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Current thumbnail: Early myoclonic encephalopathy, an epileptic syndrome with onset either in the neonatal period or first months of life, is characterized by erratic, fragmentary, or massive myoclonus, partial seizures, and late tonic spasms. The prognosis is severe. Early myoclonic encephalopathy with the Ohtahara syndrome make the entity of severe neonatal epilepsies with suppression burst pattern. In this update, Federico Vigevano, Head of Neurology Division, Bambino Gesù Children’s Hospital, Rome, Italy, presents the clinical and neurophysiological data, management, and different etiologic factors of early myoclonic encephalopathy. The disorder is believed to have various prenatal etiologies that often remain unknown; inborn errors of metabolism are sometimes found.

Historical Note and Nomenclature
Since 1978, numerous papers have been published that describe an epileptic syndrome with onset either neonatally or in the first months of life and characterized by erratic, fragmentary myoclonus, massive myoclonus, partial seizures, late tonic spasms, and EEG signs such as suppression-burst pattern. Various terms have been used: neonatal myoclonic encephalopathy (Aicardi and Goutieres 1978; Vigevano et al 1981), myoclonic encephalopathy with neonatal onset (Cavazzuti et al 1978), neonatal epileptic encephalopathy (Martin et al 1981), and early myoclonic epileptic encephalopathy (Dalla Bernardina et al 1983). In 1989, the ILAE Commission of Classification and Terminology recognized this syndrome with the term "early myoclonic encephalopathy" and classified it under "symptomatic generalized epilepsies and syndromes with non-specific etiology" (Commission of Classification and Terminology of the International League Against Epilepsy 1989). The same Commission distinguished this syndrome from similar clinical pictures, such as "early infantile epileptic encephalopathy with suppression-burst" or Ohtahara syndrome.

Finally, the ILAE Task Force on Classification and Terminology (Engel and International League Against Epilepsy 2001) proposed to include this entity in the list of “epileptic encephalopathies,” that is, those conditions in which not only epileptic activity, but also “the epileptiform EEG abnormalities themselves are believed to contribute to the progressive disturbance in cerebral function.” In addition to early myoclonic encephalopathy, in this group we also find Ohtahara syndrome, West syndrome, and Lennox-Gastaut syndrome.

Clinical Manifestations
Early myoclonic encephalopathy is characterized clinically by the onset of erratic or fragmentary myoclonus. Other types of seizures, including simple partial seizures, massive myoclonia, and tonic spasms can also occur.
Erratic, partial myoclonus usually appears as the first seizure, even 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 shift typically from one part of the body to another in a random, asynchronous fashion. Frequency varies from occasional to almost continuous. In addition to limited partial myoclonus, generalized myoclonus may also be observed occasionally in some cases.
Partial seizures are frequent and occur shortly after erratic myoclonus. The semiology of partial seizures is subtle, consisting, for instance, of eye deviation or autonomic phenomena such as apnea or flushing of the face (Dalla Bernardina et al 1983). Tonic seizures are reported frequently and can occur in the first month of life or afterwards; they may occur both in sleep and wakefulness (Aicardi and Ohtahara 2002). From a clinical standpoint, the child presents a diffuse tonic contraction, usually extending to the extremities. Real epileptic spasms are rare and generally appear later.
Neurologic abnormalities are constant: very severe delay in psychomotor acquisitions, marked hypotonia, and disturbed alertness, sometimes with vegetative state (Aicardi 1992). Dalla Bernardina and colleagues reported deterioration in the patients (Dalla Bernardina et al 1983); 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.

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. Birth weight was 2.745 kg; Apgar index was 8 to 10. The neonatal period was apparently normal. 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 burst-suppression pattern during sleep and while awake; the bursts lasting 7 to 8 seconds appeared sometimes synchronously and sometimes asynchronously on the 2 hemispheres and consisted in 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 NMR, performed also with spectroscopy, were normal.
Blood samples tested for amino acids, lactate, ammoniemia, and very-long-chain fatty acids were normal.

