SUDEP and Seizure Alert Devices

Daniel Friedman, MDAssistant Professor of NeurologyNYU Langone School of Medicine

October 25, 2014

Outline

• Introduction• Definitions• Epidemiology• Mechanisms• Developing a SUDEP Registry• Discussing SUDEP with patients• SUDEP Prevention

George Washington on SUDEPMount Vernon, June 20, 1773.Dear Sir,

It is an easier matter to conceive, than to describe the distress of this Family; especially that of the unhappy Parent of our Dear Patsy Custis, when I inform you that yesterday removed the Sweet Innocent Girl Entered into a more happy and peaceful abode than any she has met with in the afflicted Path she hitherto has trod.

She rose from Dinner about four o'clock in better health and spirits than she appeared to have been in for some time; soon after which she was seized with one of her usual Fits, and expired in it, in less than two minutes without uttering a word, a groan, or scarce a sigh. This sudden, and unexpected blow, I scarce need add has almost reduced my poor Wife to the lowest ebb of Misery; which is encreas'd by the absence of her son, (whom I have just fixed at the College in New York from whence I returned the 8th Inst) and want of the balmy consolation of her Relations…

Early Descriptions

1904

Epilepsy mortality by age

Forsgren et al, Epilepsia 2005

Disease-related mortality in epilepsy

• Status epilepticus • Accidents and drowning (~16% of deaths)• Suicide (~11% of deaths, Jones et al, 2003)• Drug reactions• Aspiration pneumonia• Sudden unexpected death in epilepsy

– Probably most common cause in difficult to treat epilepsy

Outline

• Definitions• Epidemiology• Mechanisms• Developing a North American SUDEP Registry• SUDEP Prevention

Sudden Unexpected Death in Epilespy

• Defined as:– Sudden and unexpected nontraumatic and non-

drowning death in a patient with epilepsy (excluding status epilepticus)

• Definite if: autopsy doesn’t reveal structural or toxicological cause

• Probable if: no autopsy performed but there is no other plausible cause for death

• Possible if: limited information regarding death circumstances or there is a plausible competing explanation for death

Nashef et al 1997; Annegers Epilepsia 1997

Outline

• Epidemiology• Mechanisms• Developing a North American SUDEP Registry• Discussing SUDEP with patients• SUDEP Prevention

SUDEP Incidence

Reviewed in Tomson et al Lancet Neurol 2008, Devinsky 2011

Friedman & Hirsch, 2012

Summary: the Public Health Burden of SUDEP—Annual Years of Potential Life Lost (YPLL)

Compared w/ Other Neurologic Conditions

Stroke SUDEP ALS/MND MS Alz Men/Enc PD0

20

40

60

80

100

120

140

160

180

200

YPLL

(Tho

usan

ds)

Thurman, et al Epilepsia 2014

Factors associated with increased SUDEP risk

Ongoing seizures

Frequent seizures

Antiepileptic drug (AED) therapy:

GTCS (>3 per year)

Long epilepsy duration

Lack of AED use

Subtherapeutic levels

Young adults Polytherapy (>3 AEDs)

Early epilepsy onset >2 AED changes/ year

Neurologic status Rapid AED withdrawal

Intelligence quotient <70

Non-ambulatory

History of major neurological insult

Factors associated with decreased SUDEP risk

Seizure remission Recent addition of AED

Successful epilepsy surgery Nocturnal supervision

Reviewed in Tomson et al Lancet Neurol 2008; Hesdorffer et al. Epilepsia 2011, Devinsky, NEJM 2011

SUDEP Risk Factors

Time Course of SUDEP Risk

SUDEP and LGS

• Patients with LGS have many of the clinical risk factors for SUDEP (early onset, frequent seizures)

• Reported rates of SUDEP in people with intellectual disability and epilepsy ~2-4 per 1000 pts per year

• Actual incidence in LGS is unknown

Outline

• Mechanisms• Developing a North American SUDEP Registry• Discussing SUDEP with patients• SUDEP Prevention

Understanding mechanisms

• Most likely there is a terminal seizure• Clinical observations of witnessed SUDEP or

near-SUDEP– Seizures precede 90% of witnessed cases (Langan

et al 2000; Tomson et al 2005)• Difficulty breathing observed in most

– Autopsy cases have histopathological evidence of recent seizure (Thom et al 2003)

Timing of SUDEP

• SUDEP occurs at night/sleep 58% of cases and unwitnessed in 86%

• Nocturnal seizures are associated with sleep-related SUDEP OR=3.6 (1.4-9.4)

• Compared to living controls, a history of nocturnal seizures was more common in SUDEP deaths OR=3.9 (2.5-6.0)– Adjustment for established risk factors did not change this

finding.Lamberts et al. Epilepsia 2012

Friedman et al. JCI 2013

Respiratory MechanismsPost-ictal central apneaSeizure related obstructive apneaSeizure-related hypoventilation/hypercarbia5-HT?

