Electrical Status Epilepticus in Sleep

Etiology

Different etiologies, both with or without structural abnormalities of the brain, have been associated with ESES. An early developmental lesion, such as perinatal infarct involving thalamus, has been particularly correlated with the development of ESES. In a case-control study, 14% of the patients with epilepsy and sleep activated EEG had early developmental lesion involving thalami such as stroke, periventricular leukomalacia, and cortical malformation; however, only 2% of the patients had a thalamic lesion in the control group (patients with epilepsy but not with sleep activated EEG).[4]

Recently several genetic etiologies (monogenic mutations or copy number variants) have been correlated with the development of ESES. Among monogenic mutations (SCN2A, SLC9A6, DRPLA/ ATN1, Neuroserpin/SRPX2, OPA3, KCNQ2, KCNA2, GRIN2A, CNKSR2, SLC6A1, KCNB1), GRIN2A mutations, with possible dysfunction of NMDA-receptor mediated signaling, have most commonly linked with ESES.  Recurrent copy number variants were reported in association with ESES, such as Xp22.12 deletion, 16p13 deletion, 15q11.2-13.1 duplication, 3q29 duplication, 11p13 duplication, 10q21.3 deletion, 3q25 deletion, and 8p23.3 deletion.

The exact reason for the sleep activation of EEG abnormality is unknown. Some researchers correlated abnormal EEG with the abnormal hyperactivation of the thalamic oscillatory circuit: an interplay between inhibitory GABAergic reticular thalamic neurons and excitatory glutaminergic dorsal thalamic neurons. Researches also hypothesized that the change in the thalamic oscillatory circuit might be due to a substitution from the GABAA to GABAB mediated post-synaptic inhibition. Sleep potentiation of epileptiform discharges may disrupt the cortical information processing and trigger learning and memory impairments.

Epidemiology

ESES is a rare condition. A 20- year cohort from a pediatric neurology clinic in Israel revealed the ESES prevalence of 0.2% among 440 patients with epilepsy.[5] In another retrospective review of 1497 EEG records over five years identified 102 patients with an electrographic pattern consistent with ESES. Importantly, children with generalized spike-wave discharges were noted to have global or severe developmental issues compared with focal epileptiform discharges. Besides, a spike-wave index of over 50% more likely correlated with more widespread developmental disruption.[6]

History and Physical

Typically children, between 2 and 12 years of age with a peak between 3 and 5 years, present with infrequent seizures (focal and/or generalized) and stagnation or regression of the development. Within 2 and 3 years of the onset, further regression in development occurs in association with more frequent generalized seizures, such as atonic or atypical absence seizures. The majority of the children have a normal development before the disease onset, but developmental delay and cognitive impairment may be present from the beginning depending on the underlying etiologies. Rarely, neurocognitive regression may appear as the earliest feature without any evidence of clinical seizures. Behavioral abnormalities, particularly hyperactivity, are commonly present with ESES.

Evaluation

Diagnosis of ESES is by demonstrating bilateral (rarely unilateral) continuous or near-continuous slow (1.5 to 3 Hz), diffuse, or bilateral, spike-wave discharges during NREM-sleep. During wakefulness and REM sleep, only intermittent focal or multifocal epileptiform discharges or slow waves are present; an inadequate sampling of EEG during NREM sleep may entirely miss the diagnosis. Sporadic frontotemporal or centrotemporal interictal epileptiform discharges during wakefulness become significantly activated during sleep with disruption of typical sleep background. There is controversy concerning the minimum threshold of spike-wave activity during NREM sleep for a formal diagnosis of ESES. Different studies quoted a widely variable range of 25 to 85%, but most commonly 85% or 50 % spike-wave index thresholds have been accepted for diagnosis of ESES.

Treatment / Management

Due to a lack of randomized controlled studies, current treatment options are primarily based on retrospective studies and expert opinions. The treatment goal- suppression of the EEG abnormalities, improvement of the seizure control, amelioration of the behavioral abnormalities, and reversal of cognitive regression- needs to be established at the time of the diagnosis.  The existing treatment paradigm has its basis on uncontrolled studies and case series and primarily focused use of traditional antiepileptic drugs(AEDs), including benzodiazepines, corticosteroids, epilepsy surgery, and other non-pharmacologic therapies(IVIG, the ketogenic diet, etc.). 

