Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Lennox-Gastaut syndrome is diagnosed in individuals with intractable epilepsy characterized by multiple seizure types, slow spike-wave pattern on EEG, and cognitive deterioration typically after first seizure onset. Seizure types include tonic seizures that mainly occur in sleep, atonic seizures, atypical absences, and myoclonic seizures. The condition may follow West syndrome, but has also been associated with various genetic and neurocutaneous syndromes, metabolic diseases, and early infectious or ischemic insults, or may have an unknown etiology. Numerous interventions as well as medications have been studied in treating this condition. Clobazam has been studied in controlling drop attacks and cannabidiol is being researched as an adjunctive antiepileptic agent in patients with Lennox-Gastaut syndrome and other intractable epilepsy syndromes.
• Lennox-Gastaut syndrome is defined by severe seizures of multiple types in infancy and childhood, cognitive impairment and on the EEG by slow spike wave, as well as bursts of generalized fast activity in sleep.
• Many associated conditions are identified as preceding Lennox-Gastaut syndrome, such as West syndrome, various genetic syndromes, and early CNS insults of various etiologies; however, many patients have unknown etiology.
• Treatment options include medications, ketogenic diet, surgery, and devices such as vagal nerve stimulation; however, seizures remain difficult to control even when all of these modalities are employed.
• Further study is needed to identify etiology in an effort to improve therapeutic targets and outcomes.
The history of Lennox-Gastaut syndrome begins in 1939 when a “slow” (2.5 Hz) spike-and-wave pattern was described by Gibbs, Gibbs, and Lennox (48). It was termed “petit mal variant,” as it was associated with a type of absence seizure characterized by incomplete loss of consciousness, in contrast to “petit mal absence,” which was associated with rhythmic generalized 3 Hz spike-and-wave.
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 (76). Dravet first published a precise description of the syndrome in 1965 entitled “epileptic encephalopathy of infancy with slow spike-waves (petit mal variant)” (29). Later, Gastaut and his colleagues described the clinical manifestations and EEG patterns of 100 patients with slow spikes-and-waves (44). They called this syndrome "Lennox syndrome" or "childhood epileptic encephalopathy with diffuse slow spike-and-waves."
The term "Lennox-Gastaut syndrome" first appeared in the literature in 1969 (87) after it was suggested by Margaret Buchtal-Lennox as a tribute to the work of Lennox and the Marseille School headed by Gastaut. The International Classification of Epilepsies, Epileptic Syndromes, and Related Seizure Disorders classifies the Lennox-Gastaut syndrome as a cryptogenic or symptomatic generalized epilepsy (03). In 2001, the ILAE Task Force on Classification and Terminology classified Lennox-Gastaut syndrome among the epileptic encephalopathies (Engel and International League Against Epilepsy 2001; 33). Berg and colleagues organized the etiologies of the syndrome as genetic, structural/metabolic, and unknown (12).
The Lennox-Gastaut syndrome is a severe epileptic encephalopathy that is characterized by the clinical triad of diffuse slow spikes-and-waves on EEG, intellectual disability, and multiple types of generalized seizures including atypical absences and tonic and atonic seizures, all of which may manifest as drop attacks or may progress to status epilepticus (10; 88; 01; 31).
Although the new classification of epilepsies tends to abolish the terms symptomatic and cryptogenic (12), symptoms of Lennox-Gastaut syndrome can appear de novo without apparent cause (unknown cause) or result from obvious brain insult (structural/metabolic) or genetic cause (35). The Lennox-Gastaut syndrome is, with rare exception, a condition of infants and children and affects boys more frequently than girls (114; 16). The age of onset is between 2 and 8 years, with peak at 3 to 5 years in most cases overall. In unknown cases, there is a slightly older average age of onset between 6 and 8 years (66). Rarely, late onset forms (onset greater than 10 years of age) have been described (108).
In infants and young children, the earliest sign of Lennox-Gastaut syndrome may be head drops or head nodding, typically prior to onset of walking (16). The walking child usually comes to clinical attention with episodes of sudden falls. In the school-age group, behavioral disturbances may be the heralding signs, along with drop attacks. This is soon followed by frequent seizures, episodes of status epilepticus, progressively deteriorating intellectual functions, personality disturbances, and chronic psychosis (103).
