The use of novel treatments such as cannabidiol has emerged as a promising strategy to address two types of epileptic encephalopathies: Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS).

Epileptic encephalopathies are severe but rare epileptic disorders that commence early in life. Like all epileptic encephalopathies, LGS and DS are characterized by drug-resistant generalized/focal seizures, persistent severe abnormalities on EEGs, and cognitive dysfunction/decline, according to research published by Pharmacy and Therapeutics.

Lazaridis D, Eraikhuemen N, Williams K, et al. Treatment of seizures associated with Lennox-Gastaut and Dravet syndromes: A focus on cannabidiol oral solution. Pharmacy and Therapeutics. 2019;44(5):255–266.

 

Having a deeper understanding of these pathologies may help physicians determine the efficacy of how emerging treatments may help patients who suffer from them.

 

Lennox-Gastaut syndrome explained

LGS was first described in the 1930s and named for two neurologists: William Lennox and Henri Gastaut, according to research published by US Pharmacist.

Jacob EC, Jacob SC. Emerging treatments for Dravet and Lennox-Gastaut syndromes. US Pharm. 2019;44(1):HS-8-HS-12.

It occurs in 0.1 to 0.28 people per 100,000 and represents 1%–4% of all cases of childhood epilepsy with a slight male predominance, according to research published in Epilepsia.

Camfield PR. Definition and natural history of Lennox-Gastaut syndrome. Epilepsia. 2011;52:3–9.

 

LGS has no specific diagnostic biomarker and is a clinical diagnosis. It is diagnosed by the following signs/symptoms: multiple seizure types (tonic, atypical absence, atonic, myoclonic, nonconvulsive status epilepticus, focal and epileptic spasms), slow spike-wave complexes on EEG (≤ 2.5 Hz) predominantly in the frontal region, behavioral disorders, and impairment of cognitive function, according to the Pharmacy and Therapeutics research.

Recurrent seizures are hard to control in these patients and are a hallmark of LGS, with tonic and atypical absence seizures being the most common. Other symptoms include loss of consciousness/drop seizures and loss of muscle tone/contractions, which can lead to falls. Cognitive impairment is marked by intellectual disability and psychiatric disease that worsens over time.

Although LGS is difficult to diagnose prior to the onset of symptoms, early diagnosis and management can improve patients’ clinical course. LGS can be symptomatic or cryptogenic, and its causes can be known or unknown.

Symptomatic LGS usually manifests during the first year of life and can stem from cerebral insults occurring due to hypoxic-ischemic encephalopathy, brain malformations, neurocutaneous syndromes (tuberous sclerosis), meningitis, head trauma, radiotherapy, and more.

Diffuse/multifocal insults at the level of the cortical gray matter may also contribute to LGS. Up to 25% of patients have a history of infantile spasms (West Syndrome), according to a multicenter study published by Elepsia.

Widdess-Walsh P, Dlugos D, Fahlstrom R, et al. Lennox-Gastaut syndrome of unknown cause: Phenotypic characteristics of patients in the epilepsy phenome/genome project. Epilepsia. 2013;54(11):1898–1904.

 

Approximately 40% of patients have no known cause, and genetic abnormalities may contribute to LGS, with a family history observed in up to 30% of patients, according to US Pharmacist. Epilepsy gene panels, chromosome microarrays, and whole-exome sequencing can be useful in identifying an etiology.

 

Dravet syndrome facts

In 1978, Charlotte Dravet, a pediatric psychiatrist and epileptologist, first described DS (ie, severe myoclonic epilepsy of infancy). After years of intense study, DS is understood to be a rare, severe, and inheritable epileptic encephalopathy and voltage-gated sodium (Nav) channelopathy, with a genetic cause identified in 2001.

The most common genetic abnormality occurring in DS is a heterozygous mutation in the SCN1A gene, which codes for the neuronal voltage-gated sodium channel (Nav1.1) and presents in up to 85% of DS patients.

Roughly 90% of patients identified with a pathogenic variant of the SCN1A gene are de novo mutations with approximately 10% of patients due to familial causes according to research published by The American Journal of Human Genetics.

Claes L, Del-Favero J, Ceulemans B, et al. De novo mutations in the sodium-channel gene scn1a cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001;68(6):1327–1332.

