Myoclonic Epilepsy Beginning in Infancy or Early Childhood 

Updated: Oct 02, 2020
Author: Michael C Kruer, MD; Chief Editor: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA 

Overview

Background

Myoclonic seizures are characterized by rapid, jerklike movements that can affect the face, limbs, or axial musculature. Most families are familiar with hypnic jerks; that is, a sudden jerk that jolts one awake while falling asleep. In contrast to sleep-related myoclonus, myoclonic seizures occur during wakefulness and are associated with abnormal cortical discharges on EEG. Myoclonic seizures can occur in isolation or as part of a mixed-generalized epilepsy syndrome. Myoclonic epilepsies with onset in infancy and childhood are clinically and etiologically heterogeneous but, as a group, may be refractory to treatment.

The overall prognosis associated with myoclonic epilepsy in childhood depends on the underlying etiology. Identification of a distinct epilepsy syndrome may enable more accurate prognostication (see Etiology).

Clinical features can aid in the differentiation of myoclonic epilepsies from other forms of epilepsy and paroxysmal movements of childhood (see Clinical).

EEG is required to distinguish myoclonic seizures from nonictal causes of myoclonus, which can arise from lesions of the cortex, brainstem, spinal cord, or even peripheral nerve (see Workup).

The mainstays of therapy for myoclonic seizures are valproic acid (sodium valproate) and benzodiazepines (see Treatment). Some anticonvulsants may precipitate myoclonic seizures in predisposed individuals.

Pathophysiology

Myoclonic seizures are generally the product of hypersynchronous, generalized cortical discharges. These discharges arise from hyperexcitable neuronal networks.

Etiology

Seizures associated with early myoclonic encephalopathy can be due to a number of etiologies. The International League Against Epilepsy (ILAE) revised concepts and terminology related to the classification and description of seizures in 2010.[1] This report emphasized that concepts related to the characterization of seizures, their etiologies, and meaningful electroclinical syndromes are evolving. Practically speaking, myoclonic seizures can be grouped into the following categories (myoclonic absences, myoclonic tonic seizures, and myoclonic clonic seizure types are not discussed here):

  • Early infantile epileptic encephalopathies[2] - This includes early myoclonic encephalopathy (EME) and early infantile epileptic encephalopathy (EIEE). These are severe disorders with a grave prognosis. Causes of early infantile epileptic encephalopathies include brain malformations, inborn errors of metabolism, and neurogenetic disorders.

  • Myoclonic epilepsy occurring as part of a mixed generalized epilepsy syndrome - This includes Doose syndrome (myoclonic-atonic epilepsy),[3] Dravet syndrome (severe myoclonic epilepsy of infancy),[4] and Lennox-Gastaut syndrome,[5] as well as other syndromes that feature several kinds of generalized seizures. Progressive spasticity is frequently seen in older children and adolescents with Dravet syndrome, often associated with the development of crouch gait.[6] Causes may include cortical malformation and ion channel mutations, such as SCN1A mutations.

  • Nonprogressive myoclonic epilepsies - This group of disorders overall has a more favorable prognosis and includes benign neonatal myoclonic epilepsy, familial myoclonic epilepsy, and autosomal dominant cortical myoclonus and epilepsy, among others. However, nonprogressive myoclonic encephalopathies may also occur, with a more guarded prognosis. These disorders are usually genetically determined conditions.

  • Progressive myoclonic epilepsies[7] - In this class of myoclonic epilepsies, seizures occur in the context of an underlying neurodegenerative disorder. Representative diseases include Unverricht-Lundborg disease, Lafora body disease, myoclonic epilepsy with ragged red fibers (MERRF), the neuronal ceroid lipofuscinoses, sialidosis, and dentate-rubral-pallidoluysian atrophy (DRPLA). Myoclonus occurring in the context of these disorders may be stimulus-sensitive or action-induced.

Some children may not be readily classifiable in any of the above categories.