Tonic seizures occur in most affected children. They are usually brief, lasting only seconds. Depending on the extent and groups of muscles involved, they may appear as axial (characterized by flexor movements of the head and trunk), axorhizomelic (characterized by elevation and adduction of proximal upper limbs, stiffening of posterior neck muscles, elevation of shoulders, opening of the mouth, upward deviation of the eyes and brief apnea), or global, leading to sudden falls if the patient is in an upright position (44). The seizures can be asymmetrical or predominantly unilateral. Sometimes, automatic behaviors follow the tonic stage. Tonic seizures occur most frequently when falling asleep, but they can occur at any time of the day. They are often absent at the onset of epilepsy (16). They may be subclinical and revealed only by a sleep EEG recording showing fast bursts of 10 Hz to 12 Hz activity during sleep in association with muscle contraction. They may be precipitated by stimuli such as noise, contact, or movement (103).
Atypical absence seizures occur in approximately two thirds of patients. Both the onset and the termination are gradual in contrast to typical absences. Atypical absences are usually long and are often followed by some postictal cognitive impairment. Patients may continue their activity to some degree, as episodes are characterized by "clouding" rather than complete loss of consciousness (44; 16). Associated motor manifestations are more common in atypical than in typical absences and include eyelid or perioral myoclonus, progressive flexion due to loss of postural tone, and localized motor phenomena, such as neck-stiffening or head-nodding (103).
Atonic seizures are characterized by sudden, intense loss of postural tone that involves either the whole body or only the head (103).
Other seizure types, including focal and generalized tonic-clonic seizures, are less frequent (103). Myoclonic seizures may occur in Lennox-Gastaut syndrome and are clinically distinct from other causes of falls in this syndrome. They are more prominent and a distinctive feature of myoclonic-astatic epilepsy and when encountered should raise suspicion for this diagnosis (28).
Myoclonic, myoclonic-atonic, atonic, and tonic seizures all cause falls (drop attacks) and are difficult to differentiate clinically from 1 another without EEG recordings (60). The falls result in recurrent injury, including lacerations that leave disfiguring scars (103).
About 90% of patients with the Lennox-Gastaut syndrome have 1 or more episodes of status epilepticus (31). There are various forms, including absence status, which may clinically appear as a state of mild or waxing and waning confusion lasting from days to weeks. Additionally, pure tonic status epilepticus may occur more often in adolescents or adults than children, and in rare reports has been elicited by intravenous administration of benzodiazepines (112).
In young children, slowing or even complete arrest of psychomotor development occurs. In cases of later onset, the intellectual impairment may be less pronounced than in cases of early onset (44). In addition, up to 50% of affected individuals will display behavioral abnormalities such as hyperactivity (most commonly), emotional instability, aggressiveness, destructive behavior, autism, antisocial personality, or hypersexuality (81). Such abnormalities and the arrest of educational progress are more prominent in older children and adolescents than in younger children. Chronic psychosis with episodes of acute exacerbation may also occur (103; 63).
A milder phenotype has been described in 8 patients who met the electroclinical diagnostic criteria of Lennox-Gastaut syndrome but without significant cognitive impairment (22). These patients had onset in the second decade of life and had normal neuroimaging.
Neurologic symptoms seen in patients with Lennox-Gastaut syndrome are not specific and are determined by the underlying pathology. Motor signs occur in 59% of cases (81). Seventeen percent of patients have normal neurologic examinations.
The overall prognosis for patients with Lennox-Gastaut syndrome is poor, though variable. A significant majority have cognitive impairment, difficult to control seizures, and deterioration in gait causing them to require assistance in activities of daily living (91). Cognitive impairment usually persists even after seizure control (40). Remission with preserved mentation occurs in few patients; IQ tends to deteriorate with age (91). Patients with underlying brain injury, early onset, frequent and slow evolution of seizures, and repeated episodes of status, have a relatively worse prognosis (103).
The slow spike-and-wave pattern tends to resolve over time and focal epileptic discharges (typically multifocal spikes) emerge. Tonic seizures tend to persist, in contrast to myoclonic and atypical absence seizures which are more easily controlled (40).
