Lennox Gastaut Syndrome (LGS)

Overview

  • Lennox Gastaut Syndrome (LGS) is characterised by epileptic seizures, a characteristic electroencephalogram (EEG), regression, psychomotor delay and behaviour disorders. The syndrome is an example of an epileptic encephalopathy.
  • LGS occurs more frequently in males and onset is usually before the age of eight with a peak between age three and five. Late onset cases can occur in adolescence and early adulthood.
  • Seizures typically include prominent tonic seizures, atypical absences and drop attacks (tonic and atonic seizures). Other seizures such as generalised tonic clonic and focal seizures are less frequent.
  • Psychomotor delay and behavioural disturbance in the school-aged child can be heralding signs.
  • The interictal EEG is characterized by irregular slow spike wave and generalised paroxysmal fast activity. Tonic seizures are associated with paroxysms of generalised fast activity.
  • Prognosis is poor and remission with preserved cognition occurs in very few.
  • The treatment has been difficult and disappointing. Epilim, clobazam, lamotrigine, levetiracetam, topiramate, and rufinamide are reported to reduce the frequency of seizures. There have been two randomised controlled trials showing cannabis (Epidiolex) statistically reduces the incidence of drop attacks. Ketogenic diet is also an option. Surgical options of corpus callosotomy and vagal nerve stimulator are indicated when frequent injuries with drop seizures occur.
  • Early neurology referral is recommended.

According to the NICE Guideline: The Epilepsies:

  • The seizure type(s) and epilepsy syndrome, aetiology, and co-morbidity should be determined.
  • If there is diagnostic uncertainty, individuals should be referred to tertiary services soon (within 4 weeks) for further assessment.

 

Demographics

Age at onset

  • Prevalence 1-2% of all patients with epilepsy, 1-10% of all childhood epilepsies.
  • Present 1 to 8 years (greater than 90% less than 8 yrs) – peak onset 3 to 5 years.
  • Usually, there are existing neurological issues at seizure onset, with cognition affected/development delay prior to the onset of seizures. 
  • 20% have a history of epileptic spasms. 

Sex

  • Males slightly predominate.

Aetiology

About 2/3 of cases are related to an existing neurological problem.

  • Up to 75% have an identifiable cause:
    • Birth asphyxia, head injuries, Tuberous Sclerosis, previous infection, brain malformations, metabolic disorders.
    • 25% history of perinatal complications.
  • 25-35% do not have an identifiable cause (query possible genetic component).
    • SCN1A, CHD2, FOXG1, DNM1 mutations have been reported in association with LGS.

 

Signs | Symptoms

Seizure semiology

  • Tonic seizures occur in most affected children and most frequently when falling asleep. They are usually brief, lasting seconds. They may be axial, with flexor movements of the head and neck. They may involve elevation and abduction of the proximal upper limbs, stiffening of posterior neck muscles, elevation of the shoulders, opening of the mouth, upward deviation of the eyes and brief apnoea. They may lead to sudden falls if the patient is upright.
  • Atypical absence seizures are also common.  Both the onset and the termination are gradual which is very different to typical childhood absence seizures. Atypical absences are often followed by some post-ictal cognitive impairment. Associated manifestations including eyelid and perioral myoclonus, progressive flexion due to loss of postural tone, and localised phenomena such as head-nodding and neck stiffening can occur in the atypical absence.
  •  Atonic seizures are characterised by sudden intense loss of postural tone of the head or whole body.
  • Other types of seizure also occur, including generalised tonic-clonic seizures, focal seizures, and/or myoclonic seizures.  
  • Most patients with LGS have 1 or more episodes of status epilepticus which can take a number of forms including:
    • A prolonged absence status epilepticus that can last for days or weeks and looks like an insidious confused state. This can be very difficult to recognise in children with severe intellectual disability. 
    • Pure tonic status epilepticus, which is more often seen in older patients and can be life-threatening due to the inherent risk of prolonged apnoea.

Comorbidity of psychological and psychiatric difficulties

  • Behavioural disturbance in the school-aged child is also typical. Language is frequently affected, with both slowness in ideation and expression, in addition to difficulties of motor dysfunction. In most children, there is slowing or even complete arrest of psychomotor development.
  • Severe behavioural disorders (for example hyperactivity, aggressiveness, and autistic tendencies) and personality disorders are nearly always present. There is also a tendency for psychosis to develop with time.

