Clinical Spectrum of KCNQ2-related Epilepsy: for Parents and Caregivers

John J. Millichap, MD, FAAPPediatric Epileptologist

Assistant Professor of Pediatrics and Neurology

September 18, 2014

Disclosures• This presentation will discuss off-label uses of

ezogabine/retigabine.

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Summary• EEG for parents and caregivers

• Neonatal-onset epilepsy syndromes: BFNE, EME and Ohtahara syndromes

• KCNQ2 Encephalopathy

• Clinical Spectrum of KCNQ2-related Epilepsy

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EEG for Parents and caregivers

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What is an EEG?• Graphical depiction of the electrical activity of the brain,

usually recorded from the scalp.

• A direct measure of brain function.

• Low risk to the patient.

• Widely available and easily performed.

• EEG is the most important neurophysiological study for the diagnosis, prognosis, and treatment of epilepsy.

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Hans Berger (1873-1941) was an Austrian psychiatrist and the first to record the human electroencephalogram (EEG) in 1924

Clinical applications of the Electroencephalogram (EEG)• Seizures/epilepsy

• Sleep

• Altered consciousness

• Focal and diffuse disturbances in cerebral functioning

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What are the limitations of EEG?

• Relatively low sensitivity and specificity.

• Subject to artifacts.

• Influenced by state (awake or asleep), drugs, and illness.

EEG Electrode Placement

Electrodes on the scalp collect electricity that is amplified and displayed

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How sensitive is EEG?

•Wall socket = volts

• EKG = millivolts

• EEG = microvolts

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“Hertz” (Hz) is the waves per second• Beta: 13-30 Hz (that’s very fast)

• Alpha: 8 to ≤ 13 Hz

• Theta: 4 to under 8 Hz

• Delta: < 4 Hz (that considered slow)

Types of EEG• Routine (<1 hour)

• Long-term Monitoring (>1 hour or overnight at the hospital)

• Ambulatory (at home)

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Activations

• Eyes open and closed

• Hyperventilation

• Photic stimulation

• Sleep deprivation

• Sedation

• Reducing anticonvulsants

• Specific triggers– Reading

– Visual patterns

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Normal EEG Abnormal EEG

Basic steps of EEG analysis• Analysis performed by doctors with specialized training in

pediatric EEG and pediatric epilepsy.

• Evaluate the brain activity in wake and sleep:– Are the waves too fast or too slow?

– If present, how much?

– Normal sleep “architecture”: spindles and vertex ‘sharp’ waves

• Look for any abnormalities between seizures:– “Spikes” may mean brain irritability and a risk for seizures.

– Where and how often are the abnormalities?

• Look for seizures.– What types?

– How many? 16

Normal Infant EEG

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Muscle artifact

L

R

Movement artifact

Electrode artifact

Practical uses of EEG in KCNQ2-related epilepsy• To support a diagnosis of KCNQ2-related epilepsy

• New spells? Are they seizures?

• New seizures?

• Sudden worsening in condition? Is it sedation from medications or increased seizures/background slowing?

• Improvement? EEG can help confirm seizures under control or response to treatments.

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Electroclinical Epilepsy Syndromes• Age of onset

• Development– (examination)

• Seizure type

• EEG pattern

• Prognosis

• Management

Neonatal-onset Epilepsy Syndromes• Early Myoclonic Epilepsy (EME)

• Ohtahara syndrome (Early infantile epileptic encephalopathy, EIEE)

• Benign familial neonatal epilepsy (BFNE)

Berg, Epilepsia 2010.

Neonatal Encephalopathy:

EME & Ohtahara syndrome

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EME vs Ohtahara syndromes

Ohtahara (EIEE) EME

Seizures Tonic spasmsFocal seizures

Myoclonusfocal seizuresTonic spasms

Major Etiology Lesional Genetic or Metabolic

Burst-suppression continuous in sleep and wake

Accentuated in sleep

Bursts Longer Shorter

Suppression Shorter Longer

West syndrome ~75% Commonly atypical form

Ohtahara, Epilepsy Res, 2006

Benign Familial Neonatal Epilepsy (BFNE)

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Rett and Teubel, 1964

• Description of four generation family with 9 individuals with BFNC

• Seizure onset in the first week of life and occurred multiple times daily

• Seizures consisted of stiffening and cyanosis

• Seizures stopped within several weeks

• 3/9 developed seizures later in childhood

24Zimprich, Neurology, 2006

Benign Familial Neonatal Epilepsy• Onset of brief, multifocal, tonic or clonic seizures, +/- apnea

during the first week of life.

• Seizures may be treated briefly, but usually self-resolve within several months.

• Normal neurologic examination, normal EEG, and negative evaluation for another etiology of the seizures.

• Prognosis is good (10% seizure recurrence) with usually normal developmental outcome.

Berg et al. Epilepsia 2010.; Ronen et al. Neurology 1993.

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Neonatal-onset epileptic encephalopathy due to KCNQ2-deficiency• Initial epilepsy syndrome diagnosis: usually Ohtahara

syndrome or EME.

• Onset of tonic seizures in the 1st week of life.

• Seizure frequency diminished over the first few years of life.

• EEG showed burst suppression in the first week of life that gradually evolved to multifocal epileptiform activity.

• In early childhood, most patients have profound cognitive/motor disability with few seizures and little epileptiform activity on EEG.

27Weckhuysen, Ann Neurol, 2012; Kato, Epilepsia, 2013; Milh, Orphanet J Rare Dis, 2013; Weckhuysen, Neurology, 2013.

EEG: burst suppression at diagnosis

Initial tonic seizures

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Isolated spasm

Tonic seizure

Cluster of spasms

Extending the KCNQ2 spectrum• MRI

– May be normal

– If performed early during the onset of frequent seizures, may show abnormalities in the deep parts of the brain

– If performed later, may show parts of the brain have not grown as expected

• Developmental outcome– Highly variable

– Oldest reported follow up at 24 yrs old (Weckhuysen, Neurology, 2013) had onset of seizures at 2 days old with burst suppression, seizure free since adolescence, some speech, wheelchair bound since childhood

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Anticonvulsants to control seizures• Physician will choose specific anticonvulsants for the

individual patient:– seizure types

– age of patient

– potential side effects

• Carbamazepine (and phenytoin) reported as potentially helpful

• ACTH may be used, especially in cases that evolve to West syndrome

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Ezogabine/Retigabine• 2011: approved by FDA as adjunctive treatment of partial-

onset seizures in patients aged 18 years and older.

• 1 KCNQ2 Encephalopathy patient showed marked decrease in seizure frequency and severity (Weckhuysen, Neurology, 2013)

• 11 patients (unpublished series; poster accepted AES 2014)– Of 4 treated under 6 mos old, 3 reported improvement in seizures and

development

– 1 treated at 3 yrs old reported improvement in seizures and development

– 1 had improved alertness and EEG background activity

– 1 had improvement in development only35

Ezogabine

• Physicians and parents must weigh the potential risks and benefits of any treatment

• Risk of vision loss and skin pigmentation

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Clinical spectrum of KCNQ2-related Epilepsy• KCNQ2-deficiency causes a clinical spectrum of epilepsy with

similar onset, but variable course and outcomes.

• KCNQ2 testing is important in the evaluation of unexplained neonatal seizures.

• Knowing the cause is helpful for counselling parents.

• Developing an effective treatment strategy remains the most challenging clinical question.

• Collaboration is key to effectively study this rare disease.

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Thank you!

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