An 8-year-old boy with intellectual disability was developmentally normal until the age of 3 years, when he began having seizures. Initially, he was noted to have frequent falls; later, family noted episodes during sleep of whole body stiffening, screaming, and staring with eyes open. Awake EEG showed 2 to 2.5 Hz spike waves, and sleep recording revealed generalized bursts of polyspikes and paroxysmal fast activity (electrodecremental responses) at times associated with generalized tonic seizures. MRI of the brain was normal. State of the art genetic testing could not be obtained due to financial issues. Seizures, including episodes of atypical absence status epilepticus, persisted despite multiple antiepileptic drugs and a trial of the ketogenic diet. He suffered numerous injuries secondary to drop attacks and wears a helmet at all times. The addition of clobazam to his medication regimen reduced the frequency of drop attacks. The possibility of a surgical procedure (corpus callosotomy) to further reduce the drop attacks is being considered. He attends a specialized school, is in a small class setting, and receives supportive therapies.
In about one quarter to one third of cases, the syndrome develops without antecedent history or evidence of brain pathology and is categorized as Lennox-Gastaut syndrome of “unknown cause” (52; 12; 18). It is likely that genetic or immune-mediated factors account for many of these cases; however, they are as yet unidentified. Clinically, these may be difficult to distinguish from myoclonic-astatic epilepsy.
The other two thirds of cases are “structural/metabolic” and are associated with evidence of brain dysfunction either as an evolution from West syndrome, secondary to acquired structural injury, or associated with an identified metabolic or genetic syndrome.
Between 20% and 40% of patients with Lennox-Gastaut syndrome represent evolution from infantile spasms occurring in infants and young children (44; 10; 91; 114). Likewise, around 25% of patients with infantile spasms will evolve into Lennox-Gastaut syndrome (77; 101). It is rare for patients with infantile spasms to have late-onset Lennox-Gastaut syndrome (52). Patients with infantile spasms and Lennox-Gastaut syndrome nearly always have poorer prognosis with regard to intellect and epilepsy outcomes (31). Four electroclinical patterns have been described during transition from infantile spasms to Lennox-Gastaut syndrome: a) epileptic spasms with multifocal paroxysms, b) focal seizures with focal spike wave discharges in the EEG, c) epileptic spasms and myoclonic seizures with diffuse spike-wave and polyspike wave discharges, and d) mixed pattern (17).
Prenatal and perinatal factors have been implicated in “structural/metabolic” Lennox-Gastaut syndrome, namely severe hypoxic ischemic encephalopathy, among others. Postnatal factors include central nervous system infection, degenerative or metabolic disorders of the nervous system, head injury, anoxic encephalopathy, cerebrovascular accident, hypoglycemia, and irradiation leukoencephalopathy (81; 83).
Other structural malformations including tuberous sclerosis, porencephaly, and dysembryoplastic neuroepithelial tumor have been associated with the development of Lennox-Gastaut syndrome (100). With the advent of high resolution MRI, cortical dysplasias (102) as well as band heterotopias (09; 53) are being identified as increasingly common substrates of this syndrome as well.
An autoimmune mechanism has been proposed for some cases through case reports of concomitant immune-mediated disorders at epilepsy onset (52), imbalance of human leukocyte antigen (HLA) subtypes (116), and response to steroid and immunoglobulin (61; 115), but there still is little evidence to support this concept. CSF protein has been found elevated in late-onset Lennox-Gastaut syndrome (onset greater than 10 years of age), suggesting a possible role of inflammation in the pathophysiology in this subset of patients (108).
There has been an increase in research aiming to identify genes associated with Lennox-Gastaut syndrome and other epilepsy syndromes without known etiology. Numerous case reports identify novel gene mutations in patients with Lennox-Gastaut syndrome, and there is evidence that adults with the syndrome have frequent rare copy number variations compared with the general population (78). The Epilepsy Phenome/Genome Project and Epi4K Consortium sequenced 264 probands with either infantile spasms or Lennox-Gastaut syndrome along with their parents in an attempt to identify de novo mutations, identifying at least 2 (GABRB3 and ALG13) that had not previously been implicated (35). Numerous other genes have been implicated since that time as well, including SCN10A (65), BCL11A (124), ABAT (15), DNM1 (36), KCNB1 (80), KCNT2 (02), dup15 (82), CUX2 (20), PPPC3A (85), and IQSEC2 (21).
Further study is needed to establish more definitive associations, causality, and hopefully inform treatment in the future.
