Controlling Seizures Controlling Seizures Staying HealthStaying Health

Orrin Devinsky, M.D.Department of NeurologyNYU Langone School of

Medicine

What is Epilepsy?What is Epilepsy?

Occasional, sudden, excessive, rapid, and local discharge of grey matter (Jackson, 1890)

We focus on what we see, not what is missing Sudden – there are continuous disorders of

neural functioning Excessive – there is often deficient inhibition

of neuronal activity Rapid – changes may be fast at the human

sensory level but slow at the cellular level

Diagnostic ChallengesDiagnostic Challenges

Define epilepsy syndrome Video-EEG monitoring

Understand the cause of epilepsy High resolution MRI Genetic studies (GEFS+, Chromosomal microarrays)

Define factors that provoke seizures FAILURE

Identify long-term effects of epilepsy &s its treatment

Therapeutic ChallengesTherapeutic Challenges

No seizures, no side effects If patients had their choice:

No doctors, No Medicines In general, would rather see doctor

than take medication

Therapeutic ChallengesTherapeutic Challenges

Ongoing assessment: consequences of seizures and therapy

How aggressive to pursue seizure control?

Do we treat interictal EEG? ? Benign rolandic epilepsy

How to assess effects of long-term therapies?

Fooled by Experience: Fooled by Experience: Tom’s SeizureTom’s Seizure

9 am Saturday morning – Tonic-clonic seizure, witnessed by his children

My first question: any provocative factor? Missed meds, sleep deprivation, alcohol?

“Nothing really” Missed meds, but can’t be that – I do it all

the time

Risks, Rewards, Perfect Risks, Rewards, Perfect StormsStorms

Known provocative factors Missed medications Sleep deprivation/time zone Δ’s Excess alcohol (> 2 drinks) Physical or emotional stress

Factors are not additive but synergistic Linear or non-linear

Many factors unknown

Seeing patterns, Finding Seeing patterns, Finding MeaningMeaning

WWII – V2 rockets in London Germans precisely

targeted areas &avoided spies

Cancer clusters – in CA 5000 census areas, 2,750 with statistically significant but random elevations of some cancer

Your idea: find evidence it is wrong, not only right

Missing PatternsMissing Patterns

Our mind sees stabilityIt fills in holes from your visual blindspot to the sentences you hearOn chronic AED therapy – and this may only be months – one may start to forget how they felt or their relative behaved before the medicine

This is especially problematic when medicine dose is increased slowly and other factors (eg, seizures, stress) are present

Mistakes IMistakes I’’ve Made ve Made

Relying on prior diagnosis Becoming “invested” in a course of

action Not listening to the information Not challenging one’s own

conclusion Finding information that supports Explaining information that doesn’t fit

Physician Selection of Physician Selection of AEDs AEDs AED relative efficacy:toxicity

Knowledge Published studies

Randomized v. open-label Dose range, methodology Statistical v. clinical significance

Information from colleagues Personal experience Belief, Bias, & Comfort Zone

A Case StudyA Case Study

29 y.o. woman monthly CPS, rare GTCs Routine 6 mo. Checkup: complains of some

tiredness, blurred vision, nausea Exam - mild nystagmus, tremor Labs - slightly elevated LFTs

MD’s perspective - doing great Woman’s perspective - doing poorly; not

driving, underemployed, fearful of seizures, troubled by AEs

What is Seizure Control?What is Seizure Control?

Relative termAre there things to encourage the

resolution of epilepsy?Epileptogenesis – the process by which

epilepsy develops, for example, after a head injury

Anti-epileptogenesis – preventing the process by which epilepsy develops

Reverse epileptogenesis – reversing the process by which epilepsy develops

Why is Seizure Control Why is Seizure Control Important?Important?

Quality of lifePrevention of injury, accident, SUDEPPrevention of progressionThe longer you are seizure free, the

longer you stay seizure freeThe longer you are seizure free, the

greater the chances of staying seizure free off medication

Progression of EpilepsyProgression of EpilepsyFor some, epilepsy is a progressive

disorderMRI – progressive hippocampal atrophy with continued seizures41 years old 44 years old

75 Partial Seizures & 5 GTCS in 3 years

Fuerst et al, Ann Neurol 2003

Mental Status and Seizures in Mental Status and Seizures in TSCTSC

Gomez M 1979;18-19.

Mental Status

No Epilepsy

With Epilepsy

Total

Normal 19 40 59

MR 0 89 89

Total 19 129 148

Mental Status and Seizures in Mental Status and Seizures in TSCTSC

Gomez M 1979;18-19.

Age (yr) Sz Onset

Normal Intelligence

Mentally Retarded

0-1 7 72

2-4 13 9

5-9 6 3

10-14 2 1

=>15 11 2

Total 39 87

Histological Studies of Histological Studies of TLETLE

Dendritic spine density remote from seizure focus reduced with increased epilepsy duration Multani et al, Epilepsia 1994;35:728-36

Hippocampal neuron density declines with chronic habitual seizures Mathern et al, Brain 1995 Epilepsy Res

1996

PET Temporal HypometabolismPET Temporal Hypometabolism

Results from neuronal loss and functional factors. Can occur without atrophy. Extends beyond seizure focus.

