Epilepsy and SeizuresPart 2: Introduction to Two Epilepsy Syndromes and Therapeutics

Jacquelyne S. Cios, MD MSAssistant Professor

Department of Neurology, Division of Epilepsy

Jacquelyne.Cios@osumc.edu

“It is thus with regard to the disease called Sacred: it appears to me to be nowise more divine nor more sacred than other

diseases, but has a natural cause like other affections.”

- Hippocrates, 400 BC

Learning Objectives

Be able to describe some clinical, pathological, electrographic and radiographic features of the syndromes of Mesial Temporal Lobe Epilepsy and Childhood Absence Epilepsy.

Be familiar with a the availability of a range of epilepsy therapeutics including pharmacological and procedural based options.

Be able to recognize status epilepticus and be familiar with the basic treatment algorithm.

Part 2: Outline

Treatment Anti-epileptic drugs – mechanism and side effects

First generation Second generation

Vagal nerve stimulator Surgery Experimental: RNS Ketogenic diet

Role of the epilepsy monitoring unit (EMU) Status epilepticus

A closer look at two important syndromes

Mesial temporal lobe epilepsy vs. childhood absence epilepsy

Both commonly encountered in the adult population Illustrates partial vs. generalized dichotomy

Both have events of staring and unresponsiveness Both have events of tonic-clonic seizures But MTLE - partial onset seizures; CAE – generalized onset

seizures They differ in the focus or origin of the seizures and pattern of

spread

Let’s look at their clinical, electrographic, and radiographic features

Mesial temporal lobe epilepsy: clinical presentation

Risk factors include: History of childhood febrile seizures (81%) - this is a strong predictor Meningoencephalitis at presentation (10%) Head trauma (10%) No apparent risk factor (7%) Birth trauma (3%)

Histopathologically, many have mesial temporal sclerosis There is an interval between cerebral insult and onset of seizures (>95%, mean 7 years) Mean age at seizure onset – 9 years Some have only complex partial events (50%) without Gen tonic-clonic events

GTC is not the primary (most frequent) sz type Convulsive status epilepticus (repeated seizures constituting a medical emergency) is

uncommon(4%) Auras are common (96%)

Abdominal visceral sensation is most common Evolution of the disease over time

A silent interval of mean 6.7 years after onset of epilepsy Seizure phenomenology becoming more elaborate over time

Auras

Simple partial seizures that often precede a seizure Can last for seconds up to 1-2 minutes Common auras

Viscerosensory – “rising epigastric sensation” Altered perception - Déjà vu or jamais vu Unpleasant or metallic taste

Less common Visual and auditory illusions or hallucinations Tactile sensation

Impaired consciousness

Following the aura, the patient has altered consciousness

May still have upright posture, with eyes open, and still be talking in some cases

Commonly a behavioral arrest with staring for 30-60 seconds

Patients have amnesia for the event May also have variable amount of retrograde amnesia, including

the aura Due to bilateral hippocampal impairment of function during the

seizure

Automatisms

The behavioral arrest commonly includes involuntary, purposeless, repetitive motor activities

These are stereotypic (look identical when compared between seizures) Patient is amnestic to these Involving hands (Fumbling, picking, fidgeting) Or mouth (chewing, swallowing, lipsmacking)

These usually help localize the onset

May be de novo Doing something that is triggered after seizure onset , ie, chewing something placed in

patient’s mouth These include release phenomena- actions that are normally inhibited by frontal lobe

function ie, socially unacceptable behaviors

May be preservative (continuing to do something that patient was engaged in previous to sx onset)

Have localizing value Generally ipsilateral to the side of the seizure onset (the lesion)

Quiz - 06 Seizures and Epilepsy

Less common seizure manifestations

Leaving Running away, out of the room (cursive)

Vocalizations Ictal speech (or sign language) Affective behaviors (out of fear)

There is commonly a fearful look on the patient’s face Stems from involvement of the uncus, hence the early term for this

sz type, “uncinate fits”

Dacrystic (crying) Gelastic (laughing) – associated with hypothalamic

hamartoma Whistling

Spread to the motor areas

As the temporal lobe discharge recruits more territory, it marches across the brain

Contralateral limb dystonia is often seen There may be an early, nonforced head turn toward the side of the

sz onset There may be a forced head turn (version) later in the sz away from

the side of onset May be associated with gaze deviation also contralateral to the

lesion Spread to the supplementary motor area (SMA) precedes

generalization (involvement of whole cortex and resultant tonic-clonic activities) May be a fencing posture (head turned toward extended arm, c/L to the lesion,

also called M2E) May be a figure 4 sign (extended leg c/l to the lesion, flexed leg at the knee

joint I/L to the lesion)

