Clinical manifestations

Presentation and course

Seizures typically occur within the first 3 months of life, often in the first weeks and sometimes as early as a few hours after birth (53; 11). Tonic seizures are common. They may be either generalized and symmetrical or lateralized and occur during both wakefulness and during sleep. The seizures are very frequent, with affected patients experiencing as many as 100 to 300 isolated seizures or 10 to 20 clusters of seizures per day (55).

Myoclonic seizures are also common and, in some patients, may be the predominant seizure type. The myoclonus usually involves the face or extremities and may be restricted to an eyebrow, a single limb, or a finger, or it may be bilateral. 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.

Focal motor seizures can be present as well. In some patients, there may be subtle focal seizures involving, for example, eye deviation or autonomic phenomena, such as apnea or flushing of the face (14). Sequential seizures may be present, involving several different seizure semiologies occurring in sequence as part of a single seizure event (58).

Neurologic abnormalities are nearly universal, including very severe delays in psychomotor acquisitions, marked hypotonia, and disturbed alertness. Dalla Bernardina and colleagues reported deterioration in their patients (14); this characteristic is difficult to confirm because the onset of the disease is very early. Movement disorders may be seen, including chorea, tremor, and dystonia (68). Status dystonicus has been described (25).

The EEG in early infantile epileptic encephalopathy is abnormal. A suppression burst pattern is commonly seen, consisting of spikes, sharp waves, and slow waves, which are irregularly intermingled and separated by periods of electrical suppression. 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 (57). Other abnormalities include multifocal epileptiform discharges, diffuse slowing, and discontinuity (68). There is no normal background activity (01).

Prognosis and complications

The clinical progression of this condition is marked by severe psychomotor retardation, and death in infancy is common and often attributed to pneumonia/respiratory illness or sudden unexpected death in epilepsy (SUDEP). Those who survive are typically mentally and physically handicapped, even among those in whom seizures are eventually relatively well controlled (31).

In some cases, the epilepsy may evolve into focal epilepsy or into infantile epileptic spasms syndrome over time; some of these patients may subsequently evolve to Lennox-Gastaut syndrome.

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 involving the face and body.

The child was hospitalized at the age of 45 days. On examination, he was hypotonic with decreased reactivity; 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 two hemispheres, and consisted of discharges of slow waves overlapped by spikes and fast activity. The suppression phases lasted 10 to 15 seconds.

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. Vigabatrin 100 mg/kg per day did not control the seizures, after which clonazepam 1 mg/kg per day was added, but still without results. At about 3 months of age, tonic spasms appeared.

In the following months, the child continued to be hypotonic, nonreactive, and lethargic, sometimes with poor distinction between waking and sleep. Myoclonic manifestations and 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.

Biological basis

Etiology and pathogenesis

Early infantile epileptic encephalopathy is believed to have various possible underlying etiologies that often remain unknown, ultimately resulting in a diffuse process that likely involves the brainstem and white matter and possibly leads to deafferentation and hyperexcitability of the cortex (06). Because of the close relationship between early infantile epileptic encephalopathy, infantile epileptic spasms syndrome, and Lennox-Gastaut syndrome, it is suggested that these all represent age-specific responses of the brain at various developmental stages to heterogeneous, nonspecific exogenous factors (53).

Pathology. Associated structural brain abnormalities include agenesis or dysgenesis of the corpus callosum, dentato-olivary dysplasia, cerebellar hypoplasia, pontine hypoplasia, delayed or abnormal myelination, cerebral atrophy, focal polymicrogyria, and ventriculomegaly (11; 56; 43; 59; 35). There is a strong association between early infantile epileptic encephalopathy and hemimegalencephaly (23). Several studies discuss the role of cortical dysgenesis in relation to the early infantile encephalopathies (60).

Metabolic disorders are also common. Numerous cases have been associated with nonketotic hyperglycinemia (11; 45; 07). Pyridoxine dependency and pyridox(am)ine-5-phosphate oxidase deficiency must also be considered (65; 27; 56). Other metabolic disorders have been reported, including D-glyceric acidemia (26), propionic acidemia (45), molybdenum cofactor deficiency (31), carnitine palmitoyltransferase deficiency (23), glycosylation disorders (09), and methylmalonic acidemia (45).

Pathologic findings reported in early infantile epileptic encephalopathy 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).

Spreafico and colleagues reported that the presence of numerous large spiny neurons dispersed in the white matter along the axons of the cortical gyri is common; this has been interpreted as an abnormal persistence of interstitial cells (60).

Reviewing published autopsy cases, Djukic and colleagues found that brainstem and cerebellar abnormalities were consistently present (17; 18). It is possible that the prominence of tonic seizures in early infantile epileptic encephalopathy may be an indication of brainstem dysfunction. It has been shown that the bursts in the suppression burst EEG pattern may be associated with the brainstem, thalamus, and cortex and the periods of suppression only with the cortex, suggesting a deafferentation between cortical and subcortical structures (34). Of note, brainstem dysfunction is also thought to contribute to the development of hypsarrhythmia in infantile spasms (42) and may play a role in the transition from early infantile epileptic encephalopathy to infantile epileptic spasms syndrome.

Genetics. Genetic mutations have been increasingly recognized in early infantile epileptic encephalopathy. Common genetic abnormalities involve pathogenic variants in KCNQ2, SCN2A, STXBP1, CDKL5, ARX, and SCN8A (56; 43; 48; 62; 68; 35).

