Juliann M. Paolicchi, MA, MD

DESCRIPTION

• Lennox–Gastaut syndrome (LGS) consists of multiple seizure types, cognitive impairment, and a characteristic pattern on the EEG of a generalized, slow spike-and-wave pattern. Considered an epileptic encephalopathy, LGS typically leads to further cognitive deterioration, and the seizures tend to be refractory to antiepileptic drugs (AEDs).

EPIDEMIOLOGY

Incidence

LGS accounts for 1–4% of all childhood epilepsies, but 10% of epilepsies present in the first 5 years. The annual incidence is estimated at 2 per 100,000 children.

Prevalence

• Prevalence rates are 0.1–0.28 per 1,000.
• No racial differences have been identified.
• Although LGS is defined as having onset in children 1–8 years, the mean age at onset is 26–28 months (range 1 day–14 years).
• Males are affected more than females.

RISK FACTORS

30–40% of patients with infantile spasms (IS) develop LGS.

Genetics

Any of the genetic syndromes associated with IS can subsequently lead to LGS – especially strong is the association with tuberous sclerosis.

GENERAL PREVENTION

Early pre- and postnatal care, vaccinations, and trauma prevention play a role in lessening of neonatal brain injury that can lead to LGS.

PATHOPHYSIOLOGY

Although there are limited studies, a recent study of simultaneous recordings of EEG and functional MRI in patients with LGS revealed significant activation of brainstem and thalamus associated with epileptiform discharges compared to control patients (1).

ETIOLOGY

The syndrome is divided into primary (idiopathic) or secondary (symptomatic). Secondary cases (65–75% of patients with LGS) are associated with a host of injuries to the developing brain: Genetic causes (tuberous sclerosis), cerebral dysgenesis, infectious, hypoxic-ischemic, or traumatic etiologies.

COMMONLY ASSOCIATED CONDITIONS

At onset, 20–60% of patients have cognitive impairment which worsens due to deterioration that occurs with LGS. Behavioral/psychological conditions, ranging from hyperactivity to autism spectrum disorders, are common comorbidities.

HISTORY

• The patient with LGS typically presents with a history of epilepsy, developmental delay, or cognitive impairment, and often a previous neurologic insult or condition. Development of LGS is suggested by a change in seizure type, lack of response to medications, and/or cognitive deterioration.
• The most frequent seizure types in LGS are tonic, tonic–clonic, myoclonic, atypical absence, and “head drop,” which are a form of atonic, tonic, or myoclonic seizures.
• Tonic seizures are the most prevalent, occurring in 74–90% of patients. They occur in both awake and sleep states, and can involve the head and trunk, including the arms or the whole body. Apnea and facial flushing are commonly associated. Events tend to be brief, lasting only a few seconds to a minute. They can occur multiple times per day, sometimes up to hundreds per day.
• Atypical absences are often subtle with a gradual onset and offset and an incomplete loss of consciousness. They may be accompanied by myoclonic jerks or automatisms.
• Atonic, myoclonic, and myoclonic–atonic seizures can produce sudden injurious “drop attacks.” Frequency ranges from 10% to 56%.
• Generalized tonic–clonic seizures occur in 15% of patients; complex partial seizures occur in 5%. Status epilepticus (SE) (54–75% of patients) can develop from multiple seizure types and tends to be prolonged, resistant to treatment, and recurrent. Nonconvulsive status epilepticus (NCSE) can be difficult to detect clinically.

PHYSICAL EXAM

The neurologic examination typically demonstrates evidence of the etiological neurologic condition (cognitive impairment, developmental delay, cerebral palsy, etc.).

DIAGNOSTIC TESTS AND INTERPRETATION

Lab

Initial Lab Tests

If there is no previous history of neurologic insult or disease, evaluation requires extensive metabolic evaluation to determine the etiology.

Imaging

Initial Approach

Brain MRI is indicated to determine etiologies such as cerebral dysgenesis, stroke, and hypoxic-ischemic encephalopathy.

Diagnostic Procedures/Other

• The EEG provides the pathognomonic finding of generalized, slow spike-and-wave, interictal pattern in an otherwise slow background. The slow spike-and-wave or sharp-and-slow-wave complexes occur as generalized bursts with frequencies between 1.5 and 2.5 Hz. The interictal background slowing may be transient or continuous. Continuous slowing is associated with a poor cognitive outcome. The ictal (seizure) EEG patterns depend on the seizure type.
• Monitoring in a video-EEG unit plays an important role in differentiating the cause of periods of epilepsy and cognitive deterioration.