Urine tested for urinary organic acids and purines was normal. Liquor was also normal, and the glycorrhachia/glycemia ratio was within normal range. Sulfite test performed later 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 suspended 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 substituted by diffuse subcontinuous epileptiform abnormalities, but prevalently in the frontal regions and more evident during sleep.

At age 18 months, repeat NMR evidenced 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 retardation: he occasionally followed with gaze and started to smile, but he could not control his head or trunk and did not make any voluntary movement; muscle tone had increased. He occasionally presented segmentary or massive myoclonic jerks. The EEG evidenced slow, unorganized brain activity and many multifocal and diffuse epileptiform abnormalities; in sleep, diffuse abnormalities sometimes assumed a rhythmic course. Final diagnosis was cryptogenic early myoclonic encephalopathy.

Etiology
No obstetrical complications or other perinatal problems were observed in the reported cases. Consequently, early myoclonic encephalopathy is believed to have various prenatal etiologies that often remain unknown.
Siblings have been affected in a few instances (Dalla Bernardina et al 1983; Aicardi 1992; Wang et al 1998); the parents were believed to be healthy and no consanguinity was recognized. Autosomal recessive inheritance appears likely but has not been proved.

Some conditions, such as inborn error of metabolism, can produce the clinical and EEG picture typical of early myoclonic encephalopathy. To date, cases have been reported with nonketotic hyperglycinemia (Dalla Bernardina et al 1979; Lombroso 1990; Aicardi 1992; Ohtahara et al 1998; Wang et al 1998), D-glyceric acidemia (Grandgeorge et al 1980), propionic acidemia (Vigevano et al 1982; Lombroso 1990), molybdenum cofactor deficiency (Aukett et al 1988), and methylmalonic acidemia (Lombroso 1990). Schlumberger and colleagues found urinary excretion of an abnormal oligosaccharide in 3 of their patients (Schlumberger et al 1992). Wang and colleagues reported a patient with a clinical picture of early myoclonic encephalopathy and an atypical suppression-burst pattern, with full recovery after administration of pyridoxine (Wang et al 1998). Pyridoxine-dependency has to be considered also in patients with early myoclonic encephalopathy and, therefore, in cases with intractable seizures and suppression-burst EEG pattern (Vigevano and Bartuli 2002).
Some malformative disorders can also cause early myoclonic encephalopathy (Martin et al 1981), but more often they produce Ohtahara syndrome.

Pathogenesis and Pathophysiology
The lack of consistent neuropathologic features suggests that 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 (Aicardi 1985). On the other hand, absence of pathologic abnormality was reported in 2 affected cases (Dalla Bernardina et al 1983).

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 (Spreafico et al 1993). 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 (Oka et al 1995). The prevalence of early myoclonic encephalopathy was higher than Ohtahara syndrome (0.04%), but much lower than West syndrome (1.68%). Similar results were obtained more recently in the same region (Oka 2002).

Prevention
No information is available.

Differential Diagnosis
Early myoclonic encephalopathy and Ohtahara syndrome share common clinical and EEG characteristics, such as onset in the first few months of life and suppression-burst pattern on EEG, but there are several features that distinguish these 2 entities (Aicardi and Ohtahara 2002; Ohtahara and Yamatogi 2003).

The presence of erratic myoclonus and the absence of tonic spasms distinguish early myoclonic encephalopathy from Ohtahara syndrome.

In Ohtahara syndrome, the suppression-burst pattern is characterized by longer paroxysmal bursts and shorter periods of suppression. Etiologically, Ohtahara syndrome is mainly due to structural abnormalities; in the early myoclonic encephalopathy case series we found metabolic disorders and a high proportion of cryptogenic cases. The prognosis is more severe in early myoclonic encephalopathy.

The EEG pattern of "burst- suppression" with long suppression periods, without variations between different vigilance stages, distinguishes early myoclonic encephalopathy from other conditions that produce a neonatal "burst-suppression" picture, such as hypoxic-ischemic encephalopathy and neonatal convulsions.