Quiz - 07 Seizures and Epilepsy

A complex partial onset seizure temporal lobe onset

Secondary generalized seizure

Partial onset with secondary generalization

The EEG of mesial temporal lobe seizure

Mesial temporal sclerosis: MRI and histopath

A : a kainic acid induced rat model of MTS 3 days after injection. Inset shows degenerating hippocampal neurons at higher powerB: same specimen at 14 days showing aberrant mossy fiber sprouting in the dentate gyrus (Timm’s stain)

Quiz - 08 Seizures and Epilepsy

Childhood absence epilepsy: clinical presentation A model for idiopathic generalized epilepsies Seizures start between 3- 8 yrs old (peak 6-7) Typical absence seizure

Sudden brief impairment of consciousness Accompanied by characteristic EEG change 3 Hz (2.5-4 Hz) generalized spike and wave May have automatisms, non stereotyped Eyes, open, staring Impairment of consciousness and amnesia for event Lasting generally 10 seconds May occur up to 200 times per day

Childhood absence epilepsy

No developmental, metabolic, neurological, pathological abnormalities evident

May spontaneously go into remission (70%), around adolescence

Generally do not have frequent generalized tonic clonic sz (GTC)

Except in those 30% who continue to have absences into adulthood

May also have febrile seizures (30%) May be due to a Arg-> Glu polymorphism in GABA A receptor Prognosis is generally good for seizure freedom with or

without pharmacologic treatment (65%)

Video of Typical Myoclonic Seizures

Video of typical myoclonic seizures

Juvenile myoclonic epilepsy, like childhood absence epilepsy, is another type if idiopathic generalized epilepsy

3 Hz generalized spike and wave

Quiz - 09 Seizures and Epilepsy

Part 2: Treatment of epilepsyTreatment

Anti-epileptic drugs – mechanism and side effectsFirst generationSecond generation

Vagal nerve stimulatorSurgeryRNSKetogenic diet

Differential diagnosis and the epilepsy monitoring unit (EMU)Status epilepticus

Anticonvulsants: first generation drugs

1945 - 1963 Tridione , methsuximide ethosuxamide, Primidone, ethotoin,

diazepam

1974 Carbamazepine - discovered by Walter Schindler in 1953 at

J.R.Geigy (now Novartis) marketed for trigeminal neuralgia in 1962 – anticonvulsant in the

UK 1965

1978 Valproic acid - Pierre Eymard discovered anticonvulsant activity

in 1962 First synthesized by Burton 1882 (Bromide)

Anticonvulsants: second generation

1993 – felbamate 1994 – gabapentin, lamotrigine 1996 – topiramate, fosphenytoin 1997 – tiagabine, rectal diazepam 1999 – levetiacetam 2000 – zonisamide, oxcarbazepine 2005 – pregabalin 2008 – lacosamide, rufinamide

Anticonvulsants by mechanism

Ca channel Na Channel GABA Glutamate Other

EthosuximidePregabalinZonisamide

CarbamazepineLacosamideLamotrigineOxcarbazepinePhenytoinRufinamideZonisamide

BarbituratesBenzodiazepinesGabapentinTiagabineValproateVigabatrin

FelbamateTopiramate

LevetiracetamLacosamideRetigabine (Ezogabine)

Special topics relating to AED use

Phenytoin, carbemazepine, oxcarbazepine are generally used for partial epilepsy

Broad spectrum anticonvulsants are known to be useful for both partial and generalized onset seizures These include levetiracetam, topiramate, valproic acid

A few AEDs are only used in very specific clinical indications Vigabatrin – infantile spasms Ethosuximide – absence seizures

Some AEDs have nonlinear kinetics As the dose of phenytoin is increased, the steady state plasma

concentration rises exponentially Starting phenytoin efficiently require a “loading dose”

Example: 20 mg / kg iv followed by 5 mg /kg/ day divided into twice daily doses

Drug- drug interactions First generation anticonvulsants are heavily P450

metabolized Carbemazepine and phenytoin are P450 inducers

Carbemazepine can auto-induce Valproate is a P450 inhibitor

This can cause interactions which are clinically relevant When adding valproate to the medication regimen of a patient on

lamotrigine, would you add it slowly or quickly to avoid side effects of lamotrigine?

