Clinical manifestations

Presentation and course

	Early myoclonic encephalopathy is characterized clinically by the onset of erratic or fragmentary myoclonus.
	Simple focal seizures, massive myoclonia, and tonic spasms are the other types of seizures that can also occur.
	Cognitive and developmental disabilities are typical.
	EEG often shows a suppression burst pattern.

Erratic, focal myoclonus usually appears as the first seizure, occurring typically within the first 3 months of life, and sometimes as early as a few hours after birth. The myoclonus usually involves the face or extremities and may be restricted to an eyebrow, a single limb, or a finger. The jerks occur when infants are awake or asleep, and they are often described as "erratic" because they can shift from one part of the body to another in a random, asynchronous fashion. Frequency varies from occasional to almost continuous. In addition to limited focal myoclonus, generalized myoclonus may also be observed in some cases.

Focal seizures are frequent and occur shortly after erratic myoclonus (37). The semiology of focal seizures can be subtle, involving eye deviation or autonomic phenomena such as apnea or flushing of the face (16). Tonic seizures are reported frequently and can occur in the first month of life or afterwards; they may occur both in sleep and wakefulness (04).

Neurologic abnormalities are nearly universal, including very severe delays in psychomotor acquisitions, marked hypotonia, and disturbed alertness, sometimes with vegetative state (02). Dalla Bernardina and colleagues reported deterioration in their patients (16); this characteristic is difficult to confirm because the onset of the disease is very early. Signs of peripheral neuropathy may also occur in rare cases. Status dystonicus has been described (20).

The typical EEG finding in early myoclonic encephalopathy is the suppression burst pattern. This consists of bursts of spikes, sharp waves, and slow waves, which are irregularly intermingled and separated by periods of electrical suppression. There is no normal background activity (01). The burst-suppression pattern is not always found at seizure onset, and repetition of EEG may be necessary to demonstrate the presence of this pattern (44).

Prognosis and complications

The prognosis for early myoclonic encephalopathy is poor. Mortality may be as high as 50% in the first 2 years of life, and survivors are typically severely neurodevelopmentally impaired (25). Early myoclonic encephalopathy can persist into childhood or evolve into severe focal epilepsy.

Clinical vignette

After a normal pregnancy, this first-born son of nonconsanguineous parents was delivered by cesarean section because the umbilical cord was wrapped around the neck. On about the 10th day of life, the parents noticed myoclonic jerks, sometimes massive, involving the face and body.

The child was hospitalized at age 45 days. On examination, he was hypotonic and scarcely reactive, almost lethargic; localized and segmentary myoclonic jerks, sometimes massive, were observed. The EEG showed a suppression burst pattern during sleep and while awake; the bursts lasted 7 to 8 seconds, appeared sometimes synchronously and sometimes asynchronously over the 2 hemispheres, and consisted of discharges of slow waves overlapped by spikes and fast activity. The suppression phases lasted 10 to 15 seconds; myoclonic jerks did not have an evident EEG counterpart.

During EEG recording, 100 mg pyridoxine administered intravenously failed to modify the EEG pattern.

Results of MRI, performed also with spectroscopy, were normal. Blood samples tested for amino acids, lactate, ammonia, and very-long-chain fatty acids were normal. Urine tested for urinary organic acids and purines was normal. The glycorrhachia/glycemia ratio was within normal range. Sulfite test was negative, thus excluding molybdenum cofactor deficiency.

The child was treated with folic acid 5 mg/day without improvement. The patient was treated first with vigabatrin 100 mg/kg per day without results, after which clonazepam 1 mg/kg per day was added, but still without results. At about 3 months of age, tonic spasms appeared in series with EEG counterpart of diffuse fast activity.

In the following months, the child continued to be hypotonic, nonreactive, and lethargic, sometimes with poor distinction between waking and sleep. Myoclonic manifestations and rare tonic spasms persisted. Clonazepam was discontinued at 4 months of age. At age 6 months, the seizures suddenly stopped spontaneously. The child seemed to react slightly more to stimulation. The EEG showed progressive regression of burst-suppression pattern that was replaced by diffuse nearly continuous epileptiform abnormalities, which were more prevalent in the frontal regions and more evident during sleep.

