US Pharm. 2019;44(1):HS-8-HS-12.
ABSTRACT: Dravet syndrome and Lennox-Gastaut syndrome are severe epileptic encephalopathies that manifest during early childhood. Challenging to diagnose and treat, patients often develop severe neurologic, intellectual, and behavioral disorders that progressively worsen. While multiple pharmacologic and nonpharmacologic interventions exist, careful selection of therapy is paramount as some medications can exacerbate seizures. With the recent approval of Epidiolex (cannabidiol) for the treatment of seizures associated with Lennox-Gastaut or Dravet syndrome, providers and patients have an additional therapeutic option to consider. Within this context, pharmacists have a vital role in educating providers, caregivers, and patients on medication therapy.
Approximately 3 million adults and 470,000 children in the United States are diagnosed with epilepsy disorders.1 Among patients who report adherence to their medication therapy, only 44% achieve adequate seizure control.2 This statistic is alarming, as uncontrolled seizures markedly increase mortality, cognitive deficits, physical and psychiatric disease, and reduce quality of life.2 Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are two rare and severe epilepsies that develop during childhood, and seizure control associated with these disorders is challenging.3,4 The recent approval of Epidiolex (cannabidiol) brings hope for DS and LGS patients.5
Dravet syndrome, or severe myoclonic epilepsy of infancy, was first described in 1978 by Charlotte Dravet, a pediatric psychiatrist and epileptologist.6 Since it was first recognized, DS has been studied extensively and is now accepted as a rare, severe, and inheritable epileptic encephalopathy and voltage-gated sodium (Nav) channelopathy.7
A 2015 epidemiological study revealed that the incidence of DS in the United States is one in 15,700 births.8 Approximately 80% of patients diagnosed with DS are thought to have a genetic mutation in the voltage-gated sodium channel 1 A gene (SCN1A).9 Mortality for patients with DS is high, and the annual rate of sudden unexpected death in epilepsy is approximately 0.6%, significantly higher than all patients with epilepsy.10 In addition to the immense humanistic burden this disease presents, it also poses an enormous financial burden, with direct and indirect patient-care costs reported to be over $106,000 per annum.11
Diagnosis and Clinical Presentation
The diagnosis of DS is based on distinctive early clinical findings.12 Patients generally present with initial episodes of prolonged febrile seizures that are generalized or partial between the ages of 1 and 18 months.13,14 Electroencephalography (EEG) in these patients displays nonspecific findings, and magnetic resonance imaging is generally normal.12 Following seizure onset, patients continue to have recurrent tonic-clonic, myoclonic, or atypical absence seizures triggered by hyperthermia or by flashing lights, overexertion, bathing, and visual patterns.12,15 The seizure types that patients exhibit evolve over time, with myoclonus presenting around age 2 years. Initially, patients present with normal development and neurologic examination, but by age 18 to 60 months, permanent intellectual disability and abnormal neurologic examination are observed.12,16 In addition, patients often develop behavioral concerns, impaired social skills, and comorbid conditions such as attention-deficit/hyperactivity disorder.17
Etiology and Pathophysiology
Epilepsies including DS are a manifestation of abnormal electrical activity in the central nervous system, and a significant percentage of idiopathic epilepsies is related to genetic abnormalities.18 In DS, the genetic abnormality is often a heterozygous mutation in the SCN1A gene, which encodes the neuronal voltage-gated sodium channel (Nav1.1).9,18 This variation is noted in up to 85% of DS patients.12
A careful balance of activity in excitatory and inhibitory neurons orchestrates normal brain rhythms. NaV1.1 is preferentially expressed in inhibitory GABAergic interneurons and permits rapid sodium influx that initiates action potentials.19-21 These channels thus limit excess excitatory activity and enable stable brain rhythms. Emerging research using mouse models and neurons differentiated from patient-derived, induced pluripotent stem cells suggests that DS-associated NaV1.1 mutations result in a marked loss of channel function that causes an imbalance in excitatory versus inhibitory neurotransmission and promotes seizure activity.18,20,22
As complete seizure remission is rare, the goal for therapy is to reduce seizure severity and frequency, minimize adverse effects of medication therapy, improve quality of life, and maximize neurodevelopmental potential.12,17
Optimization of medication therapy is the cornerstone of managing seizures in DS. First-line pharmacologic options includes valproic acid and clobazam.12,17,23 If patients continue to exhibit a lack of seizure control, second-line agents include topiramate and stiripentol.17 Third-line pharmacologic options include levetiracetam, clonazepam, zonisamide, ethosuximide, and phenobarbital.12,17,23 Recent literature suggests that cannabidiol is a safe and effective option for DS patients.3,24
Nonpharmacologic management includes avoiding triggers such as hyperthermia, antipyretics for fever, ketogenic diet as a second-line option, and vagal-nerve stimulation as a third-line option.12,17 Of note, several antiepileptics exacerbate seizures in patients with DS, primarily due to sodium channel blockade, and must be avoided. These medications include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, rufinamide, phenytoin, and vigabatrin.17,23
Named for two neurologists, William Lennox and Henri Gastaut, LGS is a severe epileptic encephalopathy of childhood onset first recognized in the 1930s.25-28
LGS accounts for 1% to 4% of all childhood epilepsies with an onset usually between ages 3 to 7 years and potentially lasting through adulthood.29,30 The lifetime prevalence of LGS at the age of 10 years is estimated to be 26 per 100,000 people.31 Ninety-one percent of LGS patients develop intellectual disabilities, and the mortality rate is estimated to be between 4% and 7%.31,32