No specific pathophysiological mechanisms have been demonstrated to underlie the Lennox-Gastaut syndrome; however, the age range of occurrence suggests that some maturational yet unidentified factor plays a determinant role in its development. Although there are various neurologic injuries and conditions noted to precede Lennox-Gastaut syndrome in some patients, the syndrome does not develop in all patients with these conditions, and reasons for this are not clearly understood (13).
The 2 hallmark electrophysiologic findings in Lennox-Gastaut syndrome, slow spike wave and paroxysmal fast activity (electrodecremental responses), appear to be mediated by distinct brain networks, the former having primary cortical and subcortical involvement whereas the latter is more diffuse, involving many areas of association cortex as well as simultaneous activation of numerous subcortical structures (96).
Interictal spike-wave activity seems to play a major role in the development of cognitive impairment. This is supported by the observation that cognitive effects are often most profound with earlier onset of disease, as well as by research demonstrating reduced interictal cortical excitability in Lennox-Gastaut syndrome (08).
Although both frontal lobes are thought to be affected, patients have been described to have an epileptogenic “leading” site in 1 frontal lobe, with subsequent spread to adjacent cortical areas (14). At the onset of the epilepsy, focal spike-waves and focal discharges are often recorded (59). Subcortical structures may also be involved in the epileptogenic process (117).
Simultaneous EEG-functional MRI studies have demonstrated that the epileptogenic process is driven by the cortex. The generalized paroxysmal fast activity (GPFA), the characteristic EEG signature of Lennox-Gastaut syndrome, has been shown to be initiated by the prefrontal cortex, with propagation to the thalamus via the brainstem. (121). It has also been shown that focal cortical lesions can produce a generalized Lennox-Gastaut syndrome phenotype (120), whereas lesionectomy can abolish tonic seizures. Lesionectomy in such lesions has been observed to lead to cessation of tonic seizures and abolition of the generalized paroxysmal fast activity (120).
The incidence of Lennox-Gastaut syndrome is low, each year afflicting 2 in 100,000 children under age 14 (56). Due to the intractable nature of this disorder, the prevalence is somewhat higher, occurring in 1% to 5% of all epilepsies and 3% to 10% of all patients with childhood epilepsy (16). Among children with intellectual disability, 7% have Lennox-Gastaut syndrome, whereas 16.3% of institutionalized patients with intellectual disability have Lennox-Gastaut syndrome. There is no ethnic or geographic predilection, and boys are more often affected than girls (43; 114).
There is no definitive method for prevention of Lennox-Gastaut syndrome as its pathophysiology is not well elucidated. Perhaps effective disease-modifying treatments of epilepsies known to evolve into Lennox-Gastaut syndrome, such as West syndrome, may prevent its occurrence. Additionally, prevention of known underlying etiologies may reduce the incidence of this syndrome.
Lennox-Gastaut syndrome is diagnosed through the combination of defining electrographic patterns and multiple clinical seizures types in a child with cognitive impairment. These features, however, may not all be present at onset and clinical presentation can be highly variable. Therefore, initial differential diagnosis is often broad.
Drop attacks and slow spike-and-wave discharges on EEG may be seen in patients who have conditions other than Lennox-Gastaut syndrome, including overdose of certain antiepileptic medication and focal seizures secondary to structural lesions. Both may produce continuous spike waves in slow sleep (94).
Epilepsy with myoclonic-astatic seizures begins between 2 and 5 years of age with generalized tonic-clonic seizures. This is followed several weeks or months later by frequent daily drop attacks due to myoclonic-astatic seizures with atypical absences and perhaps even nonconvulsive status epilepticus (28). The EEG reveals 2 Hz to 3 Hz spike-and-wave discharges and a slow baseline activity. Genetic testing may be of help.
Late-onset infantile spasms that produce drop attacks may begin in the walking child between 1 and 4 years of age. The drop attacks can be identified as the result of epileptic spasms only through video-EEG recordings of the seizures (11; 32).
Posttraumatic epilepsies and encephalopathy with multifocal epilepsy associated with secondary generalization may produce frontal lobe epilepsy with secondary generalization of the spike-wave activity (103). In these patients, the tonic seizures are usually missing, and onset is at a later age. Additionally, focal frontal lobe seizures that secondarily generalize can produce bilateral tonic features and may be associated with slow generalized spike-wave discharges on EEG as result of rapid spread across the corpus callosum (04).