 

This intractable pediatric epilepsy syndrome typically starts in early childhood and affects 1 of 15,700 births in the US. Clinical features of DS include frequent, prolonged different seizure types, speech impairment, neurological disability, neurodevelopmental delay, hypotonia, ataxia, and sleep disturbance, according to the US Pharmacist research.

DS should be suspected in patients that have new drug-resistant seizures with precipitating fever and neurodevelopmental regression after seizure onset. Diagnosis of DS depends on distinct findings, including:

• Episodes of prolonged febrile (ie, generalized or partial) seizures in patients aged between 1 and 18 months

• Following seizure onset, patients continue to exhibit recurrent tonic-clonic, myoclonic, or atypical absence seizures, which are triggered by hyperthermia, flashing lights, overexertion, bathing, and visual patterns, according to Pediatric Neurology research.

  Wirrell EC, Laux L, Donner E, et al. Optimizing the diagnosis and management of Dravet syndrome: recommendations from a North American consensus panel. Pediatric Neurology. 2017;68:18-34.e3.

   

• Nonspecific EEG findings and normal MRI findings

• Seizures evolve over time, with myoclonus manifesting at around age 2

• Genetic testing for SCN1A is strongly recommended when the diagnosis is suspected

Although patients initially present with a normal neurological exam, by ages 18 to 60 months, permanent intellectual disability and abnormal neurologic examination are evident. These individuals also present with behavioral concerns, depression or anxiety, ADD, ADHD, and other comorbidities, as per the Dravet Syndrome Foundation.

Comorbidities in Dravet syndrome. Dravet Syndrome Foundation.

 

 

Patient burden shared by LGS and DS

Although LGS and DS are different types of epileptic encephalopathies, the toll that both take on patients is similar. Results of a pilot study conducted in France and the UK published in Epilepsy & Behavior demonstrated that quality of life (QoL) statistics were influenced by both seizure frequency and seizure-free days.

Auvin S, Damera V, Martin M, et al. The impact of seizure frequency on quality of life in patients with Lennox-Gastaut syndrome or Dravet syndrome. Epilepsy Behav. 2021;123:108239.

However, reducing seizure-free days had a greater impact on QoL.

 

The investigators suggested that their results could help build models to explore treatment options for patients with LGS and DS.

“These data could then be converted into utility values and utilized in cost-utility models for the approval of new anti-seizure medications, for example, cannabidiol (CBD, approved as Epidiolex in the US and Epidyolex in the EU),” the authors wrote. “This model has been accepted within the EU and will be expanded globally to evaluate the cost-effectiveness of CBD for add-on treatment of LGS and DS.”

 

Treatment approaches

LGS is challenging to treat because patients are often resistant to anti-epilepsy regimens. Treatment goals include controlling seizures, minimizing adverse effects, and improving QoL. First-line approaches include valproic acid, with adjunctive options including lamotrigine and rufinamide, as well as topiramate, fenfluramine, clobazam, and felbamate.

Nonpharmacologic strategies for the treatment of LGS include the ketogenic diet, vagal-nerve stimulation, and corpus callosotomy. Data do not support efficacy for more than two antiseizure medications (ASM) due to side effects, but there are some instances when the short-term use of clobazam in addition to two ASMs could be beneficial, according to Frontiers in Neurology.

Cross JH, Auvin S, Falip M, et al. Expert opinion on the management of Lennox-Gastaut syndrome: Treatment algorithms and practical considerations. Front Neurol. 2017;8:505.

 

For DS, the optimization of medication therapy is a goal, with first-line options including valproic acid and clobazam. For medication-resistant patients, second-line options include topiramate and stiripentol, while third-line pharmacologic options include levetiracetam, clonazepam, and phenobarbital.

Non-pharmacologic strategies include trigger avoidance (eg, hyperthermia), as well as antipyretics for fever. The keto diet is a second-line non-pharmacologic option, with vagal-nerve stimulation a third-line option.

Cannabidiols have shown to be safe and effective for both LGS and DS, with the FDA approving Epidiolex in 2018 for LGS or DS patients aged 2 years or older, as reported in the US Pharmacist research.