Across subtypes of childhood myoclonic epilepsy, many patients have an underlying genetic cause for their seizures. In some cases, myoclonic seizures may be a prominent feature of a syndrome with wider central nervous system and systemic manifestations, such as is seen in mitochondrial diseases (ie, MERRF or Alper syndrome [POLG1 mutations]). However, despite advances in identifying causes of epilepsy, for most cases of infantile and early childhood myoclonic epilepsy, no clear etiology will be found despite an appropriate workup.

Epidemiology

The incidence of myoclonic epilepsy is approximately 1 case in 40,000 children. Typically, the onset of these disorders is during the first 3 years of life. There are no known racial or sexual differences in the overall frequency of myoclonic epilepsies, although there may be differences in prevalence among specific populations for certain forms of myoclonic epilepsy (ie, Baltic epilepsy).

Prognosis

The prognosis depends heavily on the underlying etiology and the epilepsy syndrome. Patients with a benign syndrome typically respond well to medication and may outgrow their epilepsy. In other myoclonic epilepsy syndromes, the prognosis is usually less favorable.

Death in patients with myoclonic epilepsy may be related to the underlying disorder but is unlikely to be due to the myoclonic seizures themselves. Aspiration pneumonia is more common in this population and may result in frequent hospitalizations.

Patient Education

For patient education information, see the Brain and Nervous System Center, as well as Epilepsy.

 

Presentation

History

Once myoclonus is identified and confirmed to be associated with abnormal generalized discharges on EEG, it is important to ascertain the frequency and course of the patient’s myoclonus, as well as the time of onset. In order to better characterize the patient’s electroclinical syndrome, it is important to distinguish whether other seizure types co-occur, to carefully delineate neurodevelopmental progress (paying attention to evidence of regression), and to identify systemic manifestations of disease. Identification of a distinct epilepsy syndrome may guide diagnostic testing and management, and it may aid in prognostication and long-term care decisions.

Physical Examination

Brief, abrupt myoclonic jerks typically occur several times a day, but they may or may not be observed during an office-based examination. Manifestations often include head nodding, abrupt abduction of the arms, or sudden falls. Eyelid or facial muscles are affected commonly, although axial myoclonic jerks are most common and occur in 90% of patients. The differential diagnosis of rapid, brief, hyperkinetic movements includes tics and stereotypies. As with many paroxysmal episodic disorders of childhood, in questionable cases, having caregivers videotape spells of concern may be helpful, particularly if direct observation is not possible.

Myoclonic seizures commonly occur on awakening, and some may be precipitated by photic stimuli. In neurodegenerative disorders, myoclonic jerks may be precipitated by abrupt stimuli. Rarely, myoclonic seizures occur continuously as myoclonic status epilepticus with partial preservation of consciousness. This is a particularly prominent feature of Alper syndrome associated with POLG1 mutations.[8]

Although myoclonic seizures may occur as the sole type of seizure in some patients, they more commonly are associated with other forms of generalized seizures. Generalized tonic-clonic seizures are most common. Brief generalized clonic seizures or unilateral clonic seizures also may be seen. Atypical absence seizures occur in 40%, and pure atonic seizures may also occur.

 

DDx

Diagnostic Considerations

Disorders that may be confused with myoclonic epilepsy include the following[9] :

  • Benign neonatal sleep myoclonus

  • Benign infantile myoclonus

  • Startle reflex

  • Tics

  • Stereotypies

  • Blepharospasm

  • Astatic seizures

Differential Diagnoses

 

Workup

Approach Considerations

EEG is the centerpiece of the diagnostic evaluation. If neuroimaging is performed, magnetic resonance imaging is preferred. Results are often normal, reflecting a genetic rather than structural etiology, although congenital brain abnormalities sometimes are observed. In some forms of childhood myoclonic epilepsy, progressive cortical atrophy may be seen.

Electroencephalography

The ictal EEG correlate of myoclonic seizures consists of fast spike-wave discharges (>2.5 Hz), which, at times, are associated with slower 2- to 2.5-Hz discharges.[10] Interictal recordings may be normal or show slowing, depending on the etiology. Like other generalized epilepsies, abnormalities are frequently seen on routine EEG, even if myoclonus is not captured.

Brief (< 3 seconds) interictal bursts of irregular polyspike-waves may be seen either spontaneously or with photic stimulation. The occurrence of these discharges is increased during non–rapid eye movement (REM) sleep.