The syndrome of continuous spike-waves in slow sleep begins between 3 years and 6 years of age with atonic seizures and atypical absences with slow spike-waves, but there are no tonic seizures (94).
Atypical benign partial epilepsy, or the so called “pseudo-Lennox syndrome,” may be difficult to clinically distinguish from Lennox-Gastaut syndrome. These children, too, present with drop attacks and abnormal EEG often described as “continuous spike-wave of slow sleep.” They do not typically have tonic seizures or paroxysmal fast activity on EEG and course is benign, often remitting in adolescence (54).
The diagnosis is based in part on identifying the combination of several generalized seizure types and other electrographic signatures. Tonic seizures and atypical absences may need ictal EEG recording to be properly identified; irregular slow spike-and-waves can be identified with interictal awake tracing; whereas polyspikes-and-waves are recorded during sleep. Cognitive and behavior deterioration may be missing at onset.
The interictal EEG reveals slow spike-and-wave consisting of a blunt, slow spike (approximately 150 msec), followed by a slow wave (approximately 350 msec). The amplitude ranges from 200 to 800 microvolts. When 2 to 3 spikes precede the slow wave, they constitute a polyspike-and-wave complex. The frequency (1.5 Hz to 2.5 Hz) is relatively slow and arrhythmic compared to that of classical absence seizures (rhythmic 3 Hz). Occasionally, bursts of rapid spike-and-waves at 3 Hz or even 4 Hz may occur in combination with the slow spike-and-waves (44). These discharges are usually generalized, bilateral, synchronous, and symmetrical, but they may also be asymmetrical and predominant in 1 hemisphere or 1 region. The EEG patterns differ among individuals and change from day to day and even moment to moment (44).
During NREM sleep, generalized polyspike discharges or lower voltage fast activity (generalized paroxysmal fast activity at 10 c/s) lasting 0.5 second or more without obvious clinical correlates are commonly seen. Fast rhythms (electrodecremental responses) may also be associated with subtle seizures or tonic seizures (04). During REM sleep, there is an anterior predominance of the abnormal fast rhythms and polyspike-and-wave complexes, though they are less frequent. Also during sleep, the abnormal patterns become more symmetrical and synchronous, with even slower spike-and-waves or polyspikes-and-waves. Photic stimulation has no effect on these EEG events (81).
When evolution in EEG patterns occurs in patients previously affected by infantile spasms, the direction is from hypsarrhythmia to multifocal interictal spikes to generalized spike discharges to slow spike-and-waves, with the last representing a stable pattern that characterizes children with the Lennox-Gastaut syndrome (71).
The EEG correlate of tonic seizures consists of a 10 Hz to 13 Hz recruiting rhythm, usually followed by high amplitude slow activity rather than postictal EEG depression (31). Although the EEG during absence seizures often shows irregular spike-and-wave discharges, these patterns are not necessarily different from interictal EEG discharges and do not clearly demarcate the occurrence of an ictal event. Similarly, there is no characteristic pattern of absence status; this prolonged confused state may be associated with an increase in slow spike-and-wave activity or with irregular slowing resembling hypsarrhythmia (31).
A variety of multifocal or diffuse abnormalities on MRI are found in the structural/metabolic cases, but this finding concerns etiology, not diagnosis, of the epilepsy syndrome. Drop attacks, slow spike-waves with mainly posterior predominance and cognitive deterioration, combined with brain calcifications have been reported as a consequence of gluten intolerance and can be improved by gluten-free diet (98).
Pending further evidence, it will be prudent to undertake a detailed genetic evaluation in children with Lennox-Gastaut syndrome without an identifiable etiology on clinical evaluation and neuroimaging. In children who have associated dysmorphism, a chromosomal microarray might be considered. In children without dysmorphism, genetic panel for epileptic encephalopathy or a whole exome sequencing should be useful.
Treatment for Lennox-Gastaut syndrome has been difficult and an optimal approach has not been established. Strategies include antiepileptic medication management as the mainstay; however, devices such as the vagal nerve stimulator (VNS), surgical intervention, specialized diet, and immunotherapy have been used as adjuncts.
