Continuing Education Activity

Myoclonic epilepsy of infancy is a rare self-limited epileptic syndrome characterized by brief myoclonic seizures in previously healthy and developmentally normal children in the first three years of life. This activity reviews the evaluation and treatment of Myoclonic Epilepsy of Infancy and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the epidemiology of myoclonic epilepsy of infancy.
• Review and explain the appropriate evaluation of myoclonic epilepsy of infancy.
• Summarize the management options available for myoclonic epilepsy of infancy.
• Outline the interprofessional team strategies for improving care coordination and communication to improve outcomes in patients having myoclonic epilepsy of infancy.

Introduction

Myoclonic epilepsy of infancy (MEI) is a rare self-limited epileptic syndrome characterized by brief myoclonic seizures in previously healthy and developmentally normal children with onset in the first three years of life. MEI is popularly called "benign myoclonic epilepsy in infants" (BMEI), first described by Dravet and Bureau in 1981.[1] Before Dravet et al.'s description, several similar cases have been reported but with different names, such as "myoclonic epilepsy of childhood" by Jeavons.[2] 

BMEI does not have a benign course or prognosis in some children, so the word "benign" was removed from the name. The International League Against Epilepsy (ILAE) has included MEI among neonatal/infantile epileptic syndromes under Idiopathic generalized epilepsies with age-related onset.[3][4][5][6]

Etiology

Myoclonic epilepsy of infancy is an early form of possibly genetic idiopathic generalized epilepsy. A genetic cause is suggested for MEI, and few specific genetic changes have been recognized, such as SLC2A1 and HCN4 mutation.[7][8] Two-third of Myoclonic epilepsy of infancy occurs spontaneously, and in one-third, seizures are triggered by a sudden noise, touch, or light (reflex variant MEI). Among the reflex variant MEI, 20% may be triggered by photic stimulation, and rest may be induced by sudden acoustic or tactile stimulus.[9][10]

Epidemiology

Myoclonic epilepsy of infancy is an uncommon condition and accounts for 1% to 2% of childhood epilepsy which may be a slight underestimate than the actual situation.[11] Males are twice as likely to be affected as females. MEI occurs mostly in the age group of 6 months to 2 years. However, MEI can happen as young as four months and up to five years of age.[12]

History and Physical

Myoclonic epilepsy of Infancy occurs in previously healthy and developmentally normal children. Usually, there will be no significant past medical history, except for a history of febrile seizures in one-third of cases. A positive family history with seizures in first and second-degree relatives is noted in 30% of cases.[12]

Myoclonic seizures are the only type of seizures occurring in Myoclonic epilepsy in Infancy. MEI is characterized by a brief (1 to 2 secs) single or cluster of 2 to 8 myoclonic jerks involving predominantly the head and upper extremity. Myoclonic jerks are rapid, isolated but simultaneous jerks of various muscle groups in synchrony. Myoclonic seizures are often spontaneous, frequently occurring in wakefulness, less often during drowsiness or slow-wave sleep. The following features are noted in MEI.[13][14]

• Myoclonic jerks involving upper extremities.
• Head nodding, upward rolling of eyes, blinking.
• Falls if standing with lower extremities involved.
• Yelling/cough-like vocalization due to sudden diaphragmatic contraction may sometimes accompany the myoclonic jerks.
• Consciousness is usually intact. However, mild alteration of consciousness can accompany a cluster of myoclonic seizures. 

The following variants of Myoclonic epilepsy of Infancy have been reported. 

1. Reflex myoclonic epilepsy of infancy (RMEI) is a peculiar subtype (10% of MEI) precipitated exclusively by sudden unexpected tactile or auditory stimuli. RMEI is characterized by earlier onset, brief duration, a better prognosis with fast remission, and better cognitive outcome.[15][16]
2. Photosensitive myoclonic epilepsy in infancy is a subtype of RMEI characterized by photic-induced myoclonic seizures, which are usually difficult to manage. 
3. The nocturnal variant of benign myoclonic epilepsy in infancy has been reported in the literature characterized by excessive myoclonic jerks only during sleep.[17]
4. Familial infantile myoclonic epilepsy with autosomal recessive inheritance (chromosome 16p13) has infantile-onset prolonged myoclonic status followed by generalized tonic-clonic seizure persisting into adulthood in all patients.[18]

Evaluation

Polygraphic electroencephalography (EEG) is a key component in the evaluation of the diagnosis. The following EEG findings are observed in MEI.[15][19]

1. EEG Background activity is normal 
2. Interictal EEG is normal most of the time. 
3. Ictal EEG reveals brief bursts of generalized spike-and-wave, polyspike, or polyspike-and-wave pattern, with a frequency of 3 Hz.
4. EMG showing discharges corresponding to the myoclonus. 
5. Activation: Sleep deprivation may activate the EEG. 20% of reflex MEI have photosensitivity, and photic stimulation can activate discharges. 