DIFFERENTIAL DIAGNOSIS

• LGS can be clinically difficult to distinguish from other childhood epilepsy syndromes of multiple seizure types and cognitive dysfunction. Admission to a pediatric epilepsy video monitoring unit can be beneficial to establish the diagnosis.
• Myoclonic-astatic epilepsy consists of myoclonic, atonic, and atypical absence seizures, is predominantly idiopathic, and has a better prognosis.
• Patients with childhood myoclonic epilepsies (benign myoclonic epilepsy of infancy, severe myoclonic epilepsy of infancy, and progressive myoclonic epilepsy) have myoclonic seizures as their predominant feature, less frequent tonic seizures than LGS, faster EEG (>2.5 Hz) patterns, and more variable cognitive decline.

MEDICATION

First Line

• Broad-spectrum AEDs are the mainstay of treatment. Sedating side effects can exacerbate seizure frequency, and tolerance is common. The following AEDs have specific FDA approval for adjunctive treatment of LGS:
  • Topiramate: In double blind studies, drop seizures decreased 15% per month, and 33% of patients had 50% or greater decrease in seizures. Side effects include somnolence, anorexia, cognitive or behavioral problems, renal stones, and glaucoma.
  • Rufinamide has similar effectiveness in total seizures (2). In double blind studies, it reduced drop seizures by 42.5%. Side effects include dose-related QT shortening, somnolence, and nausea/vomiting.
  • Lamotrigine is well tolerated, and a broad-spectrum AED for LGS seizures. The most concerning side effects are idiosyncratic skin reactions: Rash in 10–12% of patients treated for LGS, Stevens–Johnson syndrome, and toxic epidermal necrolysis. Risk factors for development of lamotrigine-induced rash include younger age (children > adults), concomitant valproate treatment, a high starting dose, and rapid dose titration.
  • Felbamate: Although effective in LGS for tonic and drop seizures, it is associated with significant idiosyncratic reactions: Aplastic anemia and hepatotoxicity. The incidence of both of these reactions is low (1 in 4,000–8,000 and 1 in 18,000–25,000 treated patients, respectively), but their severity has limited its use.
  • Valproate does not have a specific FDA approval, but has broad-spectrum effectiveness for the seizure types of LGS. Sedative/cognitive side effects are minimal, except at higher concentrations. Dose-dependent side effects include ataxia, tremor, and platelet dysfunction. Idiosyncratic reactions include weight gain, alopecia, and in children <2 years of age on multiple AEDs, hepatotoxicity.

Second Line

Clobazam has been approved by the FDA as an add-on therapy for LGS. Additional broad-spectrum AEDs used for LGS include levetiracetam, which can exacerbate behavioral side effects, and zonisamide – sedation can be lessened by once nightly administration.

Additional Considerations

• Carbamazepine and long-term phenytoin are avoided; they can exacerbate the slow spike-and-wave pattern causing increased seizures or obtundation.
• Clonazepam and diazepam are effective to temporarily decrease seizures due to illness or exacerbations. Tolerance and sedation limit their long-term effectiveness.

ADDITIONAL TREATMENT

General Measures

• The primary goal of treatment is maximizing seizure control and quality of life. Monotherapy is rarely effective. Patients can have periods of relative seizure control, which usually correspond to marked improvements in cognition, alertness, and developmental progress. Unfortunately, cognitive deterioration resumes with the seizures.
• Since seizure exacerbations are expected, due to illness and the syndrome itself, caregivers should have a detailed seizure treatment plan developed with their physician such as use of long-acting benzodiazepines (clonazepam) or temporary increases in current AEDs.
• To avoid toxicity and unnecessary changes in AEDs, LGS patients should have changes to their AED regimens when exacerbations are persistent, do not respond to emergency medications, or new seizure types develop.

Issues for Referral

Patients with LGS often require neurologic care in specialized epilepsy centers to address their multiple neurologic and medical needs.