Post-ictal comaLoss of protective arousal mechanism after seizure Adenosine, 5-HT?

CardiacSeizure (sympathomimetic) related cardiac arrhythmiaVagal dysfunctionShared heart/brain channelopathies (KCNQ1, KCNH2, SCN5A, RYR2, HCN2, SCN1A, KCNA1)NE, Ach?

Mechanisms• Evidence suggests a terminal seizure in

most witnessed cases (Langan et al 2000; Tomson et al 2005)

• Is this a multi-hit model – GTC in a susceptible host who is in a susceptible state?

Problems

• Seizure-related changes in cardiopulmonary function are common– SUDEP maybe due to failure of recovery mechanisms

• EMU based physiology (EEG suppression, ictal HR changes) may bias towards mechanisms in refractory patients

• Observed cases point towards respiratory mechanisms but likely heterogenous

• 20% of SUDEPs occur in patients with rare or no GTCs– Low risk patients may have different mechanisms of SUDEP– ? Neuro-cardiac channelopathies

• Increased risk for both epilepsy & sudden death

Outline

• Definitions• Epidemiology• Mechanisms• Developing a SUDEP Registry• SUDEP Prevention

Rationale for a SUDEP Registry• SUDEP is rare

– estimated 3200 SUDEPs in US and Canada annually. – obtaining sufficient clinical material to perform studies at one or a few

centers is difficult• Epilepsy center-based case ascertainment biases towards “high

risk” patients– Need more population-based approach

• Large numbers of cases are needed to evaluate what are likely heterogeneous mechanisms

• Prevention strategies may not be generalizable• Contribution of cardiac channelopathies

• Collaborative effort involving multiple investigators from multiple disciplines

Hirsch et al. Neurology 2011

Development of North American SUDEP Registry

• Registry for SUDEP cases in the United States and Canada• Create a repository for clinical, imaging, tissue, genetic and physiological data

– Population based referrals of all decedents with epilepsy (SUDEP & non-SUDEP controls with epilepsy)

– referral through awareness of registry among epilepsy patient community, neurologists and medical examiners

• Focus on collecting tissue from eligible decedents – rare commodity

• Elligible patients currently include– All unexpected deaths in a PWE with post-mortem interval <24OR– Potential SUDEPs in specific childhood epilepsy syndromes (Dravet, Idic15)OR– Available video-EEG recordings of seizures

• Collected tissue/genetic material will be available to any investigator after review by independent advisory board

• See sudep-registry.org for more information or email info@sudep-registry.org

Outline

• Definitions• Epidemiology• Mechanisms• Developing a North American SUDEP Registry• SUDEP Prevention

SUDEP Prevention

• No evidence based method to prevent SUDEP• Emphasis is on risk mitigation• Seizure control is key

– Seizure free patients are at low risk– Being in active arm of RCT protective if randomized to effective

dose of drug (Ryvlin et al., 2011)• 7x risk reduction

• Screening EKG & history to identify potential co-existing channelopathies and other cardiac conditions

• But many patients have seizures despite appropriate treatment…

Supervision & A/V Monitoring

• Limited evidence suggests that direct or indirect supervision can reduce SUDEP risk

• Rationale:– Most SUDEP occurs at night, patients found prone– Someone to reposition or provide first aid after a

seizure may prevent some SUDEP

Supervision & A/V Monitoring

Study of 310 students in special education boarding school with epilepsy between 1970-1993

– At school about 2/3rds of the year– While at school, supervised by staff

and nocturnal audio monitoring system

– In 4135 person-years of follow-up, no SUDEPs occurred while at school, 14 occurred while on leave or after graduation (p= 0.075)

Nashef et al, Epilepsia, 1995;36:1187

Supervision & A/V Monitoring

Study of 154 SUDEP cases vs 616 controls in UK between 1989-1998

– Nocturnal supervision was associated with a reduced risk of SUDEP (OR 0.4, 95% CI:0.2-0.8)

– Nocturnal supervision includes room partner > 10yrs of age, monitoring device or regular checks

Langan et al, Neurology, 2005;64:1131

Devices for SUDEP Prevention

• Devices to prevent fatal complications of seizures

• Devices to detect seizures and notify caregivers– Indentify most vulnerable period– May be tied to intervention

• No device has been proven to prevent SUDEP

29

Devices to prevent fatal complications of seizures

• Anti-suffocation pillows• Never have been tested as

means to prevent SUDEP• One study shows that in

laboratory may reduce CO2 elevations but perhaps not to levels necessary to prevent asphyxia

• Class I medical device in UK (not approved as such in US)

Seizure Detection Devices: Principles

Transmitter

Sensors

Intervention?