Drug treatment. Carbamazepine and phenytoin can control generalized tonic-clonic convulsions and reduce tonic seizures, but these drugs can also exacerbate atypical absence seizures (58). Valproate offers a chance for improvement of all seizure types with a single drug but soon loses its effect and may have increased risk of causing pancreatitis with polytherapy (as is the case in many of these patients) (55).
Lamotrigine has also been shown to significantly reduce drop attacks (from atonic, tonic, and major myoclonic seizures) as well as generalized tonic-clonic seizures, although atypical absences were not greatly affected (84). This drug should be used with caution and introduced slowly in patients receiving valproate in order to prevent serious rash (30).
Topiramate has been shown in several double-blind trials to significantly reduce the frequency of drop attacks and generalized tonic-clonic seizures when used as an adjunctive treatment in patients with Lennox-Gastaut syndrome (104; 51). However, the cognitive side effects of the drug may cause significant disability in these patients, making it intolerable (49).
Felbamate has been reported to reduce the frequency and severity of drop attacks (38; 07) and other seizure types (64) and can improve behavior in some patients (46). Patient quality of life improved overall in patients on felbamate due to improved level of alertness and verbal responsiveness (38). Though effective in these patients, this drug is associated with a high incidence of serious side effects such as aplastic anemia and hepatic failure, and thus should be used with caution. It should be used with bimonthly follow-up of transaminases and blood cell counts, restricted to cases intractable by other compounds, and should not be given for long periods if there is no clear response.
The efficacy of rufinamide was shown in a single, randomized, placebo-controlled study (50). The efficacy was shown mainly on tonic-atonic seizures, but reduction was also seen in absence and atypical absence seizures. Further randomized or open studies confirmed this efficacy. Moreover, efficacy was maintained long term in an open-label extension study (69). Reductions in seizure frequency were observed throughout this study with almost 40% of patients presenting 50% or greater reduction in total and tonic-atonic seizure frequency. The most common adverse events were vomiting (30.6%) and pyrexia (25.8%). Similar results have been reported in more recent open-label studies as well (92). A pooled analysis of data from pediatric studies of rufinamide as adjunctive therapy suggests a favorable safety and tolerability profile in this patient population, with somnolence and vomiting being the most common side effects (Wheless and al 2009). These findings on safety and tolerability have been replicated by other groups as well (89). No negative effects on cognition, adaptive function, and emotional profile were noted in 1 study (93). In a study on the correlation of the response with etiology and genotypes, it was noted that patients with structural malformation of cortical development achieved a 40% in response rate, whereas patients with mutations in DEPDC5, KCNQ2, MMACHC, and SPATA5 genes achieved greater than 90% of seizure reduction (90).
Zonisamide has been successfully used as an adjunctive medication in adults with focal epilepsy. It was studied in Lennox-Gastaut syndrome and patients using this medication as long-term adjunctive treatment were found to have an overall reduction in seizure frequency by more than 50%. Most prominent effects were seen in atonic seizures and myoclonic seizures, though generalized tonic clonic seizures were also reduced (126).
Levetiracetam has been an effective and well-tolerated add-on in children with Lennox-Gastaut syndrome. In an open-label, multicenter clinical trial of levetiracetam in 55 children with Lennox-Gastaut syndrome, 58.2% of the enrolled children had greater than 50% reduction in seizures, and 27.3% became seizure free (68).
The benzodiazepine class has long been under consideration for use in maintenance therapy in Lennox-Gastaut syndrome. Examples of the 1,4-benzodiazepine class include nitrazepam, clonazepam, diazepam, and lorazepam, which have been shown to be effective in some small uncontrolled trials (19; 04). Clobazam, in the 1,5-benzodiazepine class, was shown to significantly reduce drop attacks and some nondrop seizures, though tonic seizures (112), behavior problems, and sedation may be worsened (23). A double-blind, placebo-controlled trial assessed the effect of low dose and high dose clobazam on drop attacks in patients with Lennox-Gastaut syndrome. This study revealed that 56% of patients on low dose clobazam had a reduction of at least 25% in the number of drop attacks compared with 89% of patients in the high dose group (23). The phase 3 study compared low, medium, and high dose clobazam against placebo. Results showed a statistically significant decrease in drop attacks when placebo was compared with each of the 3 clobazam groups. They found a linear trend of increasing efficacy with increasing dosage (86) and subsequent studies have confirmed a dose-dependent improvement in seizure control (62). Tolerance to clobazam has been reported in anywhere from 10% to 87% of patients (73), however, this is difficult to interpret in patients with intractable epilepsy where a confounder of disease progression may be present.