The most common AEDs used for ESES include valproate, ethosuximide, and levetiracetam.[7] In a placebo-controlled, double-blind, cross-over study, researchers noted that levetiracetam decreased the spike-wave index to 37 (mean) from a baseline of 56 (mean) at the end of the treatment period (P<0.0002).[8] Rarely, ethosuximide and sulthiame have been reported to improve ESES as a monotherapy, but as an adjunctive and combination therapy, both have had extensive use. Although valproate has not been associated with worsening seizures in ESES, definitive efficacy of this agent is unknown and should not be used as first-line therapy.[9](A1)

Benzodiazepines, particularly diazepam and clobazam, have been extensively used as one of the most commonly used AEDs for ESES. A group of researchers treated 29 children with ESES with oral high dose diazepam (1 mg/kg, maximum of 40 mg) and noted a reduction of the spike-wave index from 76.7% to 40.8% within 24 hours. These patients received 0.5 mg/kg of diazepam for three weeks after the initial high dose before gradual tapering. Reversible side effects- sedation, dizziness, respiratory depression, hypotonia, paradoxical aggravation- occurred in approximately one-quarter of patients.[10] Larrieu et al. first described the utility of clobazam in 1986.[11] Only rare reports of precipitation of absence status in ESES have appeared in association with clobazam.[12] Caraballo et al. demonstrated that clobazam was effective alone in 5 out of 117 patients and in combination with other agents in 86 of 117 patients.[13](B2)

Few specific AEDs such as phenytoin, phenobarbital, and carbamazepine can worsen seizure control in ESES and requires withdrawal in the presence of worsening drop or absence seizures.[14][15](B3)

Corticosteroids (methylprednisolone, prednisolone, ACTH) have been utilized in different regimens, both long term continuous therapy lasting for months or intermittent monthly high dose therapy. Buzatu et al. retrospectively reviewed the efficacy and safety of a 21-month regimen of hydrocortisone (5 mg/kg/day during the first month, 4 mg/kg/day during the second month, 3 mg/kg/day during the third month, 2 mg/kg/day for next nine months, and slow taper during remaining of the treatment period) in 44 patients with positive response in 34 patients during the first three months of the treatment, with normalization of EEG in 21 patients. However, among 34 responders,  14 patients had a subsequent relapse. Higher IQ/DQ and shorter duration of the disease before the initiation of the treatment were associated with a positive outcome. Due to side effects, seven patients discontinued treatment early.[16] Chen et al. reviewed the efficacy of a different regiment of corticosteroid that used a combination of intravenous methylprednisolone with oral prednisone for six months. They saw a high response rate, but with a high relapse rate at 1-year follow-up.[17] Due to fear of side effects from long-duration corticosteroid therapy, methylprednisolone pulse therapy (15 to 30 mg/kg/day for three days consecutively, once a month for four months) has also been used successfully.[18] A recent review calculated a response rate (improvement in the EEG or cognition) of 80% in response to steroid therapy in 575 patients compared to 49% with AEDs and 68% from benzodiazepines.[19] The subgroup of ESES patients with structural brain pathology such as perinatal infarction or cortical malformation may benefit from epilepsy surgery. Different surgical procedures- multiple subpial transections, focal lesionectomies, and hemispherectomies- have been utilized mainly in patients with structural brain pathology. Children with unilateral brain pathology were frequently seizure-free after hemispherectomy or focal resection with the disappearance of the EEG pattern, and improvement in the cognitive status.[20] However, more studies are needed to assess long term neurocognitive status to help determine the role of surgery.(B2)

The ketogenic diet and intravenous immunoglobulin infusions have been the target of study in small numbers of patients, and no specific recommendation are possible regarding their efficacy.

Differential Diagnosis

Landau-Kleffner syndrome patients develop less frequent seizures, and severe regression of language development(auditory agnosia) rather than more global regression noted with ESES. EEG pattern in Landau-Kleffner syndrome is typically unilateral or lateralized.

Children with benign pediatric focal epileptic syndromes- benign childhood epilepsy with centrotemporal spikes and late-onset childhood occipital epilepsy (Gastaut type)- can present with relatively easy to control seizures and milder neuropsychological deficits. EEG of these patients shows potentiation of the epileptiform activities during sleep but much less prominent compared with near-continuous spike-wave abnormalities of ESES.

During acute stages of ESES, children may experience intractable atonic and absence seizures, closely mimicking Lennox-Gastaut syndrome. However, contrary to LGS, these patients do not have tonic seizures.[21]

Prognosis

Both clinical seizures and EEG abnormalities spontaneously improve after puberty, with only partial reversal of cognitive deterioration. A longer duration of ESES may be associated with a poor outcome regarding cognitive impairment. EEG may continue to show focal or multifocal interictal abnormalities.

Complications

Inadequate treatment and delayed diagnosis may lead to a worse cognitive outcome.