LENNOX-GASTAUT SYNDROME: A PRECISE INSIGHTPRESENTED BY:VISHNU.R.NAIR,5TH YEAR PHARM.D,NATIONAL COLLEGE OF PHARMACY, KERALA.

INDEX/ CONTENTS OF THIS PPT:

• Definition

• Epidemiological statistics

• Etiology

• Pathophysiology

• Clinical manifestations

• Diagnosis

• Management strategies for LENNOX-GASTAUT SYNDROME.

• Bibliography/ Reference.

DEFINITION:

• “Pediatric encephalopathy syndrome, characterized by multiple seizure types, mental retardation & abnormal findings on ECG”.

EPIDEMIOLOGICAL STATISTICS:

• Occurs in 1-4% of patients, with childhood epilepsy

• More common in boys than in girls

• Prevalence in boys: 0.1 per 1,000 population

• Prevalence in girls: 0.02 per 1,000 population

• Age onset: 26-28 months.

ETIOLOGY:

• Mainly occurs due to the following causes:

1. IDIOPATHIC CAUSES

2. CRYPTOGENIC CAUSES

3. SYMPTOMATIC CAUSES:

- Encephalitis

- Meningitis

- Tuberous sclerosis

- Cortical dysplasia

- Hypoxia-ischemia injury

- Traumatic brain injury

- Infantile spasms.

PATHOPHYSIOLOGY:• The exact mechanism behind this disease occurrence is not clearly defined,

though some theories exist

• According to one hypothesis maturation of anterior parts of brain increases permeability of excitatory inter-hemisphere pathways in frontal areas

• Involvement of immunogenetic mechanisms in triggering LGS is also reported(via an association between LGS & HLA-Class I Ag B7).

CLINICAL MANIFESTATIONS:A. TONIC SEIZURES:

- Frequency: 17-95%

- More common during NON-REM SLEEP

B. ATYPICAL ABSENCE SEIZURES:

- Frequency: 17-100%

- Associated with incomplete loss of consciousness

- Eye myoclonias may occur

C. ATONIC/ MASSIVE MYOCLONIC/ MYOCLONIC+ ATONIC SEIZURES:

- Frequency: 10-50%

- May lead to a sudden fall, causing injuries

D. OTHER TYPES :

Include:

1. GTCS(15%)

2. Complex partial seizures(5%)

3. Absence Status Epilepticus(SE)

4. Tonic SE

5. Non-convulsive SE

E. GENERAL SYMPTOMS:

Include:

1. Abnormalities in mental status functions

2. Abnormalities in levels of consciousness

3. Mood instability

4. Personality disturbances

5. Acute psychotic episodes(in older children)

6. Social isolation(in older children)

7. Memory impairment.

DIAGNOSIS:A. ELECTROENCEPHALOGRAPHY:

- Here both waking & sleeping EEG is recorded

- Helps to capture & classify different seizure types in the patient

- Video/EEG Telemetry is also helpful

B. INTERICTAL EEG:

- Helps to detect prognosis of the disease

- Used to check spikes pattern observed in an EEG

C. NEUROIMAGING STUDIES:

- MRI is preferred over CT-Scan

- Used to detect:

a. Brain malformations

b. Tuberous sclerosis

c. Hypoxia-ischemia injury

- PET/SPECT scan is not commonly used.

MANAGEMENT STRATEGIES FOR LGS:

• Includes:

a. Goals of therapy

b. Treatment guidelines

c. Pharmacotherapy

d. Non-pharmacotherapy.

A. GOALS OF THERAPY:

• To avoid complications

• To focus on reducing/eliminating seizure frequency

• To focus on minimum ADRs, with maximal drug effectiveness

• To focus on using minimum number of drugs

• To focus on ameliorating symptoms

• To improve HRQoL.

B. TREATMENT GUIDELINES:• Usually, 3 categories of drugs can be used:

1. FIRST-LINE AGENTS

2. SECOND-LINE AGENTS

3. THIRD-LINE AGENTS.

1. FIRST-LINE AGENTS:

- Based on clinical experience

- Drugs include:

a. Valproic acid

b. Benzodiazepines(Clonazepam, clobazam, nitrazepam)

- NOTE: NITRAZEPAM is not FDA-APPROVED for treatment of LGS, yet, it is used in some Western Countries

2. SECOND-LINE AGENTS:

- These are treatments, that are believed to be effective, based on OPEN-LABEL CONTROLLED STUDIES

- Drugs include:

a. Vigabatrin

b. Lacosamide.

3. THIRD-LINE AGENTS:

- They are treatments, that are believed to be effective, based on DOUBLE-BLIND PLACEBO-CONTROLLED STUDIES

- Include:

a. Lamotrigine

b. Topiramate

c. Felbamate

d. Rufinamide.

C. PHARMACOTHERAPY:• Drugs include:

1. Valproic acid 10. Clobazam

2. Lamotrigine

3. Topiramate

4. Felbamate

5. Zonisamide

6. Vigabatrin

7. Levetiracetam

8. Rufinamide

9. clonazepam

1. VALPROIC ACID:

- Considered as 1st line choice for treating LGS(for the past 2 decades)

- More effective in CRYPTOGENIC LGS

- Used mainly as DIVALPROEX

- Use in children, greater than 10 years of age

- ADRs:

a. Hepatotoxicity(if used in children < 3 years of age)

b. Weight gain

c. Alopecia

d. Tremors.

- DOSE: 60 mg/kg/day(Max. dose).

2. LAMOTRIGINE:

- Useful for LGS patients, in spite of high risk of IDIOSYNCRATIC DERMATOLOGICAL REACTIONS

- Use other anticonvulsant medications along with it, cautiously

- Start with a low dose, and then titre slowly

- ADRs:

a. life-threatening hypersensitivity(skin rashes)

b. SJS

c. TEN.