Vigabatrin, an irreversible inhibitor of GABA transaminase, has yielded variable results (39). In 1 case report, seizures were made worse by the GABA analog gabapentin (119). Other medications such as amantadine (acts on multiple neurotransmitter pathways), tryptophan (an essential amino acid), flumazenil (a GABA antagonist), and imipramine (a tricyclic antidepressant), among others, have had anecdotal and limited success in some patients (31). There is an anecdotal report on the efficacy of the calcium channel blocker verapamil in a patient with Lennox-Gastaut syndrome who was found to have mutations affecting the calcium signaling pathway. This reinforces the importance of genetic diagnosis in developing targeting treatment approaches in patients with this condition (27).
Auvin and colleagues studied perampanel as an adjunct treatment in a cohort of 13 pediatric and adolescent Lennox-Gastaut syndrome patients. After a median of 10.8 months on the treatment, 9 out of 13 (69%) achieved greater than 50% reduction in seizure frequency. Four (30%) discontinued treatment for inefficacy (2) or worsening of seizures (2). Adverse effects in the responder group were minimal and managed by tapering the medication dose. This small study suggested that perampanel may be efficacious and fairly well tolerated in Lennox-Gastaut syndrome patients (06). In a retrospective study on adults with Lennox-Gastaut syndrome, add-on perampanel, two thirds of the patients had greater than or equal to 50% reduction in seizures (24). At least 1 side effect was noted in around half of the enrolled patients. Significant side effects such as irritability, aggressive behavior, and agitation were noted in 34% of the patients.
Cannabidiol is the main nonpsychoactive component of cannabis. It has several mechanisms of action, including enhancing activity of the 5HT1a receptor and the a3 and a1 glycine receptors, among others (95). It has been shown to be anticonvulsant in many animal models (57) and its use has been under study in patients with various intractable epilepsy syndromes including Lennox-Gastaut syndrome. One small retrospective study of patients receiving oral cannabis extract found that 8 of 9 (89%) of patients with Lennox-Gastaut syndrome had a greater than 50% reduction in seizure frequency after initiating this treatment. This was a significantly higher response rate when compared to patients with Doose syndrome and Dravet syndrome (99). An additional open-label interventional trial was conducted in patients with Lennox-Gastaut syndrome and other intractable epilepsies and found that adverse effects such as diarrhea, somnolence, decreased appetite, fatigue, and convulsion were reported in 79% of patients (25). Significant adverse effects were reported in 30% of patients, though only 12% of patients reported significant events such as status epilepticus, diarrhea, pneumonia, and weight loss, which were thought to be possibly related to the cannabidiol. The median reduction in monthly motor seizures was 36.5%. This trial highlighted the importance of randomized control trials to determine the efficacy of cannabidiol and further assess its safety. The results of the first randomized, double-blind, placebo controlled trial was published and revealed that add-on cannabidiol was efficacious in the treatment of drop seizures in Lennox-Gastaut syndrome patients and was fairly well tolerated (113), and other groups have since corroborated these findings (26). Further data on safety and efficacy are being collected through the open-label extension of this trial.
With the repurposing of fenfluramine, an appetite suppressant used for weight loss and used as an antiseizure medication, it was found that it may be effective in Dravet syndrome and Lennox-Gastaut syndrome. In a phase II open-label dose finding study on the use of fenfluramine on 13 children with Lennox-Gastaut syndrome, 67% had greater than or equal to 50% reduction in seizures (72).
Immunotherapy. Corticosteroid treatment is often used in the epileptic encephalopathies and in Lennox-Gastaut syndrome may be useful at gradually tapered dosages in cases of unknown etiology during periods of worsening in the course of evolution (103). Several case series have reported an approximately 70% rate of seizure freedom in Lennox-Gastaut syndrome patients treated with prednisone therapy for short (6-12 weeks) course (107; 125), though it is not clear whether these effects would endure after cessation of therapy. Clinical trials of intravenous immunoglobulin have yielded equivocal results (61; 115; 47). Studies have reaffirmed the efficacy of the ketogenic diet in children with Lennox-Gastaut syndrome, with half of the children started on the diet experiencing greater than 50% reduction in the seizure burden (75; 128). Similar efficacy has been reported with the use of the modified Atkins diet, a less restrictive variant of the ketogenic diet (106).
