Introduction

Lennox‑Gastaut Syndrome, also known as LGS, is a rare and intense form of childhood epilepsy that typically begins between the ages of 3 and 5 years. It affects about 0.014% to 0.028% of the general population and is known to be slightly more common in boys.¹ Children with this condition typically experience different types of seizures along with slower cognitive development and abnormal EEG (Electroencephalogram) patterns. 

Managing LGS is especially difficult due to the ability of seizures to resist certain types of treatments. 

Valproic acid, also known as sodium valproate, is a well-known antiepileptic medication that offers broad protection against many seizure types. Although not specifically approved for LGS, it remains a first-line therapy option for this condition.²

In this article, we will discuss in depth the efficacy of Valproic acid in managing LGS.

Understanding lennox-gastaut syndrome

Clinical features

Children with LGS experience different types of seizures that vary among individuals. The common seizure types are:

• Tonic seizures - Includes body stiffness, upward eye gaze, dilated pupils, and abnormal breathing patterns
• Atypical seizures - Include staring spells (means stares blankly into space with reduced level of awareness)
• Atonic seizures - Symptoms are a temporary loss of muscle tone, which could cause sudden falls
• Myoclonic seizures are characterised by rapid involuntary muscle jerks
• Generalised tonic-clonic seizures are characterised by body muscle stiffness and rhythmic jerking

There may be intervals of frequent seizure episodes mixed with relatively seizure-free periods. Children with LGS not only experience different seizure types, but they may also encounter developmental delays, difficulty processing information, behavioural challenges and abnormal EEG findings.²

EEG findings and diagnostic criteria

To diagnose Lennox-Gastaut Syndrome, physicians start by reviewing the child’s complete medical history, such as details about development, behaviour, learning, and past seizures, with a proper physical check-up. ^1,7

Lab tests

Listed below are the different lab tests that are done to check overall health:

• Complete blood count (CBC)
• Blood tests for sugar, salts, calcium, magnesium, liver and kidney function
• Urine tests for drug screening
• Tests for ammonia, lactic acid, amino acids and other metabolic substances

EEG (electroencephalogram)

• An EEG can be used to diagnose LGS by looking at the electrical activity of the brain when the child is awake and asleep
• It commonly shows a particular slow spike and wave pattern, usually 1.5 to 2.5 waves per second, mostly seen in the front part of the brain^3,5
• The EEG may also show fast bursts of brain activity, especially during sleep

Brain MRI

It is done to check for any damage in the brain’s structure, but it’s not always needed to confirm LGS.

Genetic testing

This includes checking for epilepsy related genes and chromosomal changes.

Causes

LGS can be caused by different conditions, which include the following:²

• Brain malformations
• Tuberous sclerosis  (an uncommon non-cancerous genetic tumour on different parts of the body, like the brain, skin, e.t.c)
• Perinatal asphyxia (lack of oxygen and perfusion to organs before, during or after birth)
• Severe head injury
• Central nervous system infection
• Inherited genetic and degenerative or metabolic conditions 

Pharmacological profile of valproic acid

Mechanism of action

It is a broad-spectrum drug which is one of the most common medicines for a variety of seizure types. Valproic acid works by calming the overactive electrical signals in the brain by blocking voltage-gated sodium channels, enhancement of GABA synthesis and mildly inhibiting T-type calcium current.⁴

Routes of administration

It comes in both extended and delayed release versions. Valproic acid can be administered by 2 different routes:⁴

• Oral (tablets, sprinkles, capsules, oral suspension)
• Intravenous route 

Valproic acid in LGS

Evidence from clinical studies and trials

Although no large-scale randomised trials focus only on valproic acid in LGS, it is evidently widely accepted as the primary medicine for newly diagnosed cases. Clinical evidence supports its effectiveness.

In one observational study of 336 epilepsy patients (38 with LGS), valproic acid alone or with at least one  among other drugs like Phenytoin, primidone and benzodiazepines led to complete seizure control in 21% and at least 50% reduction in seizures in people with this condition. It was especially effective in reducing drop attacks, atypical absences, and myoclonic seizures.⁵

Comparative efficacy with other anti epileptic drugs (AEDs) used in LGS

In a prospective study of 43 newly diagnosed LGS patients, a combination of valproic acid, clobazam, lamotrigine,  topiramate and levetiracetam resulted in more than half experiencing a ≥50% seizure reduction after six months.⁶

Consensus guidelines from epilepsy experts endorse valproic acid as the initial monotherapy for LGS, with lamotrigine and rufinamide recommended if additional control is needed.