At age 18 months, repeat MRI showed mild dilatation of lateral ventricles and cortical spaces; new metabolic screening failed to show any alteration.

At age 2 years, the child showed very severe cognitive impairment. He occasionally tracked and started to smile, but he could not control his head or trunk and did not make any voluntary movement. Diffuse hypertonicity was present. He occasionally had segmentary or massive myoclonic jerks. The EEG showed slow, disorganized brain activity and many multifocal and diffuse epileptiform abnormalities; in sleep, diffuse abnormalities sometimes assumed a rhythmic pattern. Final diagnosis was cryptogenic early myoclonic encephalopathy.

Biological basis

	Early myoclonic encephalopathy is associated with a variety of underlying etiologies.
	Classically, the condition was described as being secondary to metabolic abnormalities.
	Genetic mutations are increasingly being recognized.
	There may be a final common pathway whereby multiple underlying disorders can lead to the same pathologic abnormalities and/or phenotypic syndrome.

Etiology and pathogenesis

Early myoclonic encephalopathy is believed to have various prenatal etiologies that often remain unknown, ultimately resulting in a diffuse process likely involving the brainstem and white mater and possibly leading to deafferentation and hyperexcitability of the cortex (09).

Metabolic disorders are common. Numerous cases have been associated with nonketotic hyperglycinemia (33; 02; 10). Pyridoxine dependency and pyridox(am)ine-5-phosphate oxidase deficiency must also be considered (50; 22). Other metabolic disorders include D-glyceric acidemia (21), propionic acidemia (33), molybdenum cofactor deficiency (06), and methylmalonic acidemia (33). Schlumberger and colleagues found urinary excretion of an abnormal oligosaccharide in 3 of their patients (45).

Some malformative disorders can also cause early myoclonic encephalopathy (34), but more often they produce the clinical picture of Ohtahara syndrome. Lee and colleagues reported a patient with early myoclonic encephalopathy and cerebral atrophy, ventriculomegaly, and thinning of the corpus callosum who was also found to have a mutation in SCN2A (32). Watanabe and colleagues reported a patient with Schinzel-Giedion syndrome, a rare genetic syndrome characterized by several facial dysmorphisms, midface hypoplasia, and multiple skeletal anomalies (including a short and sclerotic skull base, short neck and post axial polydactyly) along with cardiac and urogenital malformations; the patient had a persistent burst suppression pattern on the EEG with erratic myoclonus of the extremities and face (51).

Genetics. Genetic etiologies are increasingly being described. Early myoclonic encephalopathy has been associated with mutations in AMT (10), CDKL5 (47), ErbB4 (07), GABRB2 (26), KCNQ2 (30), KCNT1 (20), PNPO (22; 25), PIGA (28), RARS2 (52), SCN1A (27), SCN2A (32), SETBP1 (08), SIK1 (23), SLC25A22 (14), and UBA5 (35). Nicita and colleagues reported a patient with early myoclonic encephalopathy and a genetic deletion encompassing the STXBP1, SPTAN1, ENG, and TOR1A genes (39). Aravindhan and colleagues reported a patient with early myoclonic encephalopathy and a deletion involving STXBP1 and SPTAN1 (05). Howell and colleagues reported a patient with Wolf-Hirschhorn syndrome and early myoclonic encephalopathy (25). Of note, mutations in SIK1, PIGA, SCN2A, SLC25A22, PNPO, KCNQ2, KCNT1, GABRB2, and STXBP1 have also been associated with Ohtahara syndrome. It is important to note that a significant number of individuals with this condition still do not have an identifiable genetic abnormality; during a study of infantile epileptic encephalopathy patients in India, no genetic abnormalities were identified among any of patients identified as having early myoclonic encephalopathy (36).

Pathology. The lack of consistent neuropathologic features suggests that the etiology may vary from case to case. Pathologic findings include a drop-out of cortical neurons and astrocytic proliferation, severe multifocal spongy changes in the white matter, perivascular concentric bodies, demyelination in cerebral hemispheres, imperfect lamination of the deeper cortical layers, and unilateral enlargement of cerebral hemisphere with astrocytic proliferation (01). On the other hand, absence of pathologic abnormality was reported in 2 affected cases (16).

