Vitamin-responsive epileptic encephalopathies are rare but important causes of EOEE. They commonly result in refractory seizures with poor neurocognitive outcomes if specific treatment is delayed. The type of seizures, etiologies, and treatments are summarized in Table 1. If seizures persist despite the use of two or more appropriate anticonvulsants at maximum tolerated doses, then add-on vitamin treatment should be considered. Pyridoxine-dependent epilepsy (PDE) and pyridoxal-5-phosphate-dependent epilepsy share similar clinical presentations as pyridoxal-5-phosphate is derived from pyridoxine¹⁴⁾. In the early onset type, patients will typically develop abnormal movements soon after birth and electroencephalogram (EEG) can be either completely normal or exhibit a burst suppression pattern¹⁵⁾. Prognosis is generally good with prompt treatment, but death or significant intellectual and motor disability may occur if treatment is delayed¹⁶⁾. Pyridoxal-5-phosphate may be used as an initial treatment, which would be effective against both PDE and pyridoxal-5-phosphate dependent epilepsy. Pyridoxine could be introduced later, replacing pyridoxal-5-phosphate as a cheaper and similarly effective alternative, if PDE diagnosis is confirmed¹⁷⁾. Folinic acid responsive epilepsies are caused by low concentration of 5-methyltetrahydrofolate (MTHF) in the cerebrospinal fluid (CSF), which is associated with various neurological conditions¹⁸⁾. Genetic or autoimmune mechanisms cause cerebral folate deficiency and delayed treatment may lead to encephalopathy with severe learning disabilities. EEG may show abnormal background activity with multifocal spike-wave complexes, but typically has no diagnostic features. Neuroimaging results are also usually normal¹⁹⁾. Patients either do not respond to pyridoxine at all or exhibit only a temporary improvement. However, such patients show a marked neurological recovery including cessation of seizures upon folinic acid treatment¹⁸⁾. Biotinidase deficiency is a biotin-responsive metabolic disorder causing impairment of functions of multiple carboxylases and presenting with seizures, hypotonia, visual/auditory symptoms, eczema, and alopecia. Untreated children usually have neurocutaneous features between the ages of 2 and 5 months^18,20). Seventy percent of patients have various type of seizures including infantile spasms²¹⁾. Seizures and other symptoms improve often within a day of treatment with biotin. It has been suggested that similarly to pyridoxine trials, biotin treatment should be considered in any child with poorly controlled seizures²²⁾. Regardless of age or weight, a dose of 5- to 20-mg biotin daily has been found to be effective and needs to be continued for the rest of patient's life if it offers stable improvement^23,24). Vitamin B12 deficiency may lead to various neurologic symptoms including developmental delay or regression, irritability, weakness, hypotonia, and convulsions. Seizures are a rare presentation of vitamin B12 deficiency but they have been occasionally reported, especially in infants, including cases of West syndrome^25,26). Vitamin B12 deficiency caused by dietary preferences of mothers, who may be vegan, is the most common cause of such symptoms in breast-fed infants between 4 and 8 months, even when the mothers exhibit no hematological or neurological symptoms themselves^26,27). Serum levels of methylmalonic acid and total homocysteine have been shown to be markedly elevated in the majority of such patients. Vitamin B12 deficiency should be considered in all infants with developmental delay, hypotonia, or seizures for whom an alternate diagnosis cannot be made.

Ohtahara syndrome is often defined as an early infantile epileptic encephalopathy with a characteristic EEG pattern, suppression-burst, during which higher-voltage bursts of slow waves mixed with multifocal spikes alternate with isoelectric suppression phase²⁸⁾. EEG shows a continuous suppression-burst pattern in both waking and sleeping states. The onset is between neonatal period and early infancy, usually within the first 3 months of age, with some mothers reporting seizure-like movements of the fetus during pregnancy²⁹⁾. Etiologically, structural brain lesions, such as diffuse subependymal band heterotopia or midbrain dysplasia, are the most probable causes of Ohtahara syndrome^30,31). Predominant seizures detected in Ohtahara syndrome patients are repetitive, frequent, tonic spasms occurring with or without series formation, although other seizure types can also be observed^29,32). Antiepileptic and immunomodulating drugs are generally ineffective in treating tonic spasms, although rare cases show improvement upon such treatment. In general, prognosis is extremely poor with chronic intractable seizures and severe psychomotor retardation. Seizure patterns usually change with time: frequently cases evolve to West syndrome and further to Lennox-Gastaut syndrome with age. Nearly 50% of affected children are likely to die in infancy or childhood^32,33).

Early myoclonic encephalopathy (EME) is characterized by fragmentary myoclonic jerks or violent myoclonic spasms, which generally occur in the neonatal period or early infancy. Partial myoclonus and partial motor seizures are the main seizure types in EME, but generalized myoclonus can also be observed in some patients. Partial motor seizures are frequent. They occur shortly after erratic myoclonus and shift typically from one part of the body to another in a random, asynchronous pattern³⁴⁾. The myoclonus usually involves the face or extremities, but may be restricted to some other part of the body. Typical interictal EEG shows a suppression-burst pattern similar to that seen in Ohtahara syndrome³⁵⁾. Suppression-bursts become more apparent in sleep and may persist until late childhood after a transient evolution to hypsarrhythmia in the middle to late infancy³¹⁾. The generalized myoclonic jerk typically is associated with a generalized or fragmentary burst of polyspike, spike, and slow wave discharges, but erratic myoclonia may or may not be related to the bursts³⁵⁾. The etiology is variable and often remains unknown, but nonstructural/metabolic disorders are most probable causes of EME. Vitamin responsive epilepsies, such as PDE, pyridoxal-5-phosphate-dependent epilepsy, or folic acid responsive epilepsy can show typical clinical and EEG features of EME. Other inborn metabolic deficiencies, such as nonketotic hyperglycinemia, methylmalonic acidemia, or propionic acidemia, can also demonstrate EME features. Concentrations of serum amino acids and urine organic acids, as well as amino acid content of the CSF should be analyzed in patients with EME^34,36). The prognosis for EME is also poor and there is no effective treatment except for vitamin responsive epilepsies. EME persists for long periods without evolution, except for the occasional transient phase of West syndrome, or changes into partial or severe epilepsy with multiple independent spike foci³¹⁾.