Differential diagnosis

  • Other epileptic encephalopathies such as Epilepsy with Continuous Spikes and Waves during Slow Wave Sleep otherwise known as ESES. This begins between 3 and 6 years of age with atonic seizures and atypical absences. This syndrome typically has no tonic seizures.
  • Myoclonic Atonic Epilepsy (MAE) – the presence of myoclonic atonic seizures in Doose syndrome helps distinguish, although some forms of severe MAE (Doose) can closely resemble LGS.
  • Infantile ceroid lipofuscinosis and other neurodegenerative disorders should be considered in the differential diagnosis.
  • Atypical childhood epilepsy with centrotemporal spikes.

Investigations

EEG

  • Background is commonly slow with paroxysms of <2.5 Hz slow spike wave.  Paroxysmal fast activity (≥ 10 Hz) is seen in slow sleep. The latter 2 features are mandatory requirements (slow spike/wave and paroxysmal fast activity).
  • Ictal EEG is variable according to seizure type. Tonic seizures are often associated with paroxysms of generalised fast activity (~20 Hz); atypical absences with <2.5 Hz slow spike and wave. Flattening of the EEG is also seen during tonic seizures.  

Neuro Imaging

  • Needs careful consideration in an obtunded patient with LGS, particularly if head injury has occurred during the tonic seizures and drop attacks (potential for injury, foe example subdural haematoma).
  • Findings depend on aetiology. Structural abnormalities are common.

Prognosis

Serious intellectual problems are noted in almost all patients within 5 years of diagnosis (75-99%).

  • A small subset do subsequently function within the normal range, with later onset having a more favourable prognosis.
  • Development of disabling drop attacks in significant proportion.
  • Gait deterioration
  • Behavioural and psychiatry problems common
    • Aggression, psychosis
  • Autism is potential comorbidity

Management

  • Early referral to a paediatric neurologist.
  • The optimum treatment for Lennox-Gastaut syndrome remains uncertain and no study to date has shown anyone drug to be highly efficacious.
  • Sodium valproate, lamotrigine, levetiracetam, clobazam and topiramate may be helpful to treat drop attacks and atypical absences. Sodium valproate and lamotrigine are synergistic in action.
  • More recent drugs such as rufinamide have efficacy as adjunctive treatment.
  • There have been two randomised controlled trials showing cannabis (Epidiolex) statistically reduces the incidence of drop attacks.
  • The ketogenic diet has been effective in some patients.
  • Others: levetiracetam, zonisamide, nitrazepam.
  • Aggravating drugs: phenytoin, carbamazepine, lacosamide may aggravate tonic seizures and drop attacks.
  • When there are drug resistant frequent drop attacks causing significant injuries then surgical options such as corpus callosotomy and/or vagal nerve stimulator may be indicated.It is important to consider resective surgery in particular patients.
  • Clinicians will need to continue to consider each patient individually, taking into account the potential benefit of each therapy weighed against the risk of adverse effects.
  • Behavioural problems. psychiatric illness and sleep disturbances are frequent comorbidities to be addressed. 

Discussion with family

Resources

Epilepsy Action (UK) have information for Parents on Lennox-Gastaut syndrome

References

  • Asadi-Pooya, A.A. 2018. Lennox-Gastaut Syndrome: A comprehensive Review. Neuro Sci: 2018 39:403-414. doi: 10.1007/s10072-017-3188-y
  • Cross JH, Auvin S, Falip M, Striano P, Arzimanoglou A. Expert Opinion on the Management of Lennox-Gastaut Syndrome: Treatment Algorithms and Practical Considerations. Front Neurol. 2017 Sep 29;8:505. doi: 10.3389/fneur.2017.00505
  • Devinsky et al. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N Engl J Med 2018; 378:1888-1897. doi: 10.1056/NEJMoa1714631 
  • Panayiotopoulos CP. The epilepsies: Seizures, syndromes and management: Based on the ILAE classifications and practice parameter guidelines. Chipping Norton, Oxfordshire: Bladen Medical Publishing; 2005.
  • Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence (4th ed).  Montrouge, France: John Libbey Eurotext Ltd ; 2005.
  • Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K; GWPCARE4 Study Group. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018 Mar 17;391(10125):1085-1096. doi: 10.1016/S0140-6736(18)30136-3

Content last reviewed November 2020.