Introduction

Lennox-Gastaut Syndrome (LGS) is a severe childhood epilepsy syndrome characterised by multiple seizure types accompanied by cognitive and behavioural impairment. It begins in early childhood and is associated with perinatal injuries.¹ Perinatal injuries are known to worsen LGS. This condition is not curable and remains difficult to treat despite the availability of multiple therapeutic options.

Seizure Types Associated with LGS

1. Tonic Seizures: Sudden stiffening of muscles, usually during sleep
2. Atypical Absence Seizures: Brief episodes of impaired awareness
3. Atonic Seizures: Sudden loss of muscle control
4. Myoclonic Seizures: Sudden muscle jerks
5. Generalised Tonic-Clonic Seizures: Involving both loss of muscle control and muscle jerks

Aetiology and Pathophysiology

Seizures begin in early childhood, usually before the age of four. There is no identifiable cause for 30-40% of seizure cases; however, several contributing factors have been identified:

• Genetic mutations²
• Cortical malformations
• Brain tumours
• Neurocutaneous disorders such as tuberous sclerosis complex
• Hypoxic-ischaemic injury
• Infections such as meningitis
• Head trauma

The exact mechanism remains unclear but is associated with rapid neuronal firing or neuronal hyperactivity.

Epidemiology

LGS is a rare disease with an incidence of 5-30 individuals per million people, with annual treatment costs ranging from $20,000 to $90,000 per person.³ It is more common in males than females. LGS accounts for 10% of all childhood epilepsies.

Diagnosis

Electroencephalogram (EEG) findings are the most useful tool for evaluating LGS. EEG shows a slow spike-wave pattern with a frequency of less than 2 Hz.

No individual is born with LGS; the condition worsens over time due to the factors discussed above. There is always a risk of permanent brain injury, making early diagnosis crucial. Diagnosis involves EEG, MRI, and clinical symptoms evaluated by neurologists. MRI is used to rule out tumours or structural abnormalities and is not a diagnostic standard for LGS.

Treatment

There is no cure for LGS; however, different treatment approaches aim to control seizures. The primary goal is to improve the patient's quality of life (QOL). Therapeutic options include medications, surgery, and dietary modifications.⁵

Medications

No single medication controls all seizure types associated with LGS. In general, LGS is resistant to standard epilepsy treatments. Medications include:

• Anti-epileptics (Valproate, Lamotrigine, Rufinamide)
• Benzodiazepines
• Cannabidiol

These medications are tailored individually to control the specific seizure types a patient presents with.

Surgery

Surgical interventions are used only when medications fail. Initially, surgery was performed exclusively for patients with brain tumours; however, research has expanded the available surgical options, which now include:

Brain Surgery (Corpus Callosotomy)

The corpus callosum, the brain's white matter tract, is cut to prevent the spread of seizures across the two hemispheres of the brain.

Vagus Nerve Stimulation

Vagus nerve stimulation involves implanting a battery-powered device that delivers intermittent electrical impulses to the vagus nerve. This reduces seizures by decreasing neuronal hyperexcitability.

Dietary Modifications

A ketogenic diet, which is high in fat with low ratios of carbohydrates and proteins, is preferred for LGS patients. Studies show it helps control seizures in early childhood. The exact association between diet and LGS is still under investigation; however, several positive outcomes have been reported.

Lamotrigine

Lamotrigine is an anti-seizure medication with demonstrated efficacy in controlling multiple seizure types by reducing neuronal hyperactivity. It is used as adjunctive therapy for seizures associated with LGS in patients over two years of age. It is initiated at a low dose with slow titration to prevent dermatological complications. Lamotrigine is an effective and well-tolerated treatment option for LGS.⁶

Mechanism of Action

Lamotrigine works by inhibiting voltage-sensitive sodium channels at neuronal membranes. This reduces rapid neuronal firing and decreases hyperactivity, thereby stabilising the neuronal membrane presynaptically and reducing the frequency of seizures.

Sodium influx generates the action potential. In LGS, excessive uncontrolled sodium influx leads to neuronal hyperactivity. Lamotrigine acts on the resting and inactivated sodium channels, stabilising them and preventing neuronal overshooting, which decreases seizure frequency. Its broad spectrum of action against different seizure types makes it particularly effective in managing the complications of LGS.

Pharmaceutical Aspects

Pharmacokinetics

Lamotrigine is administered orally and has a high bioavailability of approximately 90%. Food does not interfere with absorption. Its half-life is approximately 25-33 hours and it is excreted primarily in urine. Lamotrigine distributes widely throughout the body and is 55% protein bound. It is highly lipophilic and therefore crosses the blood-brain barrier easily. It is extensively inactivated in the liver through phase 2 reactions; glucuronidation produces an inactive metabolite that is excreted mainly through urine, with some faecal elimination.⁷

Dose and Dosage Forms

Lamotrigine is available in several oral dosage forms:

• Immediate-release tablets
• Chewable tablets
• Orally disintegrating tablets
• Extended-release (XR) tablets

The dose ranges from 25 to 200 mg.

Drug Interactions

Dose reduction is required when lamotrigine is given concurrently with valproate, which increases its half-life by inhibiting its metabolism. Contraceptives and CYP enzyme inducers increase lamotrigine clearance by inducing rapid metabolism. Key CYP inducers include carbamazepine, phenytoin, and rifampicin. Dose adjustments and monitoring are required in patients with hepatic or renal comorbidities.

Adverse Drug Reactions (ADRs)

Dermatological complications may occur, including Stevens-Johnson Syndrome, skin rashes, and localised necrosis. Other complications include nausea, insomnia, tremors, diplopia, ataxia, and headache. Lamotrigine is contraindicated in patients with hypersensitivity to lamotrigine or any of the ingredients used in its formulation.

Pregnancy Considerations

Pregnant women taking lamotrigine must be monitored closely. There is no strong evidence of foetal congenital malformations. Lamotrigine is present in breast milk; therefore, transfer to neonates is possible.

Patient Education

FAQs

What is the life expectancy of LGS patients?

Patients may live into adulthood. Life expectancy depends on disease severity and management.

What is the average age of death in LGS patients?

The average age ranges from 14 to 18 years.

Is LGS contagious?

No, LGS does not spread from person to person.

What behavioural problems do LGS patients have?

Patients may exhibit autistic and aggressive traits.

Does LGS cause memory loss?

LGS patients have difficulty learning; cognitive impairment tends to worsen as the disease progresses.

Does LGS resolve on its own?

No, LGS is a lifelong condition that requires continuous medical monitoring.

LGS is a chronic and treatment-resistant syndrome requiring immediate and long-term management. It is important for healthcare workers, including physicians, nurses, and pharmacists, to educate patients and caregivers about the disease to help prevent injuries during epileptic episodes. Caregivers must be informed about potential side effects of therapy and the progressive cognitive decline that may occur over time. All necessary precautions should be taken when managing LGS.

Summary

Lamotrigine is an effective anti-seizure medication used in the management of LGS, with proven efficacy in reducing seizure frequency.⁸ Its mechanism of action involves blocking sodium channels at neuronal membranes, which is particularly beneficial in controlling generalised seizures. Evidence from randomised controlled trials (RCTs) supports its effectiveness in seizure reduction compared to placebo. Additionally, lamotrigine has been shown to improve cognitive and behavioural function in patients. It is well tolerated when initiated at a low dose with gradual titration.