Also see EEG in Common Epilepsy Syndromes, EEG Video Monitoring, and Generalized Epilepsies on EEG.

Additional Testing

Genetic tests

In select cases, testing for SCN1A or other genetic etiologies suggested by clinical history and/or examination may be appropriate.

Lumbar puncture

Lumbar puncture may be helpful in identifying mitochondrial disorders (elevated cerebrospinal fluid [CSF] lactate) or nonketotic hyperglycinemia (elevated CSF glycine). Elevated protein may indicate a neurodegenerative disease.

 

Treatment

Approach Considerations

The mainstays of medical therapy for myoclonic epilepsy are valproic acid (sodium valproate), ethosuximide, or benzodiazepines (clonazepam or clobazam).[11] . A number of different antiepileptic medications may be efficacious, although phenobarbital, lamotrigine, vigabatrin, and carbamazepine may worsen the seizures in some cases.[12] Combination therapy with valproic acid and benzodiazepines is often helpful. Stiripentol is indicated for treatment of seizures associated with Dravet syndrome in patients aged 2 years or older who are taking clobazam. There are no clinical data to support the use of stiripentol as monotherapy in Dravet syndrome.[13, 14] The FDA approved a purified formulation of cannabidiol (Epidiolex) in June 2018 for seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients aged 2 years or older.

Adrenocorticotropic hormone (ACTH), steroids, and immunoglobulins have been tried but have not shown conclusive benefit.

 

Antiepileptic Medication

Patients with benign forms of myoclonic epilepsy often respond well to valproic acid or clonazepam. Either one of the drugs may be started; if both fail independently, they may be combined. The duration of treatment is tailored on an individual basis but is usually approximately 5 years. Second-line medications include ethosuximide, zonisamide, and topiramate.

Treatment for the more severe myoclonic epilepsies is more difficult and similar to the approach used for Lennox-Gastaut syndrome. For example, patients with Dravet syndrome typically have medically refractory epilepsy and often require polytherapy.[15]

A purified formulation of cannabidiol (Epidiolex) is approved for seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex in patients aged 1 year or older. Cannabidiol is a structurally novel anticonvulsant and the exact mechanism by which it produces anticonvulsant effects is unknown. It does not appear to exert its anticonvulsant effects through CB1 receptors, nor through voltage-gated sodium channels.

Approval was based on results from several studies that compared cannabidiol added to conventional AEDs to placebo and the incidence of drop seizures from baseline. An international study of 225 patients with LGS (mean patient age 15 years) were randomized to receive cannabidiol 20 mg/kg/day or 10 mg/kg/day, or placebo over 14 weeks. During the 4-week baseline period, the median number of drop seizures was 85 in all groups combined. The median reduction from baseline in drop-seizure frequency per 28 days during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg group, and 17.2% in the placebo group. During treatment, 30 patients (39%) in the 20-mg group, 26 (36%) in the 10-mg group, and 11 (14%) in the placebo group had at least a 50% reduction from baseline in drop-seizure frequency. The odds ratio (OR) for 20 mg vs placebo was 3.85 (95% CI, 1.75 - 8.47; P < 0.001) and the OR for 10 mg vs placebo was 3.27 (95% CI, 1.47 - 7.26; P = 0.003).[16]

A study (n=171) conducted in 24 clinical sites in the United States, the Netherlands, and Poland showed a median percentage reduction in monthly drop seizure frequency from baseline was 43.9% (IQR -69.6 to -1.9) in the cannabidiol group and 21.8% (IQR -45.7 to 1.7) in the placebo group. The estimated median difference between the treatment groups was -17.21 (p = 0.0135) during the 14-week treatment period.[17]

Fenfluramine (Fintepla) has been reintroduced to the market and is indicated for treatment of seizures associated with Dravet syndrome in patients aged 2 years and older. 

Fenfluramine and its metabolite, norfenfluramine, increase extracellular levels of serotonin through interaction with serotonin transporter proteins, and exhibit agonist activity at serotonin 5HT-2 receptors. The precise mechanism of action for the treatment of seizures associated with Dravet syndrome is unknown. 