Seizure Detection MethodsMotor Activity

• Methods– Accelerometers (Nijsen et al 2005)– Mattress sensors – Surface EMG (Conradsen et al 2011)– Video motion detection (Karayiannis et al, 2005)

• Pros– Inexpensive– Non-invasive

• Cons– Detects only convulsive seizures– Some methods (mattress devices, video) restricted

to a specific site (e.g. bedroom)– May be some issues with specificity

Seizure Detection MethodsOther Physiological Parameters

• Heart rate– HR elevates with majority of seizures with

characteristic slope (e.g. Mosely et al, 2011; Opherk et al 2002; Nei et al, 2000)

• Pulse oximetry– SaO decreases in 44% of generalized seizures in

children (Mosely et al, 2010) and 33% of partial-onset seizures in adults (Bateman et al, 2008)

• Galvanic Skin Response/Electrodermal Activity– Measure of sympathetic system function (sweat

glands)– Increased EDA seen with CPS and SGTC in children (Poh

et al, 2010)

Seizure Detection Methods

Other Physiological Parameters

• Pros– Inexpensive– Non-invasive

• Cons– May lack specificity

34

Seizure Detection Methods

Multimodal Detectors

• Combining parameters – e.g. HR and accelerometry – may yield improved performance– Fail safe mechanism– Can improve specificity– Another dimension to “tune” detection

algorithms to specific individual

Examples

• Several detection/alarm devices currently commercially available• Designed to detect seizure-related motion

• Mattress: Medpage, Emfit• Watch: SmartWatch• Video: SAMe

• None are FDA-approved to detect seizures & have little performance data

• 3 Devices: BrainSentinel, Epilert, Proguardian are in clinical trials

• Can terminal cascade be averted if a seizure is recognized?– 5 reported cases of “near-SUDEP” in epilepsy

monitoring unit with successful resuscitation (reviewed in Devinsky, NEJM 2011)

– 2 cases of SUDEP in medical setting – death despite immediate recognition of the seizure (Swinghamer et al, Epilepsy & Behav 2012)

Potential pitfalls

Education for SUDEP Prevention

• Educating patients/caregivers about SUDEP risk factors and methods to manage epilepsy– Adherence strategies– Lifestyle factors which may exacerbate seizures

(alcohol, sleep deprivation)– Optimal therapy including diet therapy and surgery

when appropriate– Disease management plans – treating clusters and

exacerbations

• Goal – reduce rates of “breakthrough” seizures

Conclusions

• SUDEP is the leading epilepsy-related cause of death• Mechanisms are unknown and likely heterogeneous but

peri-ictal respiratory dysfunction may be most common• Further studies to identify pathophysiology are needed• Guidelines needed for physicians for SUDEP discussion• Mitigating risk is cornerstone of prevention strategies

– Further studies are needed to identify interventions

LGS- surgical therapeutic options

Satya Gedela, MD, MRCP

Medical Director of Epilepsy surgery program.

Director of Epilepsy Monitoring Unit.

Children’s Hospital of Pittsburgh of UPMC

University of Pittsburgh

Karly

17 year old

Refractory mixed epilepsy

Devastating drop seizures

Failed 5 meds and VNS

Referral to our comprehensive epilepsy center

Surgery outcome

She had resection of the seizure onset region.

Resection of the lesion.

Has been seizure free for several weeks

Had transient weakness.

More alert and better quality of life.

Victoria

13 year old girl with multiple type of seizures

Cognitively slow

Failed multiple AEDs

All the investigations were normal including MRI.

Epilepsy surgical evaluation could not localize the seizures.

Had VNS

Delayed the CC

Anterior Callosotomy – outcome

Became seizure free

Able to reduce the doses of AEDs several months after the Anterior Corpus Callosotomy.

Improved quality of life.

Lennox Gastaut Syndrome

Introduction

Lennox Gastaut Syndrome (LGS) is one of the most severe childhood epilepsies

It has precise well defined clinical and EEG characteristics and is a fairly homogeneous, but uncommon entity.

Its pathological mechanisms remain poorly understood.

Its definition has varied over time resulting in over diagnosis/ wrong diagnosis

History

Gibbs (1938) described the EEG characteristics. He called this “petit mal variant”

Lennox (1945) and Lennox and Davis (1950) described the triad of mental deficiency, polymorphic seizures and diffuse slow spike and wave discharges in EEG.

Margaret Buchtal-Lennox proposed the name LGS in tribute to the work of Lennox and the Marseille School headed by Gastaut.

ILAE Definition 2001

Onset during childhood

Coexistence of multiple seizure types

Common seizures: atypical absence, axial tonic and atonic seizures. Presence of tonic seizures in sleep is a constant feature.

Infrequent- myoclonic, GTCS and focal

EEG: Diffuse slow spike and waves and bursts of fast rhythms at 10-20 Hz during sleep.

Permanent psychological disturbances with psychomotor delay, personality disorders or both.

Classification

LGS is classified among the symptomatic or cryptogenic generalized epilepsies.

In the 2001 proposal of ILAE, it is classified as an epileptic encephalopathy, a concern formally endorsed in 2006 by ILAE and further emphasized in 2010( Berg et al, 2010).

