Alternative approaches to conventional Alternative approaches to conventional antiepileptic drugs in the management antiepileptic drugs in the management

of pediatric epilepsyof pediatric epilepsy

Dr. Vijay Sardana

MD,DM (Neurology)

Head Department of Neurology

Medical College, Kota

Epilepsy- Pharmacological Epilepsy- Pharmacological treatmentstreatments

• 1850s-Bromides1850s-Bromides• 1912-Phenobarbital1912-Phenobarbital• Last 2 decades- Many AEDsLast 2 decades- Many AEDs

• Seizure control achieved in 75 % Seizure control achieved in 75 % children with conventional AEDschildren with conventional AEDs

• Increasing concern amongst parents Increasing concern amongst parents about side effectsabout side effects

• Non conventional methods may have Non conventional methods may have role in intractable seizure/AED role in intractable seizure/AED toxicitytoxicity

Non conventional methodsNon conventional methods

• Evidence base Evidence base • non randomized uncontrolled trialsnon randomized uncontrolled trials• Retrospective StudiesRetrospective Studies

• Steroids in West SyndromeSteroids in West Syndrome

• Epilepsy SurgeryEpilepsy Surgery• Strong evidenceStrong evidence

Non conventional antiepileptic drug (AED) Non conventional antiepileptic drug (AED) treatment of Epilepsytreatment of Epilepsy

• Non-AED medical treatmentNon-AED medical treatment• Steroids (for example, ACTH [tetracosactide], Steroids (for example, ACTH [tetracosactide],

prednisolone)prednisolone)• Intravenous immunoglobulinsIntravenous immunoglobulins• Vitamins (for example, pyridoxine, pyridoxal Vitamins (for example, pyridoxine, pyridoxal

phosphate, biotin, folinic acid)phosphate, biotin, folinic acid)• MelatoninMelatonin

• Dietary manipulationDietary manipulation• Ketogenic dietKetogenic diet• Classical ketogenic dietClassical ketogenic diet• MCT dietMCT diet• Atkins dietAtkins diet• Oligoantigenic dietOligoantigenic diet

• Epilepsy Surgery TechniquesEpilepsy Surgery Techniques

• Lesional surgery (for example, tumour, amygdalo-Lesional surgery (for example, tumour, amygdalo-hippocampectomy, temporal lobectomy, extra-temporal hippocampectomy, temporal lobectomy, extra-temporal resections, anatomical hemispherectomy or functional resections, anatomical hemispherectomy or functional hemispherotomy, removal of cortical seizure foci)hemispherotomy, removal of cortical seizure foci)

• Specific surgical techniques (for example, sub-pial Specific surgical techniques (for example, sub-pial transection for Landau-Kleffner syndrome)transection for Landau-Kleffner syndrome)

• Palliative surgery (for example, callosotomy or vagus Palliative surgery (for example, callosotomy or vagus nerve stimulator implantation)nerve stimulator implantation)

Non conventional antiepileptic drug (AED) Non conventional antiepileptic drug (AED) treatment of Epilepsy contd.treatment of Epilepsy contd.

Non-pharmacological treatment of epilepsyNon-pharmacological treatment of epilepsy

• Lifestyle changesLifestyle changes• ExerciseExercise• Avoidance of sleep deprivationAvoidance of sleep deprivation• Avoidance of excessive alcohol consumptionAvoidance of excessive alcohol consumption

• Psychological approachesPsychological approaches• Techniques to abort seizures or reduce seizure Techniques to abort seizures or reduce seizure

frequency (for example, avoidance, relaxation, frequency (for example, avoidance, relaxation, biofeedback, aversive therapy)biofeedback, aversive therapy)

• Promotion of emotional wellbeingPromotion of emotional wellbeing (for example, Yoga)(for example, Yoga)• Reduction of psychiatric co-morbidity Reduction of psychiatric co-morbidity (for example, anxiety or depression)(for example, anxiety or depression)• Coping strategies for living with epilepsyCoping strategies for living with epilepsy (for example, CBT, counseling, psychotherapy, (for example, CBT, counseling, psychotherapy,

educational interventionseducational interventions))

Non-pharmacological treatment of Non-pharmacological treatment of epilepsy (contd.)epilepsy (contd.)

