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Lennox-Gastaut Syndrome

Lennox Gastaut Syndrome

Lennox-Gastaut syndrome is characterized by a pediatric onset of epileptic encephalopathy, most commonly between ages 3 and 5. Recurrent seizures that do not respond to therapy, impaired cognitive function and distinctive EEG changes are hallmarks of this condition. Imaging studies such as MRI and PET scan are used to support the diagnosis. Antiepileptics and surgery are the mainstay of therapy, but the overall prognosis is poor.

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Presentation

The clinical presentation of LGS is composed of a triad of symptoms - seizures of multiple subtypes, intellectual impairment and abnormal EEG findings [5]. Abrupt appearance of unexplained falls is often the first symptom, followed by the onset of seizures [1]. 60% of patients will develop atypical absence seizures, while tonic, atonic and generalized seizures are seen in 80%, 65% and 55%, respectively [6]. Tonic seizures are most frequently observed and they may be present only during sleep, together with sleeping difficulties. Repeated seizures and status epilepticus may be encountered and isolated studies report that up to 100 seizures may be experienced during 24 hours [2]. Mental disability and retardation are seen in more than 90% of patients [10]. Learning difficulties, behavioral changes that include hyperactivity and aggression, as well as autism-like appearance are frequently observed [1].

Falling
  • All 3 types can produce a sudden fall, producing injuries (drop attacks, Sturzanfälle) or may be limited to the head falling on the chest (head drop, head nod, nictatio capitis).[emedicine.medscape.com]
  • Division of the anterior half of the corpus callosum was performed in two patients with Lennox-Gastaut syndrome incapacitated by frequent atonic seizures leading to sudden falls.[ncbi.nlm.nih.gov]
Aggressive Behavior
  • Treatment with benzodiazepines, including clobazam, may increase aggression/behavioral problems in patients with Lennox-Gastaut syndrome.[ncbi.nlm.nih.gov]
Seizure
  • […] whose predominant disabling seizure type is atonic.[ncbi.nlm.nih.gov]
  • The most common seizure patterns are tonic, atypical absence, and “drop attacks” or atonic seizures, but generalized tonic-clonic and focal seizures can occur as well.[childneurologyfoundation.org]
  • These include myoclonic seizures, which are characterized by abnormal, jerky movements and may occur alone or in conjunction with atypical absence seizures; tonic-clonic seizures (once known as grand mal seizures), which last a couple of minutes and are[rarediseases.org]
Atonic Seizures
  • Postoperatively, the atonic seizures were completely eliminated and their mental reactivities remarkably improved.[ncbi.nlm.nih.gov]
  • The frequency of atonic seizures, rather than that of all seizures, was chosen as the primary end point. Atonic seizures are the most consistently identifiable and reliably documented seizures as well as the most debilitating in this syndrome.[doi.org]
Generalized Seizure
  • Data obtained from this child suggest that both the sleep stages and the generalized seizures of the ILGS basically depend more on the integrity of the brain stem than on the telencephalic structures.[ncbi.nlm.nih.gov]
Hyperactivity
  • None of the adverse events were life threatening, and the most common adverse event was hyperactivity (12.7%). CONCLUSIONS: This study suggests that levetiracetam is a safe and effective treatment in pediatric patients with Lennox-Gastaut syndrome.[ncbi.nlm.nih.gov]
  • Learning difficulties, behavioral changes that include hyperactivity and aggression, as well as autism-like appearance are frequently observed.[symptoma.com]
  • Based on parental answers for the Aberrant Behavior Checklist, trends towards improvements were seen in hyperactivity, irritability, lethargy, stereotypy, and inappropriate speech.[neurologyadvisor.com]
Myoclonic Jerking
  • In such cases, massive myoclonic jerks, myoclonic-atonic attacks, as well as atonic seizures may occur, though much less frequent and severe than the other manifestations.[epilepsyontario.org]
  • Lennox and Davis first correlated the slow spike-and-wave EEG pattern with a distinctive group of clinical manifestations including specific seizure types (myoclonic jerks, atypical absences, and astatic seizures) and intellectual disability ( Lennox[medlink.com]
  • Multiple seizure types Tonic seizures during sleep is the feature often used as the foundation for diagnosis, 4 but in fact LGS is characterized by multiple concurrent seizure types: tonic, atypical absence seizures, atonic, and myoclonic jerks. 2 Nonconvulsive[onlinelibrary.wiley.com]
  • The myoclonic jerks sometimes are followed by a tonic-clonic seizure or tonic-clonic seizures can occur independently.[hopkinsmedicine.org]

Workup

EEG is the first and essential diagnostic method that provides key findings in differentiating LGS from other epileptic syndromes. Slower bilateral discharge (1.5 - 2.5 Hz) over the frontocentral regions, usually in symmetric fashion are observed, together with a reduced background rhythm, while paroxysmal of very fast rhythmic activity during sleep (10 - 25 Hz) is observed [11]. Magnetoencephalography (MEG) and imaging studies such as MRI and functional MRI may be used to identify the exact location of the origin of epileptic activity [1]. Apart from smaller cortical dysplasia, however, MRI findings may be normal, in which case PET scan may be used and will show focal hypometabolism [1]. Single-photon emission computed tomography (SPECT) may also be used. In general, it is necessary to identify the part of the brain from where epileptic seizures develop, in order to determine optimal treatment strategies [3].