Associated with epilepsy duration

Extratemporal Volume Loss & Extratemporal Volume Loss & Hypometabolism in TLEHypometabolism in TLE

Whole brain volumes reduced

In TLE, thalamic volumes & metabolism are reduced

Thalamic reduction ipsilateral to focus

epilepsy duration cerebellar metabol

Normalization of PET Normalization of PET Abnormalities after Abnormalities after

Successful TLE SurgerySuccessful TLE Surgery

Metabolism normalizes in contralateral mesial temporal lobe and in ipsilateral frontal cortex and thalamus after temporal lobectomy!

Normalization of MRS Normalization of MRS Abnormalities after Temporal Abnormalities after Temporal

LobectomyLobectomy NAA/Cr increased to normal

range on side of surgery in seizure free patients

NAA/Cr (Ipsilateral & Contralateral) increased 50% by 6mos and 95% by 25 mos in seizure-free patients

Contralateral hippocampus NAA improves

Cross Sectional Cross Sectional Neuropsychological Neuropsychological

Studies in Epilepsy PatientsStudies in Epilepsy PatientsRelationship of Epilepsy Duration & Mental

DeteriorationSTRONG MODERATELennox & Lennox (1960) Dikman & Matthews

(1977)Dodrill & Troupin (1976) Jokeit & Ebner (1999)Gomez (1979) Jokeit et al (2000)Dodrill (1986)Hermann et al (2002) Oyegbile et al (2004)

MILD NONE BUT + AGE ONSETTrimble (1988) Strauss et al (1995)Jokeit et al (1999) Helmstaedter & Elger (1999)

The Value of ExerciseThe Value of Exercise

Exercise is good for your brain, whether you are a mouse or person

Salk studies – mice given access to running wheels produce more brain cells in a vital memory area of the brain

Women age 70-80 with mild cognitive impairment, brisk walking or weight training prevents memory decline and in some cases, improvements (compared with toning)

Exercise & EpilepsyExercise & Epilepsy

Animal studies – aerobic exercise increases the threshold to evoke epilepsy in several animal models (Airda)

Swedish military recruits – individuals who entered military and had low cardiovascular fitness had a 79% increase of developing epilepsy after controlling for education, heredity, and other factors (Ben-Menachem)

The Value of SleepThe Value of Sleep

Mental Improved mood, memory, attention,

judgment and reasoning Cardiovascular – lower risk of

disease Immune suppression Growth suppression Obesity Adult onset diabetes

Sleep & EpilepsySleep & Epilepsy

Sleep deprivation – reliable method to evoke seizures

Circadian shifts – can lower seizure threshold without ‘sleep deprivation’ Sudden shifts – need a

plane

Diet & EpilepsyDiet & Epilepsy

Ketogenic Modified Atkins Low glycemic

Dietary Supplements & Dietary Supplements & EpilepsyEpilepsy

? Less restrictive carbohydrate diets No evidence that any supplement reduces

seizure frequency outside rare genetic/nutritional disorders Pyridoxine & Vitamin E deficiencies

ALTERNATIVE THERAPIESALTERNATIVE THERAPIES

ACUPUNCTURE HYPNOSIS AROMATHERAPY BIOFEEDBACK &

NEURO-EEG FEEDBACK

MEDITATION CHIROPRACTIC REFLEXOLOGY

COUNSELING / PSYCHOTHERAPY

NUTRITIONAL HERBAL REMEDIES OSTEOPATHY HOMEOPATHY YOGA MASSAGE

Alternative Therapies for Alternative Therapies for EpilepsyEpilepsy

What to do: medicine fails, problems persist? Limits of proving any efficacy Doctors get it wrong

Internal mammary artery bypass Patients get it wrong

Autism and vaccine Need really good data – otherwise,

impossible to know

EVIDENCE: HEIGHT OF ABSURDITYEVIDENCE: HEIGHT OF ABSURDITY Parachute to prevent death &

trauma related to gravitational challenge: systematic review of randomized controlled trials1

No RCTs of parachute use Basis for parachute use is purely

observational; apparent efficacy could be explained by a “healthy cohort” effect

Individuals who insist that all interventions need to be validated by a RCT need to come down to earth with a bump

1Smith, GCS, Pell, JP BMJ 2003

Stopping Prolonged Stopping Prolonged Seizures &Seizure Seizures &Seizure

ClustersClusters How much water to put out a fire? Prolonged febrile seizures Lessons from Dravet – if you know there

is a tendency to have prolonged seizures, hit them early, and hard if needed

Options Diastat (rectal diazepam) Buccal midozalam Intranasal midazolam

Double-Blind, Placebo-Controlled Double-Blind, Placebo-Controlled Randomized TrialRandomized Trial

• Doctors and patients are biased–Internal mammary artery bypass–Beta blockers vs. ACE inhibitors for hypertension

•Motivated reasoning•Confirmational bias

–If you support the Death Penalty, can you objectively evaluate new data?

•The Myth of Associationism-Causation–Vaccines and seizures–Mercury and autism

Concluding ThoughtsConcluding Thoughts Think healthy - we largely are who we

decide we will be Act health – work hard to be physically

active, eat healthy, limit alcohol, sleep well, avoid stressors

Take your own pulse – as patient, as caregiver

Search hard to understand, be humble