Neuroimaging such as MRI brain (if performed) will be normal in MEI, unlike Dravet syndrome or Lennox Gastaut syndrome. 

Genetic testing may be considered to rule out specific mutations.

Treatment / Management

Myoclonic epilepsy of Infancy has an excellent response to anti-seizure drugs (ASDs). Sodium valproate (valproic acid) is the drug of choice and 80% of patients started on valproate become seizure-free. Clonazepam and levetiracetam are alternative drugs for MEI.[20] After 3 to 5 years from onset, ASD therapy can be gradually weaned over months. Reflex variant MEI with acoustic and somatosensory triggered myoclonus may not need treatment or be weaned after one year. MEI (reflex variant) with photosensitivity is more challenging to control, and levetiracetam is the most potent anti-myoclonic ASD, suppressing photosensitivity.[21]

Other forms of myoclonic epilepsy discussed under differential diagnosis are challenging to treat. The primary treatment modalities for West syndrome are ACTH/corticosteroids or vigabatrin. Clobazam, sodium valproate, and zonisamide may be second-line drugs. First-line medications for Dravet syndrome (DS) are a combination of ASD (clobazam and valproic acid), and second-line management includes stiripentol, topiramate, fenfluramine, ketogenic diet, or vagus nerve stimulation (VNS).[22] 

ASDs such as felbamate, lamotrigine, topiramate, and rufinamide have been tried for seizures associated with Lennox Gastaut syndrome (LGS). The FDA has approved cannabidiol (CBD)oral solution to treat seizures associated with LGS or Dravet Syndrome in patients aged two years and older.[23]

Differential Diagnosis

Myoclonic epilepsy in Infancy should first be differentiated from many non-epileptic conditions. 

1. Hypnagogic jerks are benign myoclonic jerks that usually occur on falling asleep. They are also called Hypnic jerks or sleep starts, and they resemble the jerks of myoclonic seizures. Hypnagogic jerks do not occur in waking states, and the EEG is normal.[24]
2. Benign non-epileptic myoclonus of infancy or benign spasm of infancy (BSI) is non-epileptic spasms occurring in the first year of life and self-resolve by two years. BSI is characterized by spasms lasting 1-2 seconds, with normal ictal and interictal EEG recordings. Ictal video EEG helps in ruling out the epileptic myoclonus of infancy and thereby helps to avoid unnecessary or over-treatment.[25]
3. Benign neonatal sleep myoclonus (BNSM) is a self-resolving condition featured by myoclonic lightning-like jerks occurring only during non-rapid eye movement sleep, with normal EEG findings. Myoclonic epilepsy of Infancy is typically noted to have onset after 6 months of age and generally not happens during sleep, which is an important distinctive feature.[26][27]
4. The jerking movements associated with myoclonic epilepsy of Infancy may be mistaken for motor stereotypies, benign shuddering spells, myoclonus-dystonia, tic, or hyperekplexia (excessive startle response). 

The following epileptic encephalopathies should be excluded before diagnosing benign myoclonic epilepsy in infancy.

• Dravet syndrome or severe myoclonic epilepsy in infancy (SMEI) is pharmaco-refractory epilepsy in previously healthy children with the onset in the first year of life. SMEI is usually a channelopathy often caused by SCN1A mutation in three-fourths patients. The seizures are usually prolonged, refractory, febrile or non-febrile, and generalized or unilateral clonic. Temperature sensitivity and onset with febrile seizures can be seen, with normal EEG initially. As seizures progress, developmental delay with cognitive impairment and behavior disorders are possible in the long run. Neuroimaging is usually normal, and interictal EEG may be abnormal with generalized or focal slowing.[28][29]
• West syndrome (infantile spasms) is characterized by the triad of infantile spasms, an abnormal EEG with Hypsarrhythmia, and developmental arrest. [30] 
• Lennox Gastaut syndrome (LGS) is featured by a triad of multiple seizures (tonic seizures in sleep, myoclonic, and or atypical absence seizures), an abnormal EEG with a slow spike-and-wave pattern, and developmental arrest. LGS presents later in childhood than infantile spasms and can be preceded by West's syndrome in 20% of cases.[31]
• Progressive myoclonic epilepsies (PME) comprises a group of rare types of epilepsies that are progressive. PME includes Lafora body disease, Unverricht-Lundborg disease, mitochondrial encephalopathy with ragged-red fibers, type 3 neuronopathic Gaucher Disease, neuronal ceroid lipofuscinosis, and sialidosis. PME typically present in late childhood or adolescence. The characteristic features of PME are multiple seizures (myoclonic or tonic-clonic), progressive neurologic deterioration including ataxia, or dementia.[32]