Diet. The ketogenic diet has been used with some success in patients with various intractable epilepsy syndromes. The first blinded study of this method was conducted in 20 children with Lennox-Gastaut syndrome, with significantly reduced seizure frequency in both arms (ketogenic diet group more so than control), perhaps because of fasting within the study design and a small amount of resultant ketosis in the control group. Nevertheless, the study results suggested that some level of ketosis improved seizures in all of these children, possibly in a dose-dependent fashion, further advocating use of the diet in these patients (41).
Surgery. Vagal nerve stimulation showed some efficacy with effects observed on atonic seizures followed closely by tonic seizures and with the least effects on generalized tonic-clonic seizures (79; 42; 67). One paper showed a maintained efficacy on long-term follow-up (median 52 months) (70). Despite some claims based on review of the literature that vagal nerve stimulation and callosotomy give similar results, it has been shown that vagal nerve stimulation was ineffective in the 10 patients with Lennox-Gastaut syndrome and prior West syndrome who were submitted to this procedure, whereas 85% of the patients who underwent total callosotomy experienced dramatic improvement of their drop attacks (97).
Corpus callosotomy can reduce or abolish drop attacks in many patients with Lennox-Gastaut syndrome provided there is no major diffuse brain malformation, but it influences the pattern of other seizure types only rarely (45). With the advent of new microsurgical techniques and the realization that anterior two-thirds section is sufficient in patients who started in school age, adverse side effects of corpus callosotomy have been minimized. The choice of total versus anterior callosotomy depends, therefore, on the age at which the epilepsy started. Early onset in the first year of life indicates a probable involvement of parieto-occipital areas. Therefore, although slow spike-waves predominate in the frontal areas, posterior areas are still involved and could reappear following anterior callosotomy (97). Small case series have shown the effectiveness of radiosurgical callosotomy (37; 109) and stereotactic laser callosotomy (111). These techniques are associated with a reduced surgical morbidity.
In rare cases where a stable focus exists in association with EEG abnormalities predominant in 1 hemisphere, the possibility of a focal resection can be investigated (105). Focal resective surgery has been reported in a few cases (127). In a study of 27 patients with Lennox-Gastaut syndrome who underwent resective surgery, multilobar resection was performed in 10 patients, single lobar resection in 11, and functional hemispherectomies in 6 patients. Engel class I (seizure-free) outcomes were achieved in 59% of patients and an improved cognition in 63% (74). It has been demonstrated that focal spike wave activity remaining ipsilateral to the MRI lesion can potentially predict better surgical prognosis in symptomatic Lennox-Gastaut syndrome patients (123).
There has been interest in exploring deep brain stimulation as a treatment for epilepsy in Lennox-Gastaut syndrome patients (118). The thalamic centro-median nucleus has been the preferred target of stimulation in patients with Lennox-Gastaut syndrome. One group found that in a small cohort (n=4) of Lennox-Gastaut syndrome patients, all treated patients experienced a greater than 50% seizure reduction following the procedure (110); however, the data thus far are limited and further study is needed to determine the procedure’s safety and efficacy. In a small pilot study, addition of transcranial direct current stimulation to the pharmacological treatment in patients with Lennox-Gastaut syndrome was more effective than pharmacological treatment alone (05).
Although there are numerous treatment modalities available for patients with Lennox-Gastaut syndrome, their seizures typically do not remit. Patients may suffer from medication toxicity and side effects and are subjected to the surgical risks associated with the above procedures. Other comorbidities include cognitive impairment, behavioral disturbances, autism spectrum disorder, other psychiatric disease, malnutrition, and/or other physical limitations. The incidence and severity of these comorbidities vary depending on the etiology of Lennox-Gastaut syndrome in the individual patient. In patients with uncontrolled convulsions, there is a high risk of SUDEP.
Although no information is available that is specific to this syndrome and pregnancy, information is available on epilepsy and pregnancy.
Solomon L Moshé MD
Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
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