Philip Kozan

}  It comes from a Greek word meaning “to hold or seize”

}  Seizures are what happens to people with epilepsy ◦  Different from a convulsion which is involuntary

muscle movement }  It is a disorder of the brain }  May cause uncontrollable “Shaking or Jerking” }  In some cases only results in a loss of

consciousness }  Two types-Generalized and localized

}  Epilepsy is not a mental illness and it is not a sign of low intelligence

}  It is not contagious }  Between seizures, a person with epilepsy is

no different from anyone else

}  Everyone’s brain has the ability to produce a seizure under the right conditions

}  Epilepsy may start at any age ◦  It is most often diagnosed before the age of 20 and

after the age of 60 ◦  There are over 40 different types of seizures ◦  Hippocrates was first to recognize that epilepsy

starts in the brain }  Epilepsy is as common as breast cancer and

takes just as many lives -CURE

}  In some cases, sometimes seizures are triggered by certain factors ◦  Some but not all seizure inducing triggers are �  Lack of Sleep �  Stress �  Infection/illness �  Diet �  Severe changes in temperature �  photosensitivity

Primary Generalized seizures Partial seizure

}  Generalized tonic-clonic seizures(Grand Mal)

}  Absence Seizure(petit mal)

}  Myoclonic Seizure }  Atonic }  Tonic Seizure }  Clonic Seizure

}  Simple partial seizure }  Complex partial

seizure

}  Grand Mal-involves uncontrollable shaking and stiffening ◦  Usually affects primary motor cortex ◦  Most visual seizure and usually lasts 1-3 minutes

�  Status epilepticus ◦  This is what most people think of when they hear the

word seizure

}  Absence seizure/Petit mal ◦  Most common in children ◦  Subtle visual cues involved- unresponsiveness, blank

staring ◦  Often mis-diagnosed as ignorance/ behavioral problem ◦  Children often out grow these seizures

}  Myoclonic seizure ◦  Very brief jerks, sometimes many can occur in brief

period of time ◦  Rapid jerking/twitching of muscles ◦  Normal people can experience “myoclonus”

randomly �  Juvenile myoclonic, Lennox-Gastaut syndrome,

progressive myoclonic

}  Tonic- stiffening in arms/legs ◦  Last for very short times

}  Clonic- rhythmic jerking of arms and legs ◦  Very rarely does it occur by itself

}  Atonic Seizure-drop attack }  Consciousness?

Simple partial

◦  Different for every person ◦  Person remains alert ◦  Divided into different

categories �  Motor-muscle activity �  Sensory-hearing, taste,

ringing, hallucinations �  Autonomic-sweating,

goose bumps, butterflies �  Psychic- ex. déjà vu,

depression, understanding/speaking

}  A simple partial that spreads }  No recollection of seizure }  Starts with warning }  Spreads to different parts of brain }  No clear diagnosis and hard to treat

}  Warning sign associated with partial seizures – aura ◦  Depends on where the seizure starts

}  Partial seizure itself also depends on area of brain }  Temporal Lobe- familiarity/unfamiliarity, mixture of different

feelings, emotions ,sensations, experiences ◦  1st most common

}  Frontal Lobe-incredible variety of auras and seizures. Ex. Uncontrollable laughing, random movements, strange thoughts and actions ◦  2nd most common

}  Occipital lobe- associated with hallucinations, flashing lights, rapid blinking, blindness, decreased vision, image repetition ◦  Similar to temporal lobes seizures but not as common

}  Parietal lobe-Somatosensory seizures, somatic illusions, vertigo, visual distortions ◦  Rarest form of epilepsy ◦  Numbness, tingling, heat, pain ◦  Sensations move in predictable paths down arm or leg

}  disruption in the normal balance between excitation and inhibition in part or all of the brain

}  Seizure occurs when excitation increases, inhibition decreases or both

}  hyperexcitability can occur at different levels of brain function ◦  Networks of neurons, neuronal membrane, neurotransmitters/receptors,

etc. }  Important neurotransmitters involved are glutamate and

GABA }  EPSP – excitatory post synaptic potential }  IPSP – inhibitory post synaptic potential