Additional Therapies

The ketogenic diet is a treatment alternative for medically refractory epilepsy. The diet consists of a high proportion of fats compared to small amounts of carbohydrates and proteins in a ratio of 3-4:1, which induces ketosis. Effectiveness in LGS is based predominantly on case reports especially in children. Side effects include an inability to tolerate the diet, sedation, GI disturbance, and social discomfort. Less restrictive dietary treatments are the modified Atkins diet and the low glycemic diet. Nutritional supervision by a dietician trained in dietary treatments for epilepsy is recommended.

SURGERY/OTHER PROCEDURES

• Two surgical procedures have been used in LGS. Anterior corpus callosotomy is performed with the goal of palliation: 8% of patients are seizure-free, 61% have improvement. Drop attacks, atonic seizures, and secondarily generalized seizures are most responsive to this procedure. Benefits are not permanent.
• The vagus nerve stimulator is approved for medically refractory partial seizures but is also used for refractory generalized seizures including LGS. Seizure freedom is rarely achieved. In small studies, 72% of LGS patients experienced a 50% reduction in seizure frequency with up to 5-year follow-up.
• Isolated cases in which resection of localized lesions improved seizures have been reported.

IN-PATIENT CONSIDERATIONS

Initial Stabilization

Treatment of seizure exacerbations and SE is individualized for each patient, based on current and past responses to AED therapy. IV benzodiazepines, fosphenytoin, valproic acid, and levetiracetam are often utilized. Continuous EEG monitoring recommended due to the propensity for NCSE, and to monitor treatment effectiveness.

Admission Criteria

Exacerbation of seizures, NCSE, SE, and encephalopathy

Discharge Criteria

Patients are discharged when the admitting issue, encephalopathy, status, or seizure exacerbation, show sustained responsiveness to treatment. Seizure freedom is not usually a goal for discharge.

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

• Patients with LGS should be monitored at regular intervals by epileptologists or neurologists familiar with medically refractory epilepsy.
• Caregiver education includes specific instructions on what conditions warrant a call or visit to the neurologist.

PATIENT EDUCATION

• Patient/caregiver education should address the many social, educational, and medical needs. Caregivers should work with available social workers and community services to obtain disability status for patients, nursing support, respite care, and residential living programs.
• The National Epilepsy Foundation provides information and support. Website: www.efa.org

PROGNOSIS

• Despite many advances, the outcome of patients with LGS remains poor. By adolescence, the combination of continued seizures, cognitive deterioration, and behavioral difficulties leads to profound social consequences. In a 10-year follow-up study, significant cognitive impairment was found in 95–100% of patients.
• Psychiatric problems can progress from mood instability and personality disturbances to acute psychotic episodes. Characteristics of mental deterioration include apathy, memory disorders, perseverance, and impaired vision or speech. Poor prognostic factors include secondary LGS, particularly after West syndrome, early onset and higher frequency of seizures, and continuous slow spike-and-wave EEG background. Mortality rates are 3–7% due to intercurrent illness/accidents.

COMPLICATIONS

SE, NCSE, progressive encephalopathy, cognitive deterioration and impairment

• Conry JA, Ng YT, Paolicchi JM, et al. Clobazam in the treatment of Lennox-Gastaut Syndrome. Epilepsia 2009;50(5):1158–1166.
• Glauser T, Diego M. Encephalopathic epilepsy after infancy. In: Pellock JM, Dodson WE, eds. Pediatric epilepsy: diagnosis and therapy, 2nd ed. Demos Medical Publishing, 2001:201.

SEE-ALSO

• Infantile spasms

ICD9

All below – with mention of intractable epilepsy

• 345.01 Generalized nonconvulsive epilepsy, with intractable epilepsy
• 345.11 Generalized convulsive epilepsy, with intractable epilepsy
• 345.91 Epilepsy, unspecified, with intractable epilepsy

• LGS is a chronic epilepsy syndrome in which the degree and frequency of seizures fluctuate. Maintaining the patient on an individualized AED regimen with efficacy and low toxicity often affords better quality of life.
• Puberty is often a challenging time for seizure and behavioral control. Psychiatric co-management is often necessary. Young adulthood typically leads to a smoother period for the epilepsy and behavior.

1. Siniatchkin M, Coropceanu D, Moeller F, et al. EEG-fMRI reveals activation of brainstem and thalamus in patients with Lennox-Gastaut syndrome. Epilepsia 2011;52(4):766–774.
2. Glauser T, Kluger G, Sachdeo R, et al. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology 2008;70(21):1950–1958.