International Classification of Epilepsies and Epileptic syndromes.

Classification

1. Cryptogenic (25%): onset between 1-8 years of age, in a previously normal child, due to an undetected but suspected cause.

(Abandoning this term has been suggested). Engel 2001

2. Symptomatic(75%): onset between 1-15 years of age, in a child with prior signs of brain damage.

Hancock and Cross, 2009, Borggraefe & Noachtar, 2010)

Epidemiology

1. LGS has been estimated to account for 1–10% of childhood epilepsies.

(Trevathan et al., 1997; Hancock & Cross,2009)

2. 12% had symptomatic generalized epilepsies (SGEs); however, only 4% of those with SGE had LGS

(Camfield et al., 1996)

3. No ethnic or geographic prediction.

4. Boys are slightly more affected than girls.

Epidemiology

The diagnostic clinical and EEG features may not be present at epilepsy onset and the diagnosis of LGS may emerge only over several years .

In the Nova Scotia cohort, there were only four patients with LGS at the time of epilepsy diagnosis; however, 20 years later the number had increased to 17, with most of the new cases evolved from West syndrome

(Camfield & Camfield, 2007).

Etiology

Brain lesions including tubers, tumors and malformations,

Hypoxicischemic encephalopathy,

Meningoencephalitis,

Neurocutaneous syndromes, and

Rarely metabolic syndromes

Amanda F. VanStraten

Etiology

30-65% of patients will have exhibited West syndrome with hypsarrhythmia before onset

The conversion to Lennox-Gastaut syndrome occurs primarily in patients with symptomatic West syndrome.

Among those patients, 41% had anoxic brain injuries early in life, and 20% had neonatal intracranial hemorrhages

Investigations

EEG and VEEG

MRI

Genetic workup

Metabolic workup

Treatment

Medical

Diet

Surgical

Medically refractory epilepsy

If the patient continues to have seizures even after 2 appropriate anti seizure medications tried adequately, we call it medically refractory epilepsy.

The chance of seizure freedom is less than 5% after failing two AEDs.

Therapeutic options for intractable epilepsy patients

Epilepsy surgery

Diet

Clinical trials

Surgical evaluation

Prolonged VEEG

Epilepsy surgery protocol MRI

PET

SPECT

DTI

MEG

f MRI

Some facts

LGS remains a treatment challenge and seizure freedom is rare

LGS is often the result of bi hemispheric pathology, but seizures may be caused by focal abnormalities of the brain

Up to 25% of patients with LGS have persistent focal abnormalities or asymmetry of slow spike-wave discharges on EEG.

Patients with LGS that is refractory to pharmacologic treatment may be considered candidates for surgical intervention.

Douglass et al 2014

Epilepsy surgery in LGS

A)Resective surgery

1. Lesionectomy,

2. Lobar/focal resections

3. Multilobar resections

4. Hemispherectomy

B)Palliative surgery

1. Corpus Callosotomy

2. Neuromodulation –VNS, RNS

Douglass et al 2014

Resective surgery in LGS – response rate

Two recent studies of resective surgery show promising results in patients with LGS, mostly those with focal lesions who had a high frequency of disabling seizures that were not controlled by antiepileptic drugs

Lee et al. conducted a retrospective analysis of clinical data from 27 individuals with LGS who had undergone resective surgery

Liu et al. reported on 18 LGS patients who underwent resective surgery.

Douglass et al. 2014

Resective surgery -LGS

27 individuals with LGS who had undergone resective surgery.

All 27 patients had daily disabling seizures (range 1–120 per day) that were not controlled by 3 or more drugs.

EEG, MRI, and functional neuroimaging studies were used to identify potential patients for surgery.

Patients who had ictal contralateral epileptiform discharges were rejected for surgery.

Lee et al. 2010

Resective surgery -LGS

Twenty-three patients (85%) had focal or unilateral lesions on MRI; 4 patients were non-lesional but had extensive encephalomalacia.

Multilobar resection was performed in 10 patients, single lobar resection was performed in 11 patients (10 frontal and 1 temporal), and functional hemispherotomies were performed in 6 patients

Follow-up was for a mean of 33.1 months (range 12.0–51.6 months).

Lee et al. 2010

Resective surgery -LGS

Engel class I outcomes were achieved in 16 patients (59%), class II outcomes in 4 patients (15%)

5 patients had no significant reduction in seizure frequency.

Sixteen patients (14 with a class I outcome and 2 with a class II outcome) showed an increase in the developmental quotient

Lee et al 2010

Resective surgery -LGS

18 LGS patients who underwent resective surgery.

Eligibilty criteria- frequent and severe seizures, seizures refractory to at least 2 AEDs and surgery considered as a last resort,

focal or multifocal lesions, , and surgically accessible lesions

EEG showing ictal or interictal hemisphere-dominant discharges

Liu et al 2012

Resective surgery -LGS

The patients included 12 male and 6 female patients, ages 3–24 years.