Generalized Sharp-and-Slow-Waves
  • .: Generalized sharp and slow wave complexes associated clinical features and long-term follow-up . Brain, 1973, 96: 289–306. Burnham W.M.: Electrical stimulation studies: Generalied convulsions triggered from the brain-stem . In: G.H. Fromm, C.L.[degruyter.com]
  • .: Generalized sharp and slow wave complexes associated clinical features and long-term follow-up. Brain, 1973, 96: 289–306. Burnham W.M.: Electrical stimulation studies: Generalied convulsions triggered from the brain-stem. In: G.H. Fromm, C.L.[content.sciendo.com]
  • Generalized sharp and slow wave complexes associated clinical features and long-term follow-up. Brain (1973) 96 (2):289–306. doi:10.1093/brain/96.2.289 CrossRef Full Text Google Scholar 42.[journal.frontiersin.org]
Hypsarrhythmia
  • There is also a tendency for psychosis to develop with time. 20% of all patients with Lennox-Gastaut syndrome have prior infantile spasms with hypsarrhythmia. [ 3 ] Although Lennox-Gastaut syndrome typically begins during childhood, it frequently persists[patient.info]
  • An estimated 20 percent to 30 percent of children with LGS have West syndrome, a condition characterized by three features: Infantile spasms Developmental regression A pattern of erratic brain activity on electroencephalogram (EEG), which is known as hypsarrhythmia[verywellhealth.com]
  • Intellect impaired Other seizure types LGS 1–8 years 80–90% in sleep Some Yes All MAE/Doose 1–5 years 4 Hz theta and G PSW Rarely M Dravet/SIME Febrile, other seizures at 2–3 years Slow with irregular spike wave Rare Rare Yes M AA GTC Focal West Usually Hypsarrhythmia[onlinelibrary.wiley.com]
  • This condition often evolves to West syndrome with infantile spasms and a chaotic EEG pattern (hypsarrhythmia) at 4-8 months of age. Over time, approximately 1/3 of children with West syndrome will eventually progress to LGS in childhood.[childneurologyfoundation.org]
Polyspike-and-Slow-Waves
  • Interictal EEG may demonstrate the following characteristics: A slow background that can be constant or transient Awake – Diffuse slow spike wave Non-REM sleep – Discharges that are more generalized and more frequent, consisting of polyspikes and slow[emedicine.medscape.com]
Multifocal Spikes
  • Interictal There may be focal or multifocal spike-and-wave or sharp-slow waves, with an anterior predominance. Slow ( CAUTION Fast spike-and-wave (3 Hz or higher) consider other epilepsy syndromes.[epilepsydiagnosis.org]
  • EEG This is abnormal in the vast majority of cases showing 2‐ to 2.5‐Hz slow spike‐wave discharges over both hemispheres with multifocal spikes and spike waves predominating in the frontal and temporal areas.[doi.org]
  • We did not include patients with interictal electrographic activity characterized by multifocal spikes, focal delta activity different to delta with maximum in the frontal region that typically differentiates LGS from severe epilepsy with multiple independent[omicsonline.org]
Generalized Polyspikes
  • Interictal EEG showed findings characteristic of LGS: generalized slow spike-wave complexes, multifocal sharp waves, generalized polyspikes and paroxysmal fast activity during sleep.[ncbi.nlm.nih.gov]
  • polyspikes or fast rhythms during sleep (required especially when daily tonic seizures are obscure), and (3) diffuse slow (  2.5 Hz) spike-wave complex on EEG.[jneurodevdisorders.biomedcentral.com]