Diagnostic Workup
In early myoclonic encephalopathy, EEG is characterized by a "burst-suppression" 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 with inactive periods of 3 to 10 seconds. The EEG paroxysms may be either synchronous or asynchronous over both hemispheres. There is no normal background activity (Aicardi 1985). The burst-suppression pattern usually evolves into atypical hypsarrhythmia or into multifocal paroxysms after 3 to 5 months of life.

Erratic myoclonus does not generally have an ictal EEG counterpart. Partial seizures have EEG characteristics similar to those of neonatal fits. The CT and MR findings vary and are related to etiology.
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 (Aicardi 1985).

Considering the inborn error of metabolism reported above, the serum levels of amino acids should be determined, especially glycine and glycerol metabolites, and organic acids, as well as the amino acids in the cerebrospinal fluid.

Prognosis and Complications
The prognosis for early myoclonic encephalopathy is poor. The patients reported either died before 1 or 2 years of life, with a mortality rate of 50% or greater, or survived in a persistent vegetative state. Early myoclonic encephalopathy can persist into childhood or evolve into severe partial epilepsy.

Management
There is no effective therapy for early myoclonic encephalopathy. Antiepileptic drugs as well as adrenocorticotropic hormone or corticosteroids cannot alter the poor prognosis.
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. Trying pyridoxine is always justified in cases of early myoclonic encephalopathy.

Pregnancy
Not applicable.

Anesthesia
No information is available.

References Cited
Aicardi J. Early myoclonic encephalopathy. In: Roger J, Dravet C, Bureau M, Dreifuss FE, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence. London: John Libbey Eurotext, 1985.

Aicardi J. Early myoclonic encephalopathy (neonatal myoclonic encephalopathy). In: Roger J, Bureau M, Dravet C, Dreifuss FE, Perret A, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence. 2nd ed. London: John Libbey, 1992:13-23.

Aicardi J, Goutieres F. Encephalopathie myoclonique neonatale. Rev EEG Neurophysiol 1978;8:99-101.

Aicardi J, Ohtahara S. Severe neonatal epilepsies with suppression-burst pattern. In: Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence. 3rd ed. London: John Libbey, 2002:33-44.

Aukett A, Bennett MJ, Hosking GP. Molybdenum cofactor deficiency: an easily missed inborn error of metabolism. Dev Med Child Neurol 1988;30: 531-5.

Cavazzuti GB, Nalin A, Ferrari F, Grandori L, Beghini GE. Encefalopatia epilettica ad insorgenza neonatale. Clin Pediatr 1978;60:239-46.

Commission of Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389-99.

Dalla Bernardina B, Aicardi J, Goutières F, Plouin P. Glycine encephalopathy. Neuropädiatrie 1979;10:209-25.

Dalla Bernardina B, Dulac O, Fejerman N, et al. Early myoclonic epileptic encephalopathy (E.M.E.E.). Eur J Pediatr 1983;140:248-52.

Engel J Jr; International League Against Epilepsy. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia 2001;42:796-803.

Grandgeorge D, Favier A, Bost M, et al. L'acidémie D-glycérique. A propos d'une nouvelle observation anatomo-clinique. Arch Franc Pediatr 1980;37:577-84.

Lombroso C. Early myoclonic encephalopathy, early infantile epileptic encephalopathy and benign and severe infantile myoclonic epilepsies: a critical review and personal contributions. J Clin Neurophysiol 1990;7:380-408.

Martin HJ, Deroubaix-Tela P, Thelliez P. Encéphalopathie épileptique néonatale à bouffées périodiques. Rev EEG Neurophysiol Clin 1981;11:397-403.

Ohtahara S, Ohtsuka Y, Erba G. Early epileptic encephalopathy with suppression-burst. In: Engel J Jr, Pedley T, editors. Epilepsy: A comprehensive textbook. Vol. 3. Philadelphia: Lippincott-Raven, 1998:2257-61.

Ohtahara S, Yamatogi Y. Epileptic encephalopathies in early infancy with suppression-burst. J Clin Neurophysiol 2003;20:398-407.

Oka E. Childhood epilepsy in Okayama Prefecture, Japan: a neuroepidemiological study. No To Hattatsu (Tokyo) 2002;34:95-102.