After a mean follow-up period of 5.4 years,

7 patients became seizure-free (Engel class I),

5 were Engel class II (almost seizure-free),

4 wereEngel class III (significant seizure control), and

2 patients had no change in seizure frequency

Liu et al 2012

Resective surgery -LGS

By combining the results from both reports, Lee et al. and Liu et al., it is clear that younger children, those 5 years or younger, are most likely to have the best outcomes

Eighty-two percent of patients 5 years or younger at the time of resective surgery had Engel class I outcomes.

Only 40% to 44% of those 5 years and older had Engel class I results.

The difference in outcomes seems to be related mostly to age.

Early surgery is beneficial

Douglass et al 2014

Corpus Callosotomy- LGS

Corpus callosotomy was first described in 1940 and subsequently used to treat drop attacks in epilepsy

The rationale for corpus callosotomy surgery is to prevent the generalized spread of a seizure via the corpus callosum

Callosotomy may be partial or complete

Callosotomy is considered a palliative, not a curative, procedure for LGS

Wong TT et al 2006; Mathews MS et al 2008; Purves SJ et al 1988

Patient selection

It is typically limited to those with catastrophic, drug-resistant, intractable epilepsy patients.

Patients with moderate-to-severe intellectual disability.

Callosotomy is considered particularly helpful for atonic, tonic, and tonic–clonic seizures.

Callosotomy is often targeted at resolving “drop” attacks in children with LGS

Wong ET AL 2006, Cukiert A et al 2006, Jadhav T et al 2012

CC in LGS- outcomes

76 patients (mean age 11.2 years, range 2–28 years)

LGS (n = 28) or Lennox- like syndrome (n = 48)

underwent complete callosotomy

(>50%) reduction in the frequency of generalized seizures was observed in 69 (91%) patients

52 patients (68%) had a ≥90% reduction in seizure frequency

7 (9%) were seizure-free

Cukiert A, et al 2006

CC in LGS- outcomes

Reduction in frequency of specific types of seizures was

1. atonic (92%),

2. atypical absence (82%),

3. tonic (51%), and

4. tonic–clonic seizures (57%).

Cukiert A, et al 2006

CC in LGS- outcomes

results obtained from corpus callosotomy were prospectively examined in 74 epilepsy patients in Taiwan

59 had LGS

Patients were male (n = 58) and female (n = 14) with a mean age of 8 years (range, 1–20 years)

All patients had the anterior corpus callosotomy

followed for at least 2 years after callosotomy

Kwan SY, et al 2000

CC in LGS- outcomes

Significant improvement in seizure reduction was observed in 66.2%

complete freedom from seizures with anticonvulsant medications was achieved in 18.9% of patients

Improvement in seizure frequency was observed in

1.generalized tonic–clonic seizures (82.1%),

2.generalized tonic seizures (76.7%),

3.atonic seizures (72.7%),

4. myoclonic seizures (64.9%),

5. complex partial seizure (61.5%), and

6. atypical absences (58.6%)

Kwan SY, et al 2000

Corpus callosotomy followed by resection

A retrospective study examined 7 patients with LGS who underwent corpus callosotomy followed by cortical resection.

median age of the patients at the time of callosotomy was 5.5 years (range 23 months to 12 years, 11 months)

The median time elapsed from callosotomy to the cortical resection was 6 months (range 2–35 months).

Four patients with Engel class I outcome and 1 patient with an Engel class II outcome following resection

Corpus callosotomy followed by resection

Patients were found to have more localized ictal and interictal epileptiform activity on EEG after corpus callosotomy.

PET and SPECT showed localized abnormalities that were concordant with the post–corpus callosotomy EEG.

Corpus callosotomy may help guide resective surgery and identify the seizure focus in patients with LGS

Hur YJ, et al 2011

Neuromodulation

VNS

Peripheral

1997

RNS

Central

2013

Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) is considered a palliative surgery

VNS has been shown to be effective in LGS with almost a 60% reduction in seizures by 6 months

VNS, is an extracranial procedure

Vagus Nerve Stimulation

The VNS Therapy System

consists of an implanted

pacemaker-like

generator and nerve

stimulation electrodes,

which deliver

intermittent stimulation

to the patient’s left

vagus nerve that sends

signals to the brain

111 USSym12-11-1003-US

Action potential propagation

NegativeElectrode(stimulates)

PositiveElectrode(blocks)

Action Potential = and

Action Potentials are blocked

Action Potentials continue to brain

Some Action Potentials are not blocked

Vagus NerveClick to see propagation of action potential

• Negative electrode generates

action potentials that travel

afferently via sensory fibers

• Efferently traveling action

potentials are mostly blocked by

positive electrode. Those not

blocked could cause side effects

Vagus Nerve Stimulation

• Offers more control for patients and their families1,2

• Initiates on demand stimulation May avoid seizures if consistent auras May abort or decrease severity of seizures1-3

May improve postictal period2

• Stops stimulation Acutely manage side effects3

Used to check if generator is still functioning

Used to help titrate dosing by acclimating patient to higher stimulation parameters

VNS vs CC

Meta-analysis found that CC is significantly more effective than VNS in achieving a 50% and 75% atonic seizure frequency reduction in LGS patients.