}  GABA main inhibitory neurotransmitter ◦  GABA is synthesized from Glutamate ◦  When GABA is released into the synapse, receptors bind and

chloride goes into postsynaptic terminal hyperpolarizing neuron ◦  This is an inhibitory post synaptic potential which makes it

harder to reach threshold for depolarization ◦  Also a neuromodulator

}  Glutamate main excitatory neurotransmitter ◦  Normal binding of glutamate to receptors allows influx of

sodium and calcium ions into postsynaptic terminal depolarizing it

}  Hyperexcitability-abnormal responsiveness of a neuron to excitatory input

}  Hypersynchrony-large numbers of neighboring neurons in an abnormal firing pattern

}  Ultimately, epilepsy is a network phenomenon requiring participation of many neurons firing synchronously

}  MRI – Magnetic Resonance Imaging }  CT scan- computerized tomography }  EEG –electroencephalogram

}  As more neurons are recruited into synchronized firing, loss of inhibitory control occurs ◦  Depolarization shift occurs-giant Action Potential ◦  It is believed that hyperpolarization is diminished

because of potentiation(strengthening) of EPSPs, decreasing IPSPs ◦  Continues to propagate to nearby neurons in a

continuous loop

}  Still no clear explanation }  Possible reasons include ◦  Restoration of ionic gradients ◦  Neuromodulators? ◦  Restoration of excitatory and inhibitory synaptic

transmission ◦  Fatigue?

}  Seizure Increases: ◦  Cerebral blood flow ◦  Oxygen consumption ◦  Glucose uptake/Metabolism

}  Decreases in brain: ◦  Glucose level ◦  ATP

}  Biggest question – “Do seizures cause brain damage” }  Many factors involved: ◦  Age ◦  Underlying brain disorder ◦  Duration, frequency and severity

}  Brain damage interpreted in different ways ◦  Structural damage; i.e. metabolic stress, Oxygen depletion, longevity ◦  Cognitive deficits ◦  Neurological disabilities ◦  Psychosocial challenges

}  When I arrived at Johns Hopkins just before Thanksgiving in 1993 I was 20 months old. I weighed about 19 pounds and was taking Dilantin, Felbatol, Tegratol, and transene several times every day. I still had a bandage on the back of my head from when they operated on my brain. I had been having dozens, sometimes as many as a hundred seizures a day for a year. Then Dr. Freeman and Diana Pillas and Mrs. Kelly changed what I ate. My seizures were gone in two days. I was off all those drugs in a month. I’m not sure what would have become of me if my family hadn’t found the ketogenic diet, but I doubt that today I would be an A student in high school with lots of friends; I doubt I would have been playing piano for the last eight years; and I doubt I could hit an eight iron 160 yards. -The Charlie Foundation

}  Form of fasting – high protein/fat diet with low carbohydrates ◦  Glucose starvation: inhibition of glycolysis

}  Entire mechanisms behind the diet remains unknown }  Possible reasons include: ◦  Ketones released in blood stream become main source of

energy for brain – Beta-hydroxybutarate ◦  Lowered calories intake ◦  Changes in fatty acids ◦  KD may affect amino acid metabolism structurally changing

GABA ◦  Hormonal changes

}  Most effective treatment for most types of epilepsy }  Most patients come off it after two years without need of

AEDs ◦  Brain plasticity?

}  Most difficult to maintain ◦  Strict diet schedule; maintain correct levels of ketones ◦  Could fall into shock if consume sugar ◦  Possibility of ketoacidosis if not strictly followed

}  Intractable Epilepsy ◦  Effective in over 50% of cases ◦  Most patients come off the diet within 2 years

}  Alzheimer's Disease (AD) ◦  Reductions in Amyloid beta plaque 42 ◦  Improvements in cognitive functioning ◦  5 million currently diagnosed and predicted to increase to 16

million people by 2050 ◦  High carb (HC) diets suggested to be cause of increase in AD

�  HC inhibit lipases causing high levels of lipoproteins; associated with AD and heart disease