Djukic and colleagues speculated that as the initial seizure type in early myoclonic encephalopathy, repeated myoclonic seizures may kindle the development of focal seizures; with time, in some cases, there may be a spread to the brainstem. Tonic seizures, which eventually appear in early myoclonic encephalopathy, develop once the brainstem lesion burden exceeds the threshold for seizures. Unlike patients with Ohtahara syndrome who may have already exceeded this threshold at birth and present with tonic seizures early, early myoclonic encephalopathy patients may have less severe brainstem involvement, and tonic seizures are not the presenting symptom. Over time, the brainstem alterations may allow the emergence of tonic seizures, possibly as a result of a kindling process increasing seizure susceptibility or as a release of the brainstem from cortical inhibitory control as the metabolic disease progresses. The pathologic data obtained from autopsies performed on 5 patients with early myoclonic encephalopathy, all of whom had tonic seizures and clinical signs of brainstem anomalies, supported this view (18).

Despite different etiologies, Spreafico and colleagues hypothesized a common neuropathologic finding: the presence of numerous large spiny neurons dispersed in the white matter along the axons of the cortical gyri has been interpreted as an abnormal persistence of interstitial cells (46). These neurons, present during neocortical histogenesis, are programmed to die near the end of gestation or soon after birth.

Epidemiology

Early myoclonic encephalopathy is very rare. An epidemiologic study on childhood epilepsy carried out in Okayama Prefecture, Japan, detected 4 cases of early myoclonic encephalopathy (0.168%) among 2378 epileptic patients younger than 10 years of age on the prevalence day of December 31, 1980 (42). An Australian study found that early myoclonic encephalopathy accounted for 2 of 114 patients (2%) with severe infantile epilepsies identified over a 2-year period (25).

Differential diagnosis

Confusing conditions

Like early myoclonic encephalopathy, Ohtahara syndrome is also associated with onset in early infancy, a suppression-burst pattern in EEG, a variety of seizure types, and poor psychomotor outcome. In the purest form, the prominent erratic myoclonia present in early myoclonic encephalopathy is not present in Ohtahara syndrome; spasms and tonic seizures predominate in the latter. The etiology has also been thought to be different; metabolic pathologies dominate in early myoclonic encephalopathy, whereas brain malformations classically dominate in Ohtahara syndrome. In 2006, Ohtahara and Yamatogi pointed out the major differences between the 2 syndromes: (1) tonic spasms in Ohtahara syndrome versus focal seizures and erratic myoclonias in early myoclonic encephalopathy, (2) continuous suppression-burst pattern in both waking and sleeping states in Ohtahara syndrome whereas this EEG pattern is supposed to be limited to sleep in early myoclonic encephalopathy, and (3) different evolutional pattern with age. Ohtahara syndrome often evolves into West syndrome and further to Lennox-Gastaut syndrome with age, but early myoclonic encephalopathy demonstrates no unique evolution; it continues as such for a long time or changes into focal epilepsy or severe epilepsy with multiple independent spike foci (40; 41). Differentiation between the 2 syndromes may be difficult, especially early on when both myoclonus and tonic seizures may coexist. There is considerable clinical overlap between the 2 conditions, with wide variations in underlying pathophysiology as well as phenotype. Therefore, they are conceptualized by some as part of the same continuum of disease, with various underlying etiologies leading to a common phenotypic spectrum (17; 09; 43).

It is important to note that the nonreactive suppression-burst EEG pattern may be found not only in patients with Ohtahara syndrome or early myoclonic encephalopathy but also in newborns with hypoxic-ischemic encephalopathy. Seizure types and evolution allow a correct diagnosis.

Associated or underlying disorders

Early myoclonic encephalopathy has been identified in association with multiple metabolic abnormalities as well as several specific gene mutations.

Diagnostic workup

	EEG shows a typical suppression burst pattern.
	Evaluation for metabolic disorders and genetic testing may help elucidate underlying etiology.
	Brain imaging may or may not show abnormalities.