Safety and tolerability of valproic acid

Common side effects

The most common side effects of VPA (valproic acid) medicines are headache, tremor, low platelet count, depression, rash, dizziness, alopecia, sleeping issues, bruising, GIT issues (abdominal pain, diarrhoea, constipation, etc.), appetite and weight changes, body ache, blurred vision, photosensitivity, and shortness of breath. However, these side effects normally resolve over time or with appropriate adjustments of the dose.⁴

Serious adverse effects

VPA can lead to several serious adverse reactions, including hepatotoxicity, hallucinations, suicidal ideation, psychosis, toxic epidermal necrolysis, Stevens-Johnson syndrome, anaphylaxis, pancreatitis, low levels of blood cells and Sodium, hyperammonemia, hypothermia, aplastic anaemia, bleeding, erythema multiforme, PCOS, encephalopathy and coma.

Although these adverse effects are uncommon, they can potentially be life-threatening. Therefore, sudden medical intervention and discontinuation of VPA may be required in such cases. It is highly important to monitor patients as discontinuation of the medication may trigger withdrawal seizures.⁴

Considerations in paediatric use and during pregnancy

• Caution and close monitoring of clinical and laboratory parameters are required in paediatric patients. The dosage should be personalised based on age, weight, seizure type, current medicines, and plasma concentration^4,8
• Taking VPA also shows teratogenic effects by passing through the placental barrier if you are pregnant. Furthermore, VPA is 10 times more likely to increase the risk of neural tube defects (NTDs) than the general population. Other malformations reported are cardiovascular and limb defects. It can also cause cognitive delays, behavioural issues and autism disorders. Consequently,  the use of VPA is not recommended during pregnancy as the risk outweighs the benefits^{4, 9}

Drug interactions

Valproic acid's interaction with different drugs can either enhance the therapeutic effect or decrease the therapeutic effect of LGS. Outlined below are examples of medications that could affect the efficacy and accumulation of VPA in the bloodstream, which could cause toxicity when combined together.⁴

• Enzyme-inducing drugs
  • Carbamazepine, Phenytoin and Rifampin
• Enzyme-inhibiting drugs
  • Statins, Felbamate and NSAIDs
•  Protein-binding drugs
  • Salicylates and Sulfonamides
• Other antiepileptic drugs
  • Lamotrigine and Phenobarbital

Limitations and considerations in use

Despite its usefulness, valproic acid does not control seizures in all LGS patients. Many require additional medications to make a meaningful difference. Newer drugs like rufinamide, lamotrigine, clobazam, fenfluramine, cannabidiol, and others can be added based on seizure types and individual tolerability.⁵

Non-drug options like ketogenic and low-glycaemic index diets, vagus nerve stimulation, or surgery may also be utilised if drug therapy alone isn’t efficacious in patients⁴

Summary

Lennox-Gastaut Syndrome (LGS) is a rare and intense form of childhood epilepsy that involves different seizure types, developmental delays and abnormal EEG patterns. Valproic Acid is commonly used as a first-line treatment due to its broad-spectrum antiepileptic action.

Clinical evidence shows that VPA can significantly reduce seizures, especially drop attacks, myoclonic, and atypical absence seizures. It works by stabilising brain activity through different mechanisms. However, it may cause side effects like liver toxicity, weight changes, and birth defects if used during pregnancy. Monitoring for side effects is important, especially in paediatric populations.

FAQ’s

Can valproic acid completely stop seizures in people with LGS?

It may control seizures in some patients, but many need additional medications or therapies to improve seizure control.

Are there any serious risks with valproic acid?

Yes,  liver damage, pancreatitis, low blood counts, hallucinations and suicide, hence the need for patients to be regularly monitored.

Is valproic Acid safe during pregnancy?

No, it may cause serious developmental issues and birth defects. It is usually advised to avoid taking it during pregnancy. 

Can valproic Acid be used with other antiepileptic drugs (AEDs)?

Yes, but it may interact with other AEDs. Dosage adjustments and close observation are necessary to avoid toxicity or reduced efficacy.

What other treatments are used if valproic Acid isn’t effective?

Some options include lamotrigine, clobazam, rufinamide, cannabidiol, ketogenic diet, and vagus nerve stimulation.

Although it is known to be effective in most circumstances, VPA doesn’t work for everyone and many children with this condition need combination therapy or additional non-drug treatments. Nevertheless, despite its risks, VPA plays an important part in LGS management.