}  Parkinson Disease (PD) ◦  Clinical studies show improvements in PD symptoms ◦  Ketone bodies protected against mitochondrial respiratory

chain defects

}  Cancer ◦  Animals fed KC had elevated levels of b-hydroxybutyrate (p = 0.0173)

and an increased median survival of approximately 5 days relative to animals maintained on SD. KC plus radiation treatment were more than additive, and in 9 of 11 irradiated animals maintained on KC the bbiioolluummiinneesscceenntt ssiiggnnaall ffrroomm tthhee ttuummoorr cceellllss ddiimmiinniisshheedd bbeellooww tthhee lleevveell ooff ddeetteeccttiioonn (p,0.0001). Animals were switched to SD 101 days after implantation and nnoo ssiiggnnss ooff ttuummoorr rreeccuurrrreennccee wweerree sseeeenn ffoorr oovveerr 220000 ddaayyss. KC significantly enhances the anti-tumor effect of radiation.

◦  Decreased Brain tumor rates Seyfried et al. (2011) }  Beneficial in stroke ◦  Pre-treatment with the KD resulted in decreased functional damage from

the stroke Tai et al. (2008) }  Positive results in Brain trauma – reduced contusion volume }  Mitochondrial disorders, autism, Depression, Migraines,

Multiple Sclerosis, Reversal of neuronal aging

}  Improved Mitochondrial function ◦  Metabolizing ketone bodies may cause decreases in

reactive oxygen species }  Reduction of apoptotic cell death }  Improved metabolism in brain cells }  New astrocytes found in the hippocampus act

as extracellular buffers }  Increased antioxidant activity in hippocampus }  Increased brain derived neurotrophic factor ◦  Partially due to decreased caloric intake

}  Medications act upon gates/mechanisms described ◦  Inhibition of glutamate receptors, hydrolysis of

glutamate, amplification of GABA etc. �  Similar to how medications such as antihistamine

work-block receptors }  Phenobarbital, Topamax, Kepra }  Not the best solutions ◦  Most AEDs cause drowsiness, low energy, mood

changes ◦  Carbamazepine and phenobarbital cause

osteoporosis over long period of time

}  Can be the best option if seizure localized }  Traditional brain surgery- scalpel ◦  Always chance of stroke

}  Gamma knife-localized radiation burns away tissue ◦  Non invasive ◦  Used more often for tumor rather than epilepsy ◦  Causes inflammation of surrounding tissue

}  Laser Ablation Therapy(newest) ◦  Real time MRI guided thermal imaging targeting lesions in brain ◦  Smaller risk of affecting surrounding tissue ◦  Guided laser probe

}  Wait to help person after seizure has occurred

}  Lay person down on side with head support }  Incapable of swallowing their tongue }  If it continues for more than 5 minutes call

911 ◦  This means that seizure will continue on for at least

20minutes causing massive damage potentially leading to stroke

}  The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders – Stafstrom, C. ; Rho, J.

}  Epilepsy and the Ketogenic Diet-Carl E. Stafstrom MD PHD, Jong M. Rho MD }  Abdelwahab MG, Fenton KE, Preul MC, Rho JM, Lynch A, et al. (2012) The Ketogenic Diet

Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma. PLoS ONE 7(5): e36197.

}  2008 Alzheimer’s disease facts and figures Alzheimer’s Association }  Duan W, Lee J, Guo Z, Mattson MP. Dietary restriction stimulates BDNF production in the

brain and thereby protects neurons against excitotoxic injury. J Mol Neurosci. 2001;16:1–12

}  Noh HS, Kim DW, Kang SS, Cho GJ, Choi WS. 2005. Ketogenic diet prevents clusterin accumulation induced by kainic acid in the hippocampus of male ICR mice. Brain Res. 1042(1):114-8.

}  Bellido T, Huening M, Raval-Pandya M, Manolagas SC, Christakos S. 2000. Calbindin-D28k is expressed in osteoblastic cellsand suppresses their apoptosis by inhibiting caspase-3 activity.J. Biol. Chem. 275, 26328–26332.

}  Prins ML, Fujima LS, Hovda DA. 2005. Age-dependent reduction of cortical contusion volume by ketones after traumatic brain injury. J Neuroscience Research 82(3):413-20.

}  High carbohydrate diets and Alzheimer’s disease - Samuel T. Henderson* }  Center for Agricultural and Rural Development