• Alternative therapyAlternative therapy• Herbal medicineHerbal medicine• HomeopathyHomeopathy

• OthersOthers• AromatherapyAromatherapy• HypnosisHypnosis• AcupunctureAcupuncture• Seizure alert dogsSeizure alert dogs

• 1958 – Intramuscular ACTH in West Syndrome1958 – Intramuscular ACTH in West Syndrome• Tetracosactide (UK)Tetracosactide (UK)

Hydrocortisone (France)Hydrocortisone (France)PrednisolonePrednisolone

• Also effective in – Non convulsive Status Also effective in – Non convulsive Status epilepticus, severe myoclonic epilepsy of infancy, epilepticus, severe myoclonic epilepsy of infancy, Lennox-Gastaut syndrome, Rasmussen’s Lennox-Gastaut syndrome, Rasmussen’s Syndrome, Landau-Kleffner syndromeSyndrome, Landau-Kleffner syndrome

• Prednisolone – 2-3 mg/kg/day x 2 weeks, taper Prednisolone – 2-3 mg/kg/day x 2 weeks, taper over 1-2 weeksover 1-2 weeks

• Mechanism – Not clearMechanism – Not clear

Non conventional Medical treatmentsNon conventional Medical treatmentsCorticosteroidsCorticosteroids

Non conventional Medical Non conventional Medical treatmentstreatments

ImmunoglobulinImmunoglobulin

• 1970- IVI1970- IVIggG for Allergic rhinitis -Epilepsy G for Allergic rhinitis -Epilepsy improvedimproved

• Tried in – West Syndrome, LGS, RSTried in – West Syndrome, LGS, RS• Dose – 100- 1000 mg / kg x 3 days, repeated Dose – 100- 1000 mg / kg x 3 days, repeated

after 1,2,3 weekafter 1,2,3 week• Mechanism – Not clearMechanism – Not clear• ExpensiveExpensive

Weak evidence Weak evidence

MelatoninMelatonin

• Chronobiotic hormone secreted by pineal Chronobiotic hormone secreted by pineal gland - regulates circadian rhythymgland - regulates circadian rhythym

• May improve Myoclonic & nocturnal seizuresMay improve Myoclonic & nocturnal seizures

• Mechanism – Improved sleep quality / Neuro Mechanism – Improved sleep quality / Neuro protectionprotection

Vitamins & EpilepsyVitamins & Epilepsy

• AEDs may lower plasma levels of Vitamins AEDs may lower plasma levels of Vitamins especially Vitamin-Despecially Vitamin-D

• General Indication of VitaminsGeneral Indication of Vitamins• Replacement therapy in inherited Replacement therapy in inherited

metabolic defectsmetabolic defects• Presumed anticonvulsant role possibly Presumed anticonvulsant role possibly

by resetting GABA & glutaminergic by resetting GABA & glutaminergic systems systems

Pyridoxine (Vitamin-B6)Pyridoxine (Vitamin-B6)

• Recessive pyridoxine dependant seizure Recessive pyridoxine dependant seizure syndromesyndrome

• Diagnosis- clinical, intractable seizures Diagnosis- clinical, intractable seizures under 18 monthsunder 18 months

• Oral Pyridoxine 100-200 mg daily, Oral Pyridoxine 100-200 mg daily, intravenous 100 mg (watch for intravenous 100 mg (watch for Respiratory arrest) Respiratory arrest)

Pyridoxal phosphatePyridoxal phosphate

• Major activated form of Vit.-B6Major activated form of Vit.-B6

• Infantile spasms, early infantile epileptic Infantile spasms, early infantile epileptic encephalopathy (Ohtahara’s syndrome)encephalopathy (Ohtahara’s syndrome)

• 50 mg/kg/day x 2 weeks 50 mg/kg/day x 2 weeks

BiotinBiotin

• Biotinidase deficiency – AR (Rare)Biotinidase deficiency – AR (Rare)

• Treatable leucoencephalopaty in Treatable leucoencephalopaty in infants and young children, intractable infants and young children, intractable seizuresseizures

• Dose - 5-20 mg Biotin supplementation Dose - 5-20 mg Biotin supplementation daily daily

Folinic acidFolinic acid

• Seizures in neonate patients not Seizures in neonate patients not responding to AEDs, Pyridoxine, Biotinresponding to AEDs, Pyridoxine, Biotin

• Rare inherited syndromeRare inherited syndrome

• Folinic acid 5-10 mg dailyFolinic acid 5-10 mg daily

Ketogenic Diet (KD)Ketogenic Diet (KD)

•Devised in 1920s, interest reawakened in 1990sDevised in 1920s, interest reawakened in 1990s

•Mimics fasting by having high Fat & low Carbohydrate Mimics fasting by having high Fat & low Carbohydrate content promoting prolonged ketone productioncontent promoting prolonged ketone production