- DOSAGE REGIMEN:

a. With Valproate: 0.5-5 mg/kg/day; PO

b. Without Valproate: 5-10 mg/kg/day; PO

c. With enzyme-inducing AEDs: 5-15 mg/kg/day; PO

d. Maximum dose: 400 mg/day; PO.

3. TOPIRAMATE:

- Safe & effective as adjunctive therapy for LGS

- ADRs:

a. Nephrolithiasis

b. Weight loss

- DOSE : 6 mg/kg/day; PO.

4. FELBAMATE:

- Effective in LGS patients

- High risk of APLASTIC ANEMIA Mandates this drug to be used as 3rd/4th line choice for LGS

- ADRs:

a. URTI

b. Aplastic anemia

c. Purpura

- DOSE:

a. Use in patients> 2 years of age

b. Max. dose: 45 mg/kg/day

c. Reduce concomitant dose of CBZ, phenytoin, valproate by 20%.

5. ZONISAMIDE:

- Effective as long-term adjuvant therapy in LGS patients

- ADRs:

a. Somnolence

b. Dizziness

c. Nephrolithiasis

- Avoid usage in children < 16 years

- DOSE: 600 mg PO daily(Max. dose).

6. VIGABATRIN:

- Approved by US-FDA in 2009, as:

a. Monotherapy for WEST SYNDROME(in patients, aged 1month-2 years)

b. Adjuvant treatment for adults with refractory complex partial seizures.

- ADRs:

a. Somnolence

b. Weight gain

c. Irreversible visual field defects, due to retinal atrophy.

- Avoid usage in patients, below 1 month of age

- DOSE : For patients, aged 1 month-2 years: 150 mg/kg/day(Max. dose).

7. LEVETIRACETAM:

- Mainly FDA-approved for partial seizures

- May be used for a number of seizure types in LGS

- ADRs:

a. Sedation

b. Increased B.P(in children <4 years)

c. Dizziness.

- DOSE:

a. For patients, aged 4-12 years: 30 mg/kg/day(Max.dose)

b. For patients, aged >12 years: 1.5 g, BD(Max.dose).

8. RUFINAMIDE:

- Drug modulates sodium channel activity prolongs its inactivated state

- Used as adjunct therapy in adults & children aged 1 year or older with LGS

- ADRs:

a. Dizziness

b. SJS

- DOSE : 3,200 mg/day(Max.dose).

9. CLONAZEPAM:

- Effective 1st line AED for LGS

- DEMERITS :

a. ADRs, with long-term usage

b. Development of tolerance

- Since there is risk of development of tolerance it is advised to:

a. Use on alternative days, OR

b. Use alternate 2 BZDs daily.

10. CLOBAZAM:

- Drug binds to GABA-A receptor potentiates GABA-ergic neurotransmission

- Drug has an active metabolite(N-DESMETHYL CLOBAZAM) shows long duration of action

- Used for LGS in patients, older than 2 years

- ADRs:

a. Sedation

b. Weight gain

c. URTI

- DOSE: 40 mg/day(Max.dose).

D. NON-PHARMACOTHERAPY:Includes:

a. Corpus callostomy

b. Vagus nerve stimulation

c. Focal cortical resection

d. Ketogenic diet

e. Patient counselling tips.

A. CORPUS CALLOSTOMY:

- Only effective to reduce DROP ATTACKS

- Considered PALLIATIVE than CURATIVE

B. VAGAL NERVE STIMULATION:

- Done by means of a surgically-implanted programmable device

- Approved by FDA, as adjunct treatment for reducing seizure frequency in LGS

- Requires follow-up period within 5 years

C. FOCAL CORTICAL RESECTION:

- Used in rare cases

- Resection of localized lesion(vascular lesion, tumor) improves seizure control in LGS

D. KETOGENIC DIET:

- Consists of high ratio of FATS to PROTEINS and CARBOHYDRATES

- Ratio is usually in between 2:1 to 4:1

- Benefits include:

a. Fewer seizures

b. Reduced drowsiness

c. Better behavior

d. Requires fewer number of concomitant AEDs.

- Diet includes:

a. HIGH FAT(Nuts, cream, butter)

b. LOW CARBOHYDRATES (Starchy fruits, bread, pasta, grains, sugar)

c. ADEQUATE PROTEINS(Pulses, soyabeans)

E. PATIENT COUNSELLING TIPS:

1. Avoid consuming artificial sweeteners/additives

2. Avoid skipping meals, especially breakfast

3. Avoid all “white products”, like:

a. White flour

b. White sugar

c. Table salt

d. White rice.

4. Do not skip taking medicines, without doctor’s approval

5. Get enough sleep(since sleep deprivation can trigger seizures)

6. Manage stress, and avoid stressful situations.

BIBLIOGRAPHY/ REFERENCE:1. Trevathan E, Murphy CC, Yeargin-Allsopp M. Prevalence and descriptive

epidemiology of Lennox-Gastaut Syndrome among Atlanta children. Epilepsia. 1997 Dec.38(12):1283-8.

2. Arzimanoglou A, et al. Lennox-Gastaut Syndrome: a consensus approach on diagnosis, assessment, management and trial methodology. Lancet Neurol. 2009 Jan.8(1): 92-93.

3. Engel J Jr; International League Against Epilepsy(ILAE). A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia. 2001 Jun.42(6): 796-803.

4. Heiskala H. Community-based study of Lennox-Gastaut Syndrome. Epilepsia.1997 May. 38(5):526-31.

5. Bare MA, Glauser TA, Strawsburg RH. Need for electroencephalogram video confirmation of atypical absence seizures in children with Lennox-GastautSyndrome. J Child Neurol. 1998 Oct. 13(10):498-500.

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