Oka E, Ishida S, Ohtsuka Y, Ohtahara S. Neuroepidemiological study of childhood epilepsy by application of international classification of epilepsies and epileptic syndromes (ILAE, 1989). Epilepsia 1995;36:658-61.

Schlumberger E, Dulac O, Plouin P. Early infantile syndrome(s) with suppression-burst: nosological considerations: In: Roger J, Bureau M, Dravet C, Dreifuss FE, Perret A, Wolf P, editors. Epileptic syndromes of infancy, childhood and adolescence. 2nd ed. London: John Libbey, 1992:35-42.

Spreafico R, Angelini L, Binelli S, et al. Burst suppression and impairment of neocortical ontogenesis: electroclinical and neuropathologic findings in two infants with early myoclonic encephalopathy. Epilepsia 1993;34(5):800-8.

Vigevano F, Bartuli A. Infantile epileptic syndromes and metabolic etiologies. J Child Neurology 2002;17(3):3S9-13.

Vigevano F, Bosman C, Gisondi A, Maccagnani F, Seganti G, Sergo M. Neonatal myoclonic epileptic encephalopathy without hyperglycinemia. Electroencephal Clin Neurophysiol 1981;52:52P-3P.

Vigevano F, Maccagnani F, Bertini E, et al. Encefalopatia mioclonica precoce associata ad alti livelli di acido propionico nel siero. Boll Lega Ital Epil 1982;39:181-2.

Wang PJ, Lee WT, Hwu C, et al. The controversy regarding diagnostic criteria for early myoclonic encephalopathy. Brain Dev 1998;20:530-5.

ILAE.
ILAE Copyright Notice

Abbreviations
CT:computed tomography
EEG:electroencephalogram
MR: Magnetic Resonance
ILAE:International League Against Epilepsy

ICD Code
345.11:Generalized convulsive epilepsy, with intractable epilepsy
783.4:Lack of expected normal physiological development in childhood

Synonyms
Neonatal myoclonic encephalopathy
Myoclonic encephalopathy with neonatal onset
Neonatal epileptic encephalopathy with periodic EEG bursts
Early myoclonic epileptic encephalopathy

Associated Disorders
Epileptic encephalopathies
Symptomatic generalized epilepsy

~24. Major Keyword Descriptors
apnea
burst-suppression EEG
D-glyceric acid
D-glyceric acidemia
eye deviation
flushing
glycine
hypsarrhythmia
massive myoclonia
methylmalonic acid
molybdenum cofactor
myoclonus
nonketotic hyperglycinemia
peripheral neuropathy
persistent vegetative state
propionic acid
simple partial seizures
spiny neurons
spongiform change
tonic seizures

Minor Keyword Descriptors
encephalopathy
epilepsy
seizures

Age of Presentation
0-01 month
01-23 months

Age of Typical Presentation
0-01 month

Population Group(s) Preferentially Affected
none selectively affected

Occupation Group(s) Preferentially Affected
none selectively affected

Sex
male=female

Family History
none

Heredity
none

Glossary
Early Myoclonic Encephalopathy: A disease that presents in early infancy and is marked by erratic, fragmentary myoclonus, developmental delay, and early death.

Permuted Topic, Synonyms, Variants
Early myoclonic encephalopathy
myoclonic encephalopathy, Early
encephalopathy, Early myoclonic
myoclonic encephalopathy, Neonatal
encephalopathy, Neonatal myoclonic
epileptic encephalopathy with periodic EEG bursts, Neonatal
encephalopathy with periodic EEG bursts, Neonatal epileptic
myoclonic epileptic encephalopathy, Early
epileptic encephalopathy, Early myoclonic
encephalopathy, Early myoclonic epileptic

Related Topics
Benign familial and nonfamilial infantile seizures
Benign neonatal sleep myoclonus
Benign nonepileptic infantile spasms
Epilepsy
Epileptic spasms including infantile spasms
Generalized convulsive status epilepticus
Lennox-Gastaut syndrome
Neonatal seizures
West syndrome

Differential Diagnosis
Ohtahara syndrome
neonatal convulsion
hypoxic ischemic encephalopathy

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