•Mechanism- Not understoodMechanism- Not understood

•Indication - Effective alternative therapy for intractable Indication - Effective alternative therapy for intractable epilepsy/unacceptable AED toxicity or bothepilepsy/unacceptable AED toxicity or both

Overview of admission of the ketogenic dietOverview of admission of the ketogenic diet

Day Day CareCareMinus1Minus1 History / physical History / physical

Day1Day1 Admit to hospital Admit to hospital Dextrostix every Dextrostix every

6h; 6h; if<40mg/dl every if<40mg/dl every 2h; 2h; Glucose <25 mg/ dl Glucose <25 mg/ dl give 30 ml orange give 30 ml orange

juice; follow juice; follow Use carbohydrate-Use carbohydrate- free medications free medications

Day2Day2 Continue monitoring Continue monitoring

NutritionNutrition

Begin fasting after dinnerBegin fasting after dinner

FastFast

Fluids restricted to Fluids restricted to

60-75 ml/kg per day; 60-75 ml/kg per day; encourage drinkingencourage drinking

Continue fluids Continue fluids

Fast until dinner then 1/3 of Fast until dinner then 1/3 of the usual caloriesthe usual calories

Day Day Care Care

Day3Day3 Continue Continue monitoring until monitoring until

tolerating mealstolerating meals

Day 4Day 4 Continue Continue monitoringmonitoring

Day 5Day 5 Discharge reivew : Discharge reivew : medications, medications,

vitamins, monitoring, vitamins, monitoring, follow-upfollow-up

NutritionNutrition

Continue fluidsContinue fluids

Breakfast and lunch: 1/3 of Breakfast and lunch: 1/3 of calculated meal calculated meal

Dinner : 2/3 of calculated Dinner : 2/3 of calculated mealmeal

Breakfast and lunch : 2/3 of Breakfast and lunch : 2/3 of calculated mealcalculated meal

Dinner: Full ketogenic diet Dinner: Full ketogenic diet mealmeal

Breakfast : Full ketogenic Breakfast : Full ketogenic diet mealdiet meal

Overview of admission of the ketogenic diet Overview of admission of the ketogenic diet contd.contd.

Ketogenic dietKetogenic diet

• Discontinue if patient seizure free for 2 Discontinue if patient seizure free for 2 yearsyears

• ProblemsProblems• Parent commitment Parent commitment • Patient compliancePatient compliance• Frequent blood/urine monitoringFrequent blood/urine monitoring• Loss of effect after many months Loss of effect after many months

Ketogenic dietKetogenic diet

• Side effectsSide effects• GI upsetGI upset• Weight lossWeight loss• HypoglycemiaHypoglycemia• HypernatremiaHypernatremia• Vitamin & trace element deficiencyVitamin & trace element deficiency• Renal stoneRenal stone• HypertensionHypertension• AtherosclerosisAtherosclerosis

Atkins dietAtkins diet

• Popular in UK for weight reductionPopular in UK for weight reduction• Lower fat and high protein content- No Lower fat and high protein content- No

fluid or calorie restriction and no fast in fluid or calorie restriction and no fast in beginningbeginning

• Single trial (2003)- benefitSingle trial (2003)- benefit• Easier to implement and sustainEasier to implement and sustain

Oligoantigenic dietOligoantigenic diet

• Diet containing one meat, one starch, Diet containing one meat, one starch, one fruit, one vegetable, one oil, one fruit, one vegetable, one oil, multivitamins, calcium and mineral watermultivitamins, calcium and mineral water

• Headache and seizure frequency Headache and seizure frequency improved (J. pediatrics1989)improved (J. pediatrics1989)

• Unlikely to become as recognized as KDUnlikely to become as recognized as KD

Epilepsy surgeryEpilepsy surgery

• Resective surgeryResective surgery

• Disconnective Surgery Disconnective Surgery

Epilepsy SurgeryEpilepsy Surgery

Selection process – 3 stepsSelection process – 3 steps• Establish epileptic nature and intractabilityEstablish epileptic nature and intractability• Match the patient to one on remediable Match the patient to one on remediable

syndromessyndromes• Mesiall Temporal epilepsyMesiall Temporal epilepsy• Lesional partial epilepsyLesional partial epilepsy• Diffuse hemisphiric syndromeDiffuse hemisphiric syndrome• Secondary generalized epilepsy in infants and Secondary generalized epilepsy in infants and

