weight gain and growthPoor weight gain and growth► ConstipationConstipation► Hepatic dysfunctionHepatic dysfunction