Prognosis

Myoclonic epilepsy of infancy (MEI) usually remits within six months to five years from onset. Reflex variant MEI induced by auditory or tactile stimuli has a better prognosis and an excellent AED response. However, the photosensitive reflex variant is difficult to manage, and EEG photosensitivity persists several years after clinical remission. Approximately one-fifth of Myoclonic epilepsy of Infancy develop afebrile generalized tonic-clonic seizures later in the clinical course when AED is withdrawn. Two-thirds of MEI has normal psychomotor development, and approximately one-third develop mild cognitive, behavioral, or motor deficits. Early-onset of seizures and poor seizure control are risk factors for a poor neuropsychological outcome.[33]

Complications

Seizures in MEI typically resolve; However, some patients have a recurrence of seizures in adolescence. Febrile seizures occur in a higher proportion.  Afebrile generalized tonic-clonic seizures occur in 20% of MEI. Development of juvenile myoclonic epilepsy and focal epilepsies have been reported rarely.

Neuropsychological deficits, including fine motor skill deficits, attention deficits, cognitive problems, language impairment, and learning disorders, are observed in long-term follow-ups of patients with MEI. Early-onset recurrent seizures can increase the risk of cognitive deficits.[34]

Treatment-related side effects include but are not limited to behavior and mood disorders with levetiracetam, thrombocytopenia, and hepatotoxicity with sodium valproate. Sodium valproate is avoided in children below 2 years of age due to increased hepatotoxicity. 

Monitoring drug levels, checking hematological parameters and liver enzymes is important to prevent complications.

Consultations

A neuropsychological evaluation is important for children with long-standing epilepsy, as cognitive and learning problems will be coexistent.

Consultations with genetic specialists and counselors are important in familial and also progressive myoclonic epilepsies.

Deterrence and Patient Education

Parents or caretakers of the patient need to be counseled about the self-limiting nature of the condition. If ASD is started for MEI, the risk-benefits of ASD should be discussed. Despite MEI being self-limiting and benign, MEI patients need careful follow-up to look for neuropsychological deficits, educational difficulties, and resurgence of seizures in the long run. 

Counseling about potential side effects and complications is important, with emphasis on specific safety profiles of the anti-seizure drugs.

Enhancing Healthcare Team Outcomes

An integrated care approach by interprofessional health care professionals is needed to ensure optimal care to patients with myoclonic epilepsy of infancy. The primary care providers, including primary care pediatricians and nurse practitioners, should have a high index of suspicion to identify patients with MEI early and rule out other forms of myoclonic epilepsy, thereby avoiding unnecessary work-up.

The patient with MEI should have structured long-term follow-up with the primary care clinicians and neurologist even after the seizure remits due to the risk of seizure recurrence in adulthood and neuropsychiatric deficits. Nurses and nurse practitioners can educate parents or caretakers on seizure safety precautions, the need for frequent follow-up, and ASD compliance. In addition, the pharmacists can educate the family on the importance of compliance and possible adverse effects of medications and communicate these findings to the primary care physicians if they occur. Pharmacists also play a role in long-term follow-up care, including drug level monitoring, weaning AED, and assessing drug-drug interactions. Nurses can answer patient questions, serve as a liaison to the clinician, and review dosing and medication administration.

Social workers help in identifying and rectifying the social barriers to optimal health care and inform the providers. Psychologists can evaluate and address cognitive and learning disabilities and appropriate strategies, including individualized education programs in school (IEP).

In summary, the treatment and management of patients with myoclonic epilepsy of infancy involve an interprofessional team that includes specialists, clinicians, mid-level practitioners, nurses, pharmacists, other allied health providers, and the patient's parents, all collaborating to achieve optimal patient outcomes. [Level 5]