Infantile spasms or West syndrome is the most common epilepsy syndrome in infancy, which presents with a combination of the triad of infantile spasms, developmental deterioration, and hypsarrhythmic EEG pattern^3,37). Typically, the spasms involve brief symmetrical contractions of musculature of the neck, trunk, and extremities, which frequently occur in clusters^38,39). An individual spasm lasts for seconds (usual duration 1-2 seconds) and is often longer than typical myoclonus (duration up to 200 ms), though not as long as tonic seizures, which last for several seconds. Spasms are usually recurrent with a period of 5-30 seconds^3,34). The spasms may be subtle and isolated at onset, typically clustering with time. Patients typically exhibit several clusters per day, particularly during drowsiness^37,40). Hypsarrhythmia, a typical interictal EEG pattern observed in this condition, consists of a disorganized pattern with asynchronous, very high amplitude multifocal spike and sharp wave discharges. The etiology can be classified into symptomatic and cryptogenic cases. The fraction of symptomatic cases has been steadily increasing due to improved diagnostic techniques, such as metabolic and genetic testing, as well as neuroimaging⁴¹⁾. Symptomatic causes are found in nearly 60% of cases, which include cerebral malformations, infection, hemorrhage, hypoxic-ischemic injury, metabolic disorders, and genetic conditions^40,42). Tuberous sclerosis complex (TSC) is an important cause of infantile spasms and 75%-80% of individuals with TSC may develop epilepsy⁴¹⁾. Outcomes are mostly dependent on the etiology; cryptogenic patients who are treated early have more favorable prognosis than patients with symptomatic varieties^43,44).

Malignant migrating partial epilepsy in infancy (MMPEI) is characterized by neonatal or early infantile onset migrating partial seizures, which usually last a few weeks or months, and the frequency becomes nearly continuous with time. Patients show frequent partial seizures of multifocal onset with autonomic manifestations, such as apnea, flushing, or cyanosis⁴⁵⁾. The interictal EEG shows multifocal epileptiform discharges with diffuse slowing of background activity. The multifocal discharges poorly activated by sleep in all cases and background activity slows down with fluctuating asymmetry between different recordings³⁴⁾. Most cases have no clear etiology of structural or biochemical abnormalities suggesting contribution of genetic factors. However, genetic tests usually fail to detect mutations in KCNQ2, KCNQ3, SCN1A, SCN2A, or CLCN2 genes in MMPEI⁴⁶⁾. Seizures are often intractable and global developmental delay is common. Most patients develop an acquired microcephaly by the end of the first year of age and a number of patients die before that time or later, in the course of the follow-up period⁴⁵⁾.

Myoclonic status in nonprogressive encephalopathies (MSNE) is an early onset epileptic syndrome characterized by dulling of consciousness and responsiveness with or without jerks, which may last for hours, days, or weeks⁴⁷⁾. Interictal EEG consists of multifocal epileptiform discharges and background slowing. Ictal EEG recording may demonstrate generalized slow spike and wave or an absence pattern, depending on the seizure type³⁴⁾. A genetic cause, such as Angelman syndrome or 4p syndrome, is found in approximately half of the children. Other reported structural causes include hypoxic-ischemic injury and cortical dysplasia³⁴⁾. Most children are resistant to different therapies, even to intravenous benzodiazepines, and the status may become a life-threatening event⁴⁷⁾. Seizures often persist into adulthood and the final outcome is very poor with developmental regression and severe mental retardation, especially in patients with repeated episodes of myoclonic status^48,49).

Dravet syndrome is a genetically determined severe epileptic encephalopathy, which begins in the first year of life in an otherwise normal infant. The epilepsy starts with seizures, which may not initially differ from those associated with febrile illnesses. Even mild fever is an important trigger factor, but some cases are provoked by a nonfebrile illness, immunization, or hot environment⁵⁰⁾. It is not easy to differentiate these children from others with febrile convulsions, who will eventually get better and will not develop other types of seizures. During the second year of the life, seizures become more frequent, persistent, and often more lateralized. At that stage, seizures no longer occur only when a child has high temperature, but can happen at any time of the day³⁴⁾. Seizures are complex febrile, afebrile generalized, unilateral clonic, or tonic-clonic. The condition evolves to other types, such as myoclonic, atypical absence, complex partial seizures, and frequent status epilepticus⁵⁰⁾. EEG is usually normal at early stages of this condition. However, by the time a child is 2 years old, epileptic discharges with spike and wave or polyspikes are observed, which occur either as single events or in bursts. Prognosis is very poor, as this syndrome is associated with developmental delay, cognitive dysfunction, and behavioral problems.