Treatment

Initial attempts to reduce the severity of symptoms seen in LGS are through use of antiepileptic drugs (AEDs). Valproic acid, which induces GABA-inhibiting signals and serves as a sodium channel blocked is considered as first-line therapy in all patients because of its broad spectrum of activity [1]. Due to the fact that it is a potent inhibitor of liver cytochromal enzymes, however, its concentrations should be monitored [6]. Lamotrigine, another AED, is effectively used in combination with valproic acid, but its use is somewhat risky because of severe adverse effects in the form of rash [12]. Clonazepam and clobazam, a recently released benzodiazepine, are also frequently used in the management of seizures, but their effects of sedation and increased sleep may in fact promote seizure activity. Topiramate, rufinamide and levetiracetam are newer AEDs that are being used in patients suffering from this condition [6] [12]. Unfortunately, LGS is frequently resistant to antiepileptic therapy and various forms of surgery are performed. Vagus nerve stimulation is a procedure that comprises insertion of a device that modulates electric signaling on the vagus nerve, while corpus callostomy (cutting of the corpus callosum) is considered as well [4]. Lesionectomy and either focal or multilobar resection has also been advocated in patients who do not respond to conventional therapy [3]. The use of a ketogenic diet, which comprises a high-fat and low-carbohydrate intake, is being more frequently used as it as shown to be effective in a certain number of patients with various forms of epilepsies [11].

Prognosis

Current treatment strategies do not possess curative abilities and the prognosis of patients are rather poor. Mortality rates from LGS range between 3-7%, while certain studies report mortality rates up to 25% in patients suffering from neurological injury, but many patients experience life-long impairment of daily life. Some reports suggest that only 40% of patients are able to perform their normal daily activities without significant difficulties, but more than 90% have some degree of mental retardation [10]. Other data indicate that more than 80% of individuals who suffer from LGS have seizures throughout their entire childhood and adult life, despite aggressive pharmacological therapy [4].

Etiology

Pre-existing brain disorder or injury that stems from various conditions has been linked to the development of LGS. Infectious diseases such as tuberculosis and neurocysticercosis in the developed world, as well as numerous other causes of meningitis and encephalitis have been described in literature, while cerebrovascular and hypoxic insults have shown to be important factors as well [1] [4]. Congenital defects, preterm birth, head trauma and hereditary metabolic diseases are mentioned as well, while cases that occur without an identifiable cause and are hence classified into the group of "cryptogenic" LGS [9].

Epidemiology

Prevalence rates of 2 per 100,000 individuals suggest that LGS is considered to be a rare disease, while isolated studies conducted in Europe suggest that approximately 0.1-0.28 per 1000 individuals are suffering from this condition [4]. In virtually all cases, seizures and other accompanying symptoms start during the first decade of life, but most commonly between ages 3 and 5. For unknown reasons, male gender is somewhat more frequently affected [6]. Although LGS is a rare disease, it is estimated that up to 10% of all patients suffering from epilepsy are attributed to this condition [5].

Sex distribution
Age distribution

Pathophysiology

Because the exact mechanism of disease is not known, pathophysiology remains to be revealed. Certain studies have hypothesized that the age of onset is correlated with the maturation of the brain, specifically the frontal lobes [1]. Aberrations in the mitochondrial chain have also been proposed as a possible cause [1].

Prevention

LGS can be hardly prevented due to its unknown mechanism of disease. Identification of factors that aggravate its appearance is necessary in order to determine adequate preventive strategies.

Summary

Lennox-Gastaut syndrome (LGS) is a rare disease that appears during early childhood and is distinguished by multiple-type seizures, aberrant electroencephalogram (EEG) findings and mental disability [1]. Since its initial description more than 40 years ago, research has shown that etiological factors may be infectious, vascular or neoplastic, but in up to 30% of patients, LGS appears de novo, without obvious causes and is termed cryptogenic in such patients [1]. 75% of children have a structural abnormality of the brain, such as cortical malformation, insults that result from hypoxia or infections of the central nervous system such as meningitis, encephalitis, or encephalopathy as a result of metabolic disturbances [2]. In most cases, both hemispheres are affected, but certain diseases such as brain tumors may target only one hemisphere [2]. The onset of LGS is usually before 8 years of age, but the peak is established to be between 3-5 years [3]. Isolated studies have reported incidence rates of 0.2-2.8/10,000 birth in European countries [1]. Although LGS is rare, with prevalence rates showing that 2 per 100,000 individuals are affected [4], it is responsible for almost 10% of all epileptic attacks during childhood [5]. Clinical presentation involves several seizure types. Firstly, tonic seizures develop, followed by absence and atonic, generalized tonic-clonic seizures eventually develop in 55% of patients [6]. Seizures cause significant impairment of daily life and reports suggest that up to 100 attacks may occur during 24 hours [2]. Mental disability and cognitive impairment are constitutive parts of LGS and are seen in many patients, together with behavioral changes such as aggressiveness, autistic-like patterns and hyperactivity [1]. To make the diagnosis, EEG studies are necessary and show reduced background rhythm and slower spike wave discharges (<3 Hz) [2]. Pathological findings on EEG may be encountered during non-rapid eye movement sleep as well, when paroxysmal fast rhythms (10-20 Hz) are observed [5]. Various imaging studies are performed to exclude other etiologies and confirm the diagnosis, such as magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) and positron emission tomography (PET) [2]. The goal of therapy is to improve the quality of life as much as possible by reducing the appearance of seizures, but neither of the recommended modalities have shown to be highly effective [7]. The use of antiepileptic drugs, such as valproic acid, clonazepam, lamotrigine, topiramat and rufinamide are considered as initial treatment, but LGS is distinguished from other epileptic diseases by its frequent resistance of pharmacological therapy [8]. For this reason, various forms of resective surgery are recommended and aim to remove the part of the brain from where the epileptic signal originates [2]. Vagus nerve stimulation and ketogenic diet are other treatment modalities used with variable success, but in general, the prognosis of LGS is poor. Mortality rates range from 3-7% and almost 80% of patients continue to have seizures despite therapy [4], which is why this condition still presents as a significant challenge in medical practice.