100% free of atonic seizures is better in CC (48.0% vs. 22.8% with VNS),

patients undergoing CC showed higher response rates for tonic, GTC, and complex-partial seizures ( statistically not significant)

Lancman G et al 2013

VNS vs CC

In medically intractable epilepsy patients with no resectable seizure focus the general consensus remains that VNS should be tried first because its perceived risk is lower and it is reversible.

In LGS patient group if the primary goal is significant reduction of these atonic drop attacks, then CC appears to be the better option. However, if other seizure types are present, then VNS can offer roughly comparable reduction rates to CC

Lancman G et al 2013

Conclusions

Resective surgery can be successful in select patients with drug-resistant LGS with focal lesions or where there is a dominance of EEG discharges from one hemisphere

Seizure reduction is achieved in most patients and some show a modest intellectual improvement when these parameters have been measured.

Conclusions

Corpus callosotomy and VNS are palliative surgeries that can reduce seizures in patients with intractable or drug-resistant LGS; both procedures are indicated for patients who are not suitable for focal resection

Corpus callosotomy and VNS often result in similar rates of seizures reduction; however, corpus callosotomy may be more effective for atonic seizures.

VNS is associated with milder complications

In both callosotomy and resective surgery, most complications are transient

Do not delay

Do the procedure early to relieve them of seizure burden and to improve their development and quality of life.

Thank you

LENNOX-GASTAUT SYNDROME

COMORBIDITIES and COMPLICATIONS

MICHAEL G. Chez M.D.

Director Pediatric Neurology and Epilepsy

Sutter Neuroscience Institute Sacramento, CA Associate Professor Neurology

Volunteer Faculty UC Davis Medical School Sacramento CA and Touro School of Osteopathic Medicine, Vallejo CA

Professional Advisory Board LGS Foundation

Lennox-Gastaut Statistics 6 % of Epilepsy Cases in Children 2-3/100,000

people overall population; 60,000-100,000 at least

> 80 % Cognitive issues/ Delays Language or Social

EEG Abnormalities Define Condition with Clinical Seizures of Mixed Type

New Genetic Findings/ Environmental ; Epigenetics

60% have Symptomatic Cause such as brain malformation or perinatal injury

30-40% may be genetic or idiopathic

Cognitive Affects Interictal and Ictal EEG Discharges

Interictal Spikes as well as Seizures can cause different activation or deactivation of resting state brain function

Even in Absence or Benign Focal Epilepsy there can be causes of learning delays despite good seizure or EEG control

Epilepsy and Learning and behavioral comorbidity may make up spectrum of whole brain changes predisposing one to LGS

What Happens in LGS or Absence Seizure

STATE OF BRAIN REGIONAL ACTIVATION in SEIZURE LGS

Activation and Inactivation LGS

Evolution of LGS seizure regionally

COGNITION LGS

Etiology of Cognition may be variable

Initial Brain injury: Malformation HIE/ Cerebral Palsy/ Infection/

Trauma Other Family Variable: ADHD

BIPOLAR ETC. Seizures Frequency and types of Seizures;

Interictal EEG frequency of spikes

Cognition

Additional Risks Head Injury/ Concussions from drop or atonic seizures

Lack of academic support ; lost developmental time

POLYPHARMACY If not see plateau or decline cognitive

ability then may suspect something other than classic LGS; perhaps Doose variant myoclonic/astatic encephalopathy

EEG and Cognition in Epilepsy and LGS

EEG PATTERNS CAN AFFECT ATTENTION (GENERALIZED SPIKE WAVE ATYPICAL ABSENCE/ STUPOR / ): Prefrontal and midline anterior cingulate frontal brain regions

Default Cortical patterns

EEG PATTERNS CAN AFFECT MEMORY (FOCAL/ temporal) affect amygdala , Hipocampus, limbic cortical interaction

Regional affect : Occipital or parietal can show visual processing issues

EEG and Cognition

EEG Improvement usually correlates with better seizure control and cognitive outcome

More Atypical Absence/ Atonic/Tonic seizure patterns lower functional IQ

Noted improvement if gain EEG control, even in genetic conditions like Frag X, Dravet variants, other genetic disorders like Tuberous Sclerosis

EEG and Cognition

Some genetic epilepsy related conditions may associate worse outcome on timing or success early treatment

Patient with different severity of genetic disorder may present differently: Examples Tuberous Sclerosis; Missense mutation vs Deletion or duplication