Diagnosis and Clinical Presentation
LGS is diagnosed based on a triad of symptoms: (1) the presence of multiple types of seizures; (2) a unique presentation on EEG; and (3) cognitive impairment.28 Patients also have recurrent seizures that are intractable, with tonic and atypical absence seizures being the most common. EEG records in LGS patients show a slow, spike-wave pattern with generalized and fast poly-spikes. Patients may experience a loss of consciousness and drop seizures, with lost muscle tone or contraction leading to an increased likelihood of falls. Patients also suffer from cognitive impairment, with intellectual disability and behavioral and psychiatric disorders that progressively worsen. Due to increased morbidity, LGS incurs substantial cost.26,31 LGS is difficult to diagnose prior to symptom presentation; however, early diagnosis and management can improve prognosis and clinical course.29
Etiology and Pathophysiology
LGS can be classified as either symptomatic, if the cause or neurologic abnormality is known, or cryptogenic, if the cause is unknown. Symptomatic LGS usually occurs in the first year of life and may result from cerebral insults from hypoxic ischemic encephalopathy, brain malformations, tuberous sclerosis, down syndrome, brain tumors, head traumas, or radiotherapy.29,33 Diffuse or multifocal insults occurring in the cortical gray matter during brain development can also contribute to LGS.33 Genetic mutations are suspected to play a role in LGS cases, with family history observed in 3% to 30% of patients.29 Cryptogenic cases, on the other hand, constitute up to one-third of LGS patients.26 These individuals have normal psychomotor development and lack overt brain-imaging abnormalities prior to seizure onset.29
LGS is a difficult syndrome to manage, as patients are resistant to commonly used antiepilepsy regimens.32 Current pharmacologic management involves using valproic acid as first-line treatment. Adjunctive treatment includes lamotrigine and rufinamide, with subsequent options of topiramate, clobazam, and felbamate. Various nonpharmacologic therapies are also used, including ketogenic diet, vagal-nerve stimulation, surgery, and corpus callosotomy. No more than two antiepileptic drugs should be used concomitantly.30 The treatment goals are seizure control, minimizing side effects of therapy, and improving quality of life.29
Cannabis has been used for over 4,000 years with varied success to treat ailments including chronic pain, eating disorders, rheumatism, and convulsions. In the 19th century, neurologists noted the potential effectiveness of cannabis for treating seizure disorders.34 Research since has continued to evaluate cannabis as a treatment option for epilepsy.
Cannabis sativa contains several active compounds, of which tetrahydrocannabidiol (THC) and cannabidiol (CBD) are the most well-studied.3,15 THC, a psychoactive agent, has both anticonvulsant and proconvulsant properties, while CBD, with no notable psychoactive effects, is consistently an anticonvulsant.3,34,35 The mechanism of action by which CBD exerts its antiseizure effect is yet to be fully elucidated. Emerging studies suggest that the anticonvulsant properties of CBD may be unrelated to its activity at the cannabinoid receptor but may stem from modulation of ion channels, transporters, enzymes, and receptors.36 Recent work suggests that CBD may inhibit voltage-gated sodium channels, though differential effects on excitatory versus inhibitory neurons are unknown.37
Multiple randomized, double-blind, placebo-controlled trials found significant improvement of seizure control when patients were treated with CBD in addition to their standard epilepsy treatment. Children and adults with DS and refractory seizures receiving CBD (20 mg/kg/day) for 14 weeks exhibited a 52% reduction in seizure frequency compared to a modest 5% reduction with placebo (P = .01).38 In fact, 5% of these patients in the treatment group were seizure-free (P = .08).38 Similarly, in another study, addition of CBD (20 mg/kg) in patients with LGS and other refractory seizures resulted in a 43.9% median reduction of drop seizures in comparison with a 21.8% reduction with placebo addition.39 A third trial evaluating CBD in patients on standard epilepsy treatment showed 41.9% and 37.2% reduction in drop seizure frequencies over a 14-week treatment period with doses of 20 mg/kg and 10 mg/kg twice a day, respectively, compared with 17.2% in the placebo group.
In these studies, adverse effects noted included decreased appetite, diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal liver-function tests.38-40 Drug interactions that may require monitoring and dose adjustment included valproic acid and clobazam.38-40 These results highlight the potential of cannabidiol as an adjunctive treatment for DS, LGS, and other refractory seizures.
The initial dosing recommendation for cannabidiol is 2.5 mg/kg by mouth twice daily. CBD may be titrated weekly by 2.5 mg/kg twice daily to a maximum dose of 20 mg/kg/day if needed and tolerated. Gradual dose titration upon initiation and discontinuation is recommended.41
On June 25, 2018, the FDA approved Epidiolex (cannabidiol) oral solution for the treatment of seizures associated with LGS or DS in patients aged 2 years and older.5 Subsequently, on September 27, 2018, the U.S. Department of Justice and Drug Enforcement Administration placed Epidiolex in Schedule V.42
Patients with refractory seizures such as DS and LGS are at an increased risk for medication errors for reasons including complex medication regimens and increased transitions of care.43 As pharmacotherapy experts, pharmacists can play a major role in ensuring safe and effective therapy for patients by educating providers on appropriate medication choices and doses; evaluating patients’ medication regimen for contraindications, drug interactions, and adverse effects; ensuring that medication reconciliation is conducted carefully; and accurately providing education and counseling on medication therapy to patients and family members.
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