In early myoclonic encephalopathy, EEG is characterized by a suppression burst pattern with bursts of spikes, sharp waves, and slow waves, which are irregularly intermingled and separated by periods of electrical silence. The bursts usually last 1 to 5 seconds and alternate with about 10 seconds of suppression. The EEG paroxysms may be either synchronous or asynchronous over both hemispheres. There is no normal background activity (01). High-frequency EEG activity in the range of 80 to 150 Hz has been associated with the bursts (49). The suppression burst pattern is not always found at seizure onset, and repetition of EEG may be necessary to demonstrate the presence of this pattern to meet the diagnostic criteria for early myoclonic encephalopathy (44). The suppression burst pattern can evolve into atypical hypsarrhythmia or into multifocal paroxysms after 3 to 5 months of life (37). However, in most cases this phase is transient, and a return to the suppression burst pattern is observed (Dalla Bernadina et al 1983).

Erratic myoclonus does not generally have an ictal EEG counterpart. Focal seizures have EEG characteristics similar to those of neonatal fits. The CT and MR findings vary and are related to etiology.

On imaging. The brain may be either grossly normal or have asymmetrical enlargement of 1 hemisphere, dilatation of the corresponding lateral ventricle, or cortical and periventricular atrophy (01).

Hirose and colleagues reported the use of functional neuroimaging analyses for a patient with early myoclonic encephalopathy (24). The interictal SPECT and (18F)-FDG-PET at 1 month of age showed hypoperfusion and hypometabolism of the bilateral basal ganglia, thalami, and right parieto occipital cerebral cortices, showing that there is profound dysfunction of the basal ganglia, thalamus, and cerebral cortex. Subtraction ictal SPECT of tonic spasms clearly showed hypoperfusion of bilateral basal ganglia, thalami, brainstem, and deep cortical layer of bilateral frontoparietal cortices, suggesting that functional deafferentation of cortex from subcortical structures exists in early myoclonic encephalopathy; these imaging findings may provide insight into the pathophysiology of the suppression burst pattern seen in early myoclonic encephalopathy (24).

Testing for metabolic disorders should be performed, including nonketotic hyperglycinemia, pyridoxine dependency, and pyridox(am)ine-5-phosphate oxidase deficiency. Screening with serum amino acid and urine organic acid testing is recommended. Genetic testing may or may not reveal abnormalities.

Management

	No definitive treatment exists.
	Treatment with antiseizure medications yields inconsistent results.
	Treatments may be available for individuals with recognized metabolic disorders, though it is unclear whether these improve long-term outcomes.

There is no consistently effective therapy for early myoclonic encephalopathy. Nakano and colleagues reported 2 female infants with early myoclonic encephalopathy whose intractable seizures were suppressed with lidocaine and carbamazepine (38). Ishikawa and colleagues reported a patient with the SCN1A mutation and early myoclonic encephalopathy who had a reduction in seizures on perampanel (27). Kosaka and colleagues reported an infant with early myoclonic encephalopathy of unknown etiology who had a significant seizure reduction on high dose phenobarbital (serum levels between 50 and 60 microgram/milliliter) (31). However, effective treatment with antiseizure medications is anecdotal; typically, these treatments do not alter the poor prognosis.

A trial of pyridoxine is always justified in cases of early myoclonic encephalopathy (50). Pyridox(am)ine-5-phosphate oxidase deficiency has also been reported, with a good improvement after pyridoxal-5-phosphate supplementation (22).

In nonketotic hyperglycinemia, pyridoxine and benzoate can normalize the levels of glycine in the blood and improve the EEG picture, but without improvements in prognosis. There have been several reported cases of a reduction in seizure frequency using the ketogenic diet in individuals with early myoclonic encephalopathy and nonketotic hyperglycinemia (29). Tekgul and colleagues report worsening in 2 cases of early myoclonic encephalopathy associated with nonketotic hyperglycinemia after the administration of vigabatrin, which inhibits GABA transaminase and elevates GABA concentrations in the brain (48).

Chien and colleagues report a case of early myoclonic encephalopathy who was initially controlled with dextromethorphan, with reversion of her burst suppression pattern on EEG to relatively normal background activity (13). At 72 days of age it progressed to alternating focal tonic seizures compatible with migrating focal seizures in infancy that responded poorly to dextromethorphan.

Outcomes

Prognosis is generally poor. Mortality is high in the first 2 years of life. Those that survive are almost universally severely cognitively and developmentally disabled, even among patients for whom seizures are relatively well controlled (25). Early myoclonic encephalopathy can persist into childhood or evolve into severe focal epilepsy.