Less commonly reported genetic abnormalities include mutations in AMT (07), AARS, ARX (05), ALG13 (09), BRAT1, CASK (43), CYFIP2 (15), DMXL2 (22), DEPDC5 (43), DOCK7 (39), ErbB4 (04), GABRA1, GABRB2 (32), GNAO1 (30), KCNT1 (25), KCNT2, NECAP1, PACS2 (10), PNPO (27; 31), PIGA, PIGQ (56), RARS2 (67), SCN1A (33), SEPSECS (56), SETBP1 (05), SIK1 (30), SLC25A22 (12), TBC1D24, UDGH (35), UBA5 (46), and VOUS (43). Nicita and colleagues reported a patient with a genetic deletion encompassing the STXBP1, SPTAN1, ENG, and TOR1A genes (52). Aravindhan and colleagues reported a patient with a deletion involving STXBP1 and SPTAN1 (03).

In some cases, genetic abnormalities have been associated with specific phenotypic features. For example, UBA5 is predominantly associated with myoclonic seizures (68). Mutations in SCN8A tend to be associated with focal seizures (24). KCNT1 mutations may present with focal tonic seizures with autonomic symptoms (20). Mutations involving SCN2A, STXBP1, and CDKL5 are associated with tonic seizures or sequential seizures (47; 20; 68).

Epidemiology

Early infantile epileptic encephalopathy has an estimated incidence of 10 out of 100,000 live births (61). It may be slightly more common in males (17).

Differential diagnosis

Confusing conditions

Other epilepsy syndromes with neonatal onset include self-limited neonatal epilepsy and self-limited familial neonatal epilepsy. These syndromes typically present with focal tonic, focal clonic, or sequential seizures in the first week of life. In contrast to the early infantile epileptic encephalopathies, the EEG is often normal, or may show minor nonspecific abnormalities (68). Development is typically normal, though minor developmental abnormalities or learning disabilities may be noted. The seizures often resolve between 2 and 6 months of age.

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

Associated or underlying disorders

Early infantile epileptic encephalopathy has been subdivided into specific syndromes in the past, including Ohtahara syndrome and early myoclonic encephalopathy. The distinction between these two syndromes was made primarily based on underlying etiology, seizure type, and subtle differences in EEG findings (55). However, differentiation between these two syndromes was often difficult, and many conceptualized them as part of the same continuum of disease, with various underlying etiologies leading to a common phenotypic spectrum (17; 06; 56).

In some cases, early infantile epileptic encephalopathy may evolve into infantile epileptic spasms syndrome or into a severe focal epilepsy. Some patients will go on to develop Lennox Gastaut syndrome.

Diagnostic workup

The EEG is often 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 attenuation. The pattern can be widespread and synchronous, asynchronous over both hemispheres, or limited to one side. Other abnormal findings may include multifocal spikes, discontinuity, and diffuse slowing (68). 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 (63). The suppression burst pattern is not always found at seizure onset (57). It can evolve into hypsarrhythmia or into multifocal paroxysms in some cases.

On imaging, CT and MRI may reveal specific findings consistent with the malformative etiologies previously described, including hemimegalencephaly, agenesis or dysgenesis of the corpus callosum, dentato-olivary dysplasia, cerebellar hypoplasia, pontine hypoplasia, and cerebral atrophy, among others. In some cases, the brain may be grossly normal (01).

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 reveal abnormalities and is recommended.

Genetic testing may be revealing. A multicenter international study suggested that rapid genome sequencing in infants with new-onset epilepsy is feasible and may have implications for treatment and prognosis (16).

Management

Drug treatment. Evidence for the use of specific antiseizure medications in early infantile epileptic encephalopathy is anecdotal. Phenobarbital, valproate, pyridoxine, zonisamide, topiramate, levetiracetam, and benzodiazepines have been used with limited effectiveness to control seizures (43; 49). Sodium channel agents were reported to control seizures in several patients with mutations in SCN1A and KCNQ2, but this did not improve long-term outcome (51; 38; 50). Sodium channel agents similarly had inconsistent effects in patients with SCN8A mutations (29). Kosaka and colleagues reported an infant who had a significant seizure reduction on high-dose phenobarbital (serum levels between 50 and 60 microgram/milliliter) (41). Ishikawa and colleagues reported a patient with an SCN1A mutation who had a reduction in seizures on perampanel (33). Adrenocorticotropic hormone therapy has also had limited efficacy and may be beneficial in cases that progress to infantile epileptic spasms syndrome (55; 37). The ketogenic diet has been reported to have a beneficial effect in some cases (11; 38; 09). No medications are effective in treating the developmental disability and progressive decline that are typical of this condition.

Metabolic treatments. Cases in which a metabolic disorder is identified and corrected may have a better outcome and improved psychomotor development. A trial of pyridoxine is always justified (65). Supplementation of pyridoxal 5′-phosphate can lead to substantial improvements in patients with pyridox(am)ine-5′-phosphate oxidase (PNPO) deficiency (27). Folinic acid was reported to dramatically reduce seizures and improve the EEG in a patient with STXBP1 mutation (64).

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 nonketotic hyperglycinemia (36).

Surgery. Cases with hemimegalencephaly or cortical dysplasia can benefit from neurosurgical treatment with hemispherectomy or focal resection (40), or possibly disconnection surgery (44). Vagus nerve stimulation has been reported to benefit some patients (19). Appropriately chosen patients who are treated surgically may have a favorable outcome in terms of seizure control and development (28).

Outcomes

Prognosis is generally poor. Mortality is high in the first 2 years of life. The seizures are often intractable to currently available antiepileptic therapy. Severe psychomotor retardation is almost universal in survivors, even among those in whom seizures are eventually relatively well controlled (31). Correction of underlying genetic and metabolic disorders, if identified, can improve prognosis.