ChildrenChildren• Sec. generalized epilepsy in older patientsSec. generalized epilepsy in older patients

• Consider functional intervention if not suitable Consider functional intervention if not suitable for resective surgeryfor resective surgery

Epilepsy surgery : work upEpilepsy surgery : work up

• Clinical HistoryClinical History

• Neuro Radiological investigations Neuro Radiological investigations • MRI (epilepsy protocol)MRI (epilepsy protocol)• SPECTSPECT• PETPET• fMRIfMRI

• Neurophysiological investigationsNeurophysiological investigations• EEGEEG• Video TelemetryVideo Telemetry

• Neuro psychological investigationsNeuro psychological investigations

• Quality of life and psychiatric assessments esp. in older childremQuality of life and psychiatric assessments esp. in older childrem

Vagal Nerve stimulation (VNS)Vagal Nerve stimulation (VNS)

• 1960- Vagal stimulation influenced EEG 1960- Vagal stimulation influenced EEG activityactivity

• 1992- (Zabara et al)- vegal stimulation 1992- (Zabara et al)- vegal stimulation controlled seizures in dogs induced by IV controlled seizures in dogs induced by IV PhenyalnetetrazolePhenyalnetetrazole

• Approved in USA for refractory partial seizure Approved in USA for refractory partial seizure in > 12 yrs old patients. Europe- any age or in > 12 yrs old patients. Europe- any age or seizure typeseizure type

Vagal nerve Stimulation (VNS)Vagal nerve Stimulation (VNS)

• Left vagal nerve stimulation - fibers Left vagal nerve stimulation - fibers predominantly afferentpredominantly afferent

• Adverse effects- Fever, cough, Adverse effects- Fever, cough, headache, voice alteration, cough/cold, headache, voice alteration, cough/cold, infection, pharyngitisinfection, pharyngitis

• MRI Body – contraindicated. MRI Body – contraindicated. • MRI Head- can be performed using MRI Head- can be performed using

closed head coilclosed head coil

Non pharmacological treatmentNon pharmacological treatment

Lifestyle changes : ExerciseLifestyle changes : Exercise

• Impact on quality of life and social Impact on quality of life and social inclusion rather than seizure controlinclusion rather than seizure control

• One trial in adults (1990)- no difference in One trial in adults (1990)- no difference in seizure frequency after 4 weeks of aerobic seizure frequency after 4 weeks of aerobic exercises.exercises.

• No RCTNo RCT

Sleep hygieneSleep hygiene

• Adequate sleepAdequate sleepSleep later, get up laterSleep later, get up later

• Idiopathic generalized seizures, Idiopathic generalized seizures, JME, Temporal lobe epilepsiesJME, Temporal lobe epilepsies

AlcoholAlcohol

• Seizures within 48 Hours of Seizures within 48 Hours of excessive / binge drinkingexcessive / binge drinking

• Alcohol Alcohol Disturbed sleep Disturbed sleep Seizure precipitation Seizure precipitation

Psychological approachesPsychological approachesAvoidanceAvoidance

• Triggers – Photosensitive seizures (light), music, Triggers – Photosensitive seizures (light), music, eating, reading, hot water, chess playing, hair eating, reading, hot water, chess playing, hair brushingbrushing

• Photosensitive epilepsy – Avoidance TechniquesPhotosensitive epilepsy – Avoidance Techniques

• Sitting more than 2.5 meter from TV in well-lit roomSitting more than 2.5 meter from TV in well-lit room

• Use remote controlUse remote control

• Approach TV with one eye closeApproach TV with one eye close

• Avoid playing video games in darkened room Avoid playing video games in darkened room

Relaxation techniqueRelaxation technique

• Only one RCT in children Only one RCT in children (Dahe,1985)- only 18 patients- no (Dahe,1985)- only 18 patients- no firm conclusionfirm conclusion

• May improve seizures through May improve seizures through improved sleepimproved sleep

BiofeedbackBiofeedback

• Popular psychological tool since 1970sPopular psychological tool since 1970s

• Patient trained to increase certain frequencies (12-14 Hz) on Patient trained to increase certain frequencies (12-14 Hz) on EEG from sensory motor cortex (sensory motor rhythm)EEG from sensory motor cortex (sensory motor rhythm)

• Known to inhibit seizures in animalsKnown to inhibit seizures in animals

• Positive visual feed back with colored lights and images- 30 Positive visual feed back with colored lights and images- 30 minutes training several times / week for 3 monthsminutes training several times / week for 3 months