Numer of Fragile X repeats/ Retts variations

EEG Treatment

Failure to Stop Infantile Spasms in Tuberous Sclerosis: if stop or catch before treat vigabatrin; then not autistic or cognitive disorder

If treat after Infantile Spams: 80-90% risk of autism or Cognitive Disorder

Dravet Cases 90 percent delayed cognition and autism co-morbidity

Case Example

EEG essentially normalized, became seizure free and cognitive and social behavior improved when course of ACTH age 7 in girl with LGS from PCDH19 and KCNAJ10 defects; Autism resolved and speech social improved as did her understanding learning; regressed after ACTH removed and EEG abnormalities returned

Case Example: 7Q21 defect 4 yr old male started LGS atypical 2-3 hz

absence and drop seizures; had dysfunctional social skills language plateau, poor eye contact met criteria for autism clinically; EEG abnormalties worsened

Failed Depakote to resolve EEG and seizures completely; Add Onfi and then 1 month later Felbatol; EEG normalized, behavior mainstreamed in 2 months 3 months later Autism label removed by same neuropsychologist

now entering 2nd grade normal child

JP 7q21.3 copy deletion post-depakote/pre-felbatol/clobazam

JP Chromosome 7q21.3 deletionpost-felbatol and clobazam July 2011 at 8 weeks

Autism

High rate of autism in chronic epilepsy clinics

As high as 40-50% in major centers Some higher Autism should be screened and

neuropsychology baseline for IQ in all potential LGS patients early and after seizure progression

If gain control of disease process through treatments than restest these values when child has improved

Autism/ Cognition

Higher rate of autism with lower cognitive and earlier under age 2-3 cases, but may become more prevelent in later onset cases of LGS

Dravets, Infantile Spasms refractive type, Lennox Gastaut refractive cases occurrance cognitive disability IQ< 70 and autism rates may be > 80-90%

AED and Cognition

Although some medications can cause slower cognition, most are not as severe

However goal of all seizure medications are suppress excitable cortical regions

Need excitement ( elevated glutamate and other receptor pathways via NMDA and AMPA) that allow learning new things or making new connection; flipside often modulate end point of seizure activation or loss of neuronal function or cell death if over-stimulated wrong way

Cognitive DRUG vs EEG Pattern In every case of LGS, suspect EEG more than

polypharmacy which can dull senses and fatigue may be an issue

However, the actual fact is if we successfully eliminate the EEG abnormalities through surgical or medical pathways , even on same drug burden, patients almost always improve social language and cognitive behaviors above baseline when EEG at worst

This suggest underlying disease process rather than treatment causes the biggest learning issues

Social

Lifelong problem Behind peers cognitively/ Grade level/

physical ability, communication Social isolation: Needs assistance in

class/ community/ helmet? Can he/she communicate needs or advocate strongly

Physical risks; cannot drive; rely on others; socioeconomic effect on patient and families or caregivers

Social

As adults problems are: Getting transition as outlive or outgrow

their child neurologist for care; Obtain records/transition book for care, social issues

Social issues : housing, income, jobs transportation , aging caregivers, lack of social system infrastructure and high costs lifelong: Prepare earlier 16-17 years old

Costs est $6M per autism case/ add more for LGS more medical issues

Chronic Health Issues

Accidents Nutrition affects chronic seizures on

lungs heart weight bone health Adequate care to prevent aspiration

and accidents Osteoporosis need to check Vit D

levels Folic Acid

SUDEP

Finally SUDEP highest cause of death in chronic intractable epilepsy

Mostly higher if cognitive delayed and uncontrolled seizures

Less likely absence more partial seizures and generalized uncontrolled seizures, rather than atypical absence or tonic events

Also polypharmacy, behavioral or AED meds if weight gain or chronic respiratory or cardiac burden may also increase risks for death, also accidental or drowning issues

LGS COMORBIDITY CONCUSION LGS usually lifelong; multiple etiology

disease state Seizures and EEG can change over

lifetime Prevent accidental and treatment

related complications Provide aggressive EEG treatment,

idnetify genetic or other etiology in 70% or more cases now

Transitional care into adulthood: Medical and Social Issues

LENNOX-GASTAUT SYNDROME

WHEN STANDARD TREATMENTS FAIL

MICHAEL G. Chez M.D.