Hint: valproate inhibits P450 mediated elimination of lamotrigine causing higher serum levels of lamotrigine

Many of the drugs are highly protein bound The free fraction is the active form Check free levels in patients with low protein states

Quiz - 10 Seizures and Epilepsy

Epilepsy therapeutics: diet

Low glycemic index diet (LGID) Originally for blood sugar control with efficacy in epilepsy More tolerable version of ketogenic (high fat, low carb) diet 30-50% SFO

LGID/KD - Complications

LGID/KD - Complications Refusal to eat Hyperlipidemia Elevated liver enzymes Constipation Metabolic acidosis Hypoglycemia Weight loss / growth retardation Nephrolithiasis (kidney stones)

Epilepsy therapeutics: VNS

Vagus nerve stimulator (VNS)1930s – carotid sinus massage1997 – FDA approval for epilepsy2004 approved for treatment of depression30% of patients obtain >50% seizure reductionNo more effective than medicines wrt SFO

Epilepsy therapeutics: surgery

One third of patients with epilepsy are medically refractory One third of patients with epilepsy are medically

refractory Failed 2-3 single drugs and/or a combination of drugs

These patients may be amenable to surgery Anteromedial temporal resection (AMTR) – chance of long term

seizure freedom or meaningful reduction in seizure frequency in medial temporal lobe epilepsy

Corpus callosotomy Functional hemispherectomy (hemispherotomy) Multiple subpial transection (MST)

Pre-surgical evaluation

Will it work? 24 hr (continuous ictal and interictal) video EEG (Epilepsy Monitoring

Unit) Intraoperative monitoring

Subdural strips or grids of electrodes placed on the cortical surface Implanted depth electrodes – longitudinally along the temporal pole

Ictal SPECT

Is it safe? Studies to determine whether the ictal onset zone is far enough away

from eloquent brain regions Neuropsychological testing WADA Electrocorticography – intraoperative Cortical mapping Functional MRI

Quiz - 11 Seizures and Epilepsy

Status epilepticus

Status Epilepticus A person is in status epilepticus if they are experiencing a seizure of

longer than 5 minutes duration OR if they have experienced 2 contiguous seizures without regaining

consciousness between seizures Convulsive or non-convulsive (eyes open)

Status Epilepticus Treatment Algorithm

Airway Breathing Circulation Dextrose (check for glucose levels as well as other

electrolyte abnormalities) Epilepsy

Labs Benzodiazepine Anticonvulsant Anesthesia Barbituate Coma (central line / EEG)

EMS/ED/Floor

ICU

Status Epilepticus Treatment Algorithm

• Treatment– If someone is seizing

• Lay on side• Clear area around them• Loosen tight clothing• Do not hold down• Do not put anything in mouth

Status Epilepticus Treatment Algorithm

ABCDEpilepsy Benzodiazepine

Lorazepam (Ativan) 1-2 mg doses IV every 5 minutes 2 mg / min max rate Repeat dosing pending AED arrival and infusion Maximum dose = 0.1 mg / kg total

Anticonvulsant Phenytoin loading dose = 20 mg/kg

Anesthesia

Status Epilepticus

• Treatment Efficacy– 35-45% of patients with status epilepticus will stop seizing with

aforementioned treatments– Patients that do not, need

• general anesthesia• brain imaging studies (head CT/CTA) • transfer to the ICU for

– continuous EEG monitoring– Possible barbiturate coma with hemodynamic monitoring

Quiz - 12 Seizures and Epilepsy

Epilepsy is a complex field

Other issues in clinical practice Social stigma Psychiatric comorbidity Functional disability and socioeconomic status Epilepsy and women’s issues SUDEP Medication adherence

References Pierce, JMS. A disease once sacred. A History of the medical understanding of

epilepsy. Brain (2002) 125 (2): 441-442. Annegers, JF, Hauser WA, et al. The risk of epilepsy following febrile convulsions.

Neurology March 1, 1979vol. 29 no. 3 297 Pitkanen A, Lukasiuk, K Epilepsy & Behavior Volume 14, Issue 1, Supplement 1,

January 2009, Pages 16–25 Kim, J. V., Kang, S. S., Dustin, M. L. & McGavern, D. B. Nature 457, 191–195

(2009). | Article | Fabene, P. F. et al. Nature Med. 14, 1377–1383 (2008). Isokawa et al. Glutamate Currents in Morphologically Identified Human Dentate

Granule Cells in Temporal Lobe Epilepsy. JN Physiol June 1, 1997 vol. 77 no. 6 3355-3369

French, JA, Williamson, PD et al. Annals of Neurology. Volume 34, Issue 6, pages 774–780, December 1993

Blair, RDG. Temporal Lobe Epilepsy Semiology. Epilepsy Research and TreatmentVolume 2012 (2012), Article ID 751510, 10 pages

Sharma, AK, et al. Mesial temporal lobe epilepsy: Pathogenesis, induced rodent models, and lesions. Toxicol Pathol December 2007 vol. 35 no. 7 984-999

Quiz - Seizures and Epilepsy

Thank you for completing this module

Questions? Contact me at:

Jacquelyne.Cios@osumc.edu

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