Patient Information

Lennox-Gastaut syndrome (LGS) is a rare but severely debilitating disorder that is characterized by the appearance of seizures and mental disability. The onset of LGS most frequently occurs during early childhood, most commonly between the ages of 3 and 5 and persists throughout adolescence and adulthood. Causes may include infections, vascular insults that lead to brain damage as a result of impaired oxygen delivery, congenital defects and brain trauma, but in up to 30% of cases, LGS may appear without an obvious preceding disease (termed "cryptogenic"). Although numerous conditions are brought into connection, the exact mechanism of disease remains unknown. LGS is present in approximately 2 per 100,000 individuals, but recent reports suggest that this disease is responsible for almost 10% of all epileptic episodes. Patients initially develop seizures that appear during sleep and unexplained falling, followed by frequent epileptic attacks and mental changes. Intellectual and cognitive disability, changes in behavior and sleep deprivation are also frequently reported. Over time, profound mental retardation may develop, leading to a severely impaired quality of life. To make the diagnosis, clinical symptoms are supported by findings during electroencephalography (EEG), a procedure that evaluates brain signaling both during the day and night. In addition, imaging studies such as magnetic resonance imaging (MRI) and positron emission tomography (PET scan) may be used to confirm the diagnosis, but also to determine optimal treatment strategies. Although antiepileptic drugs (AEDs) such as valproate, lamotrigine, clonazepam and topiramate may be used, LGS does not respond to medications and surgical treatment is often indicated. Cutting of the corpus callosum, the bridge between the two hemispheres, insertion of a device that modulates nerve signaling into the vagus nerve and resection of the parts of the brain where the aberrant signal originates are some of the procedures used in the attempt to eliminate seizures. Alternatively, implementation of a ketogenic diet that is rich in fat and low in carbohydrates has shown to be effective for many types of epilepsy. Unfortunately, up to 80% of patients have seizures throughout their life despite treatment and more than 90% have some form of mental disability that is progressive throughout life, while mortality rates range between 3-7%. LGS present as a significant burden for both the patient and the family, as extensive care is necessary in ensuring at least some quality of life.

References

Article

  1. Van Rijckevorsel K. Treatment of Lennox-Gastaut syndrome: overview and recent findings. Neuropsychiatr Dis Treat. 2008;4(6):1001-1019.
  2. Douglass LM, Salpekar J. Surgical options for patients with Lennox-Gastaut syndrome. Epilepsia. 2014;55(4):21-28.
  3. Camfield PR. Definition and natural history of Lennox-Gastaut syndrome. Epilepsia. 2011;52(5):3-9.
  4. Abu Saleh T, Stephen L. Lennox gastaut syndrome, review of the literature and a case report. Head Face Med. 2008;4:9.
  5. Bourgeois BF, Douglass LM, Sankar R. Lennox-Gastaut syndrome: a consensus approach to differential diagnosis. Epilepsia. 2014;55(4):4-9.
  6. Al-Banji MH, Zahr DK, Jan MM. Lennox-Gastaut syndrome: Management update. Neurosciences. 2015;20(3):207-212.
  7. Hancock EC, Cross HH. Treatment of Lennox-Gastaut syndrome. Cochrane Database Syst Rev. 2009;(3):CD003277.
  8. Crumrine PK. Lennox-Gastaut syndrome. J Child Neurol. 2002;17(1):S70-75.
  9. Arzimanoglou A, French J, Blume WT, Cross JH, Ernst JP, Feucht M, et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol. 2009;8(1):82-93.
  10. Kim HJ, Kim HD, Lee JS, Heo K, Kim DS, Kang HC. Long-term prognosis of patients with Lennox--Gastaut syndrome in recent decades. Epilepsy Res. 2015;110:10-19.
  11. Markand ON. Lennox-Gastaut syndrome (childhood epileptic encephalopathy). J Clin Neurophysiol. 2003;20(6):426-441.
  12. Montouris GD. Rational approach to treatment options for Lennox-Gastaut syndrome. Epilepsia. 2011;52(5):10-20.

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Last updated: 2019-07-11 20:44