Director Pediatric Neurology and Epilepsy

SutterNeuroscience Institute Sacramento, CA Associate Professor Neurology

Volunteer Faculty UC Davis Medical School Sacramento

CA and Touro School of Osteopathic Medicine, Vallejo CA

Professional Advisory Board LGS Foundation

History

William G. Lennox 1884–1960 Henri Gastaut 1915-1995

Defined EEG and Clinical Abnormalities of this disease

LGS clinically described syndrome is actually spectrum of causes

LENNOX GASTAUT SYNDROME

DEFINED BY CLINICAL FINDINGS

HETEROGENOUS/ THEREFORE VARIOUS CAUSES

NOT ONE CAUSE SO NOT ALL CASES RESPOND RESPOND THE SAME

Clinical Definition

Age of onset typically after age 2

Can be normal before onset

May rarely start in adolscence or adult

Mortality rate ranges from 3% to 7%

LGS DEFINEDEEG FINDING

LGS defined by clinical seizure type and EEG pattern

Irregular background High amplitude slow Slow spike and wave Electrodecremental

response spike wave Fast “buzz”type

discharges in sleep

LGS EEG

Clinical Manifestations

Seizure Onset may be sudden and progress rapidly if not prior seizure history (i.e. prior infantile spasms)

Spectrum of Causes Idiopathic 30% Lesional 70% Syndrome Genetics

TREATMENT

ETIOLOGY MAY DETERMINE: Structural vs Genetic

SEIZURE TYPE DETERMINE : Absence Drop/Atonic Myoclonic Generalized convulsive Partial

GOALS: LGS SEIZURE and TREATMENT

LGS Seizure Patterns want to eliminate slow spike wave and tonic /Drop seizures

Can Alter Outcome Early Intervention Drop Attacks/ Atonic Atypical Absence

Worsen EtilogyDoose vs. Dravet Head Injuries/ Status Epilepsticus Atypical Absence

Treatment Rationale

Historical Review: What current drugs worked vs. not make difference? What tried made worse( ie Sodium channel drug?) Allergy?

When last EEG awake asleep video or ambulatory?

Any alternatve diet supplements tried? Etiology last MRI risks for injury to CNS Family/Genetic history: What modern

genetics have been done?

REFRACTORY TREATMENT LGS

Rational Mechanism Polypharmacy Best Drugs: Depakote Felbatol

Topamax Lamictal ONFI BANZEL Zarontin etc older drugs vs newer

High Dose Valium or Clobazam ACTH High Dose Steroids? KETOGENIC DIET TAURINE High Dose B6 Fenfluramine? Options? CBD?

Good Decision Treatment

If Genetic any drugs to avoid or try Structural lesion? Any chance for

surgical options Other Comorbid issues behavioral/

Autism Side effects tolerated

ANTIEPILEPSY DRUGS

First Generation Phenytoin Phenobarbitol/

Primidone Carbamazepine/

oxcarbazepine Valproic Acid Ethoxsuccimide Benzodiazepines

Second Generation Felbatol Topiramate Lamotrigine Levetiracetam Gabapentin Pregabalin Vigabatrin Rufonamide Lucosamide Brevacetam

Additional AED

Clobazam /ONFI Parapamil/ Fycompa? Other Benzodiazepines

DIET: KETOGENIC

SUPPLEMENTS? SURGERY

EEG PATTERN CORRELATES WITH DEVELOPMENTAL ARREST EARLY IN COURSE/ IMPROVEMENT IF TREATMENT EEG PATTERN SUCCESSFUL

BEFORE RX: SCNA1 POST RX: HIGH DOSE CLOBAZAM

JP 7q21.3 copy deletion post-depakote/pre-felbatol/clobazam

JP Chromosome 7q21.3 deletionpost-felbatol and clobazam July 2011 at 8 weeks

Congenital Lesion Case Before and After VPA LEV LCM ONFI

Pre clobazam LGS Idiopathic Sleep EEG

Awake Pre-Clobazam Idiopathic Case

High Dose Clobazam Idiopathic Case Post Treatment

POST HIGH DOSE CBZ AWAKE

POST HIGH DOSE CBZ ASLEEP

NMc pre-treatment VGB/VPA/CBZ

NMc post- VPA VGB CLBZ

Surgical Options: Cases

Any focal onset or history risks for injury CNS

Last imaging studies? Most recent type of MRI and where?

Prior Surgeries? Where and what type?

VNS/ Callosotomy mainly drops/atonic

Focal Resective Surgery: Traditional craniotomy vs Laser type ablation?

Congenital Stroke LGS VPA pre and post combination LEV/ LCM

MEG Left MEG Right

R L

A P

L

EEG

RL

R

CASE 1MEG 7/29/11MRI 7/20/11

Above LGS 12 days post Laser Ablation Surgery

LGS Focal Injury and Potential Surgery

Evolution of LGS seizure regionally

STATE OF BRAIN REGIONAL ACTIVATION in SEIZURE LGS

Surgical Options

Early Life Injury may spread and engage thalamic nuclei and generate generalized activity

LGS may have masked original lesion Genetic Epilepsy and focal

heterotopias? Malformation can be coexistant: Palliation?

Case by case analysis needed

WHEN AED RX FAILS CONCLUSIONS

There are options for treatment if not making progress

Look at genetic EEG and imaging testing, back to basics, review prior medications history. Use EEG changes to guide therapy-probably under-utilized

Minimize co-morbidity issues Consider Diet and Surgical Options Do not try to medicate or use non-supervised

Research or FDA approved Medication without medical guidance/partner with your doctor