Approval was based on data from two phase 3 randomized, double-blind, placebo-controlled trials. When added to existing therapy, fenfluramine significantly reduced the monthly convulsive seizure frequency compared to placebo in study patients whose seizures were not adequately controlled on one or more antiepileptic drugs. Additionally,  most study patients responded to treatment within 3-4 weeks and effects remained consistent over the treatment period.[18, 19]

Go to Antiepileptic Drugs for complete information on this topic.

Dietary Modification and Activity Restrictions

The ketogenic diet may be useful in children with particularly refractory epilepsy.[20] This diet should be instituted carefully, paying particular attention to the possibility of dehydration.

Caution should be used in children with drop attacks, as they may fall and injure themselves. A helmet can be protective. Routine seizure precautions are applicable.

Consultations and Long-Term Monitoring

Patients should be evaluated by a pediatric neurologist. If dysmorphic features are present, a genetic evaluation may be useful.

Serial EEGs often are required to ensure that patients are responding to treatment and that subclinical seizures are not occurring. Typical EEG findings in responsive patients include the disappearance of polyspike and wave activity and other associated epileptiform discharges.

 

Medication

Medication Summary

The long-term goals of pharmacotherapy are to reduce morbidity and prevent complications.

Go to Antiepileptic Drugs for complete information on this topic.

Antiepileptic Drugs

Class Summary

These agents prevent seizure recurrence and terminate clinical and electrographic seizure activity. Patients with the benign form of myoclonic epilepsy often respond very well to first-line AEDs.

Valproic acid (Depakote, Depakene, Depacon, Stavzor)

Valproic acid is chemically unrelated to other drugs that treat seizure disorders. Although its mechanism of action not established, its activity may be related to increased brain levels of gamma-aminobutyric acid (GABA), or enhanced GABA action. Valproate also may potentiate postsynaptic GABA responses, affect potassium channels, or have direct membrane-stabilizing effect.

The use of valproic acid in young children (younger than 2 y) is associated with an increased risk of hepatotoxicity. Hepatotoxicity is estimated to occur in fewer than 1 in 250 children treated.

Clobazam (ONFI)

Benzodiazepine indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children aged 2 years or older.

Stiripentol (Diacomit)

Allylic alcohol that is unrelated to other anticonvulsants. The precise anticonvulsant effect in humans is unknown. Possible mechanisms of action include direct effects mediated through the GABA-A receptor and indirect effects involving inhibition of cytochrome P450 activity with resulting increase in blood levels of clobazam and its active metabolite. It is indicated for treatment of seizures associated with Dravet syndrome in patients aged 2 years or older who are taking clobazam. There are no clinical data to support the use of stiripentol as monotherapy in Dravet syndrome.

Clonazepam (Klonopin)

Clonazepam facilitates inhibitory GABA neurotransmission and other inhibitory transmitters. It is useful in immediate control of seizures, but it may be associated with relatively rapid loss of efficacy against seizures.

Ethosuximide (Zarontin)

The mechanism of action of ethosuximide is based on reducing current in T-type calcium channels found on thalamic neurons. Spike-and-wave patterns during petit mal seizures are thought to be initiated in thalamocortical relays by activation of these channels. Ethosuximide is used as adjunctive medication to valproic acid if that medication has failed to control seizures.

Cannabidiol (Epidiolex)

Purified formulation of cannabidiol indicated for treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberouis sclerosis complex (TSC) in patients aged 1 year or older. Cannabidiol is a structurally novel anticonvulsant and the exact mechanism by which it produces anticonvulsant effects is unknown. It does not appear to exert its anticonvulsant effects through CB1 receptors, nor through voltage-gated sodium channels.

Fenfluramine (Fintepla)

Fenfluramine and its metabolite, norfenfluramine, increase extracellular levels of serotonin through interaction with serotonin transporter proteins, and exhibit agonist activity at serotonin 5HT-2 receptors. The precise mechanism of action for the treatment of seizures associated with Dravet syndrome is unknown. It is indicated for treatment of seizures associated with Dravet syndrome in patients aged 2 years and older.