• Cumbersome impractical for young or cognitively impaired Cumbersome impractical for young or cognitively impaired childrenchildren

Promotion of emotional well beingPromotion of emotional well beingYogaYoga

• Stress – seizure precipitantStress – seizure precipitant

• Yoga – Believed to induce relaxation / stress Yoga – Believed to induce relaxation / stress reduction involves breathing exercise, postures, reduction involves breathing exercise, postures, meditation techniquesmeditation techniques

• Only one RCT (Ramaratnam et al,2000)- 10 Only one RCT (Ramaratnam et al,2000)- 10 patients “Sahaja yoga” 10 “Sham” yoga, 12 patients “Sahaja yoga” 10 “Sham” yoga, 12 control. Study small- no useful conclusioncontrol. Study small- no useful conclusion

• Yoga – unlikely to play role in pediatric populationYoga – unlikely to play role in pediatric population

Reduction in Psychiatric Reduction in Psychiatric Co-morbidityCo-morbidity

• Anxiety, Depression, Psychosis may Anxiety, Depression, Psychosis may complicate epilepsycomplicate epilepsy

• Antidepressants and Neuroleptics Antidepressants and Neuroleptics wherever indicatedwherever indicated

Educational interventions Educational interventions

• Residential Education programmes Residential Education programmes improves quality of lifeimproves quality of life• Improvement in knowledge and understanding of Improvement in knowledge and understanding of

EpilepsyEpilepsy• Coping with EpilepsyCoping with Epilepsy• Medicine complianceMedicine compliance• Improves social skills, scholistic performance Improves social skills, scholistic performance

Alternate (complimentary) Alternate (complimentary) therapiestherapies

Herbal medicine & HomeopathyHerbal medicine & Homeopathy

• No RCTNo RCT• Open label studies (Tyagi et al,2003)Open label studies (Tyagi et al,2003)

• Remedy containing 13 herbs in 100 patients Remedy containing 13 herbs in 100 patients had similar efficacy as phenobarbitone 3-6 had similar efficacy as phenobarbitone 3-6 mg/kgmg/kg

• Herb “Zhenxianling” (constituents -peach Herb “Zhenxianling” (constituents -peach flower buds and human placenta) given to 239 flower buds and human placenta) given to 239 patients for 6 months to 2 yrs. seizure patients for 6 months to 2 yrs. seizure reduction of > 75% in two thirdreduction of > 75% in two third

• Lack of scientific studies- can’t be Lack of scientific studies- can’t be recommendedrecommended

Aromatherapy and HypnosisAromatherapy and Hypnosis

• Betts et al 2003 – open study of 100 patients- Betts et al 2003 – open study of 100 patients- one third became seizure free for 12 months one third became seizure free for 12 months when both techniques were used togetherwhen both techniques were used together

• Time consumingTime consuming

• Hypnosis- useful in children and adults to Hypnosis- useful in children and adults to induce non epileptic seizuresinduce non epileptic seizures

AcupunctureAcupuncture

• 2 RCTs in adults (Klentz et al 1999, steven et 2 RCTs in adults (Klentz et al 1999, steven et al,2000) all patients had drug resistant epilepsy. al,2000) all patients had drug resistant epilepsy. • Acupuncture v/s sham acupuncture no difference Acupuncture v/s sham acupuncture no difference

foundfound• Acupuncture unlikely to ever have a role in Acupuncture unlikely to ever have a role in

pediatric epilepsypediatric epilepsy

ConclusionConclusion

• Seizure control achieved in 75% children with Seizure control achieved in 75% children with conventional AEDsconventional AEDs

• Tempting for parents to seek alternative non Tempting for parents to seek alternative non conventional AEDs and non pharmacological conventional AEDs and non pharmacological treatment for children with intractable epilepsy/ treatment for children with intractable epilepsy/ drug toxicitydrug toxicity

• Alternative or complementary medicine become Alternative or complementary medicine become popular, though not scientific , for many chronic popular, though not scientific , for many chronic illnesses where Allopathy has frustrating lack of illnesses where Allopathy has frustrating lack of efficacy efficacy

ConclusionConclusion

• Only ketogenic diet and Epilepsy surgery have Only ketogenic diet and Epilepsy surgery have strong evidence base and are effectivestrong evidence base and are effective

• More time should be spent to educate families More time should be spent to educate families about nature of disease and poor prognosis , about nature of disease and poor prognosis , rather than advocating use of unproven rather than advocating use of unproven remedies or alternative approachesremedies or alternative approaches