Epilepsy: A Comprehensive Textbook
2nd Edition

In 1978, Aicardi and Goutieres described a group of five patients with “neonatal myoclonic encephalopathy” commencing in the hours immediately after birth and consisting of erratic, asynchronous, nonperiodic myoclonus associated with generalized jerks and a distinctive electroencephalogram (EEG).³ Since then, the syndrome has been referred to as early myoclonic encephalopathy and also as myoclonic encephalopathy with neonatal onset,⁸ neonatal epileptic encephalopathy with periodic EEG bursts, and early myoclonic epileptic encephalopathy⁹ and neonatal myoclonic encephalopathy.^3,39

In 1989, the ILAE Commission of Classification and Terminology recognized the syndrome as “early myoclonic encephal- opathy (EME)” and classified it as generalized symptomatic epilepsies of nonspecific etiology.¹⁶ In 2001 the entity was finally recognized as one of the “epileptic encephalopathies” together with early infantile epileptic encephalopathy with suppression-bursts (EIEE, Ohtahara syndrome), West syndrome, and Lennox-Gastaut syndrome. Since 1978, there have been published reports on 50 patients with the characteristic clinical picture—onset of symptoms during the first month of life consisting of erratic, fragmentary myoclonus, massive myoclonus, partial seizures, suppression-burst EEG pattern, and, later, tonic spasms; the prognosis is grave.⁴ Some controversial issues on differential diagnosis from EIEE and physiopathology remain; there are several cases of early encephalopathy with seizures and a suppression-burst pattern that do not fulfill the criteria for either EIEE or EME.^4,10,18,33

The syndrome is rare. An epidemiologic study of childhood epilepsy in Japan detected 4 cases of EME (0.168%) among 2,378 children with epilepsy >10 years of age.^6,28 In a study of 75 infants with epilepsy of neonatal onset, Watanabe et al.⁴² observed 2 cases (2.7%) of EME. A gender difference, with female-to-male ratio of 1:1.3, is seen in the 30 cases published in the English literature.¹⁰

In most cases, the etiology of EME is unknown. Although EME is assumed to be associated with inborn errors of metabolism, even the most frequently reported diagnosis—nonketotic hyperglycinemia—is rarely documented.^{2,5,9,13,27,33,38,39} Other identified inborn errors of metabolism are D-glyceric acidemia, propionic acidemia, molybdenum cofactor deficiency, methylmalonic acidemia, mitochondrial dysfunction, and abnormal urinary oligosaccharides.

Structural brain malformations (cerebellar hypoplasia, migrational disorder with cortical dysgenesis) have also been reported.^11,23

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.⁴⁰ The syndromes of retinal pigmentary degeneration and nephronophthisis, congenital nephrotic syndrome, and Zellweger disease have all also presented with EME.^{2,5,9,13,15,19,21,23,27,33,39,40}

Familial occurrence has been reported,^2,9,33,40 reflecting the genetic nature of the underlying diseases. Because the gene locations for these metabolic errors vary widely, however, it is more likely that EME does not develop due to a specific genetic abnormality but rather due to extensive cortico-subcortical dysfunction as a consequence of a severe metabolic disorder.²⁷

Psychomotor development becomes arrested. The prognosis is grave. In 91% of the patients described in sufficient detail, the outcome is poor: Death occurs during the first years of life in at least 50%; those surviving have severe psychomotor retardation or remain in a persistent vegetative state.^2,10 In rare cases, signs of peripheral neuropathy were reported.² Normal developmental outcome has been limited to one case with pyridoxine dependency.⁴⁰ The progressive nature and the high fatality of EME cases can be attributed to the progressive nature and systemic influences of conditions with inborn errors of metabolism that remain undetected or untreated in addition to an electroencephalographic abnormality.

Seizure control is poor. The erratic myoclonus usually disappears after a few weeks or months,⁴ and partial seizures become intractable. Tonic seizures develop at age 3 to 4 months. Once tonic seizures occur, the overall poor prognosis becomes even graver. In review of 30 patients from the literature, Djukic et al.¹⁰ found that of 22 patients with EME and tonic seizures, 11 died, whereas none of the patients without tonic seizures did. The burst-suppression EEG pattern evolves into hypsarrhythmia in one third of patients. Focal or multifocal abnormalities develop in the remaining patients.

Neither the occurrence of the constellation of symptoms and findings in EME nor the pathophysiologic basis of the changing clinical picture that follows the progression of the disease have been well explained.

Ohtahara et al.²⁵ approached the problem from the standpoint of the characteristic EEG findings. They drew an analogy to the pathophysiologic basis of the other, more common conditions with suppression-burst EEG (deep anesthesia, normal premature infants <30–32 weeks of gestation, severe hypoxic ischemic encephalopathy). They pointed to a theory of abnormal “neuronal connectivity, suggesting that a disconnection in brain circuits may be involved in the genesis of EEG” and emphasized the “indispensable role of brain lesions both at the subcortical and cortical level.”²⁷

An alternative hypothesis is more symptom oriented, based on evidence from experimental studies and analysis of the clinical stages in the evolution of EME; it proposes that EME and EIEE may represent a continuum based on the burden of disease at the onset of symptoms.¹⁰ Rodin’s animal studies^31,32 clearly showed the brainstem structures associated with the onset of generalized seizures, such as tonic seizures, with the earliest sustained discharges appearing in the pons. During clonic seizures, the cortical discharges lead. Thus, there it has been suggested that clonic seizures originate in the forebrain, whereas tonic seizures originate in the brainstem.³⁶ This conclusion is supported by studies using precollicular transections: Tonic seizures also occurred when seizures were induced in animals with transections, whereas clonic seizures required forebrain connections.^1,7,12 Other studies show that repeated generalized seizures in experimental animals can kindle secondary seizure foci.⁴³ These secondary epileptic foci may persist even after the bilateral or generalized seizures abated, because descending inhibition from the hemispheres increases with maturation.²²

Thus, it is tempting to speculate that in EME, there is initially involvement of cortical structures. The repeated myoclonic seizures may “kindle” the development of focal seizures, and with time there may be a spread to the brainstem (in some cases). Tonic seizures develop once the brainstem lesion burden exceeds the threshold for seizures. Patients with EIEE may have already exceeded this threshold at birth and present with tonic seizures early. In EME, brainstem involvement may be less severe, 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 are consistent with this view. Autopsies were performed in five patients with EME.^{11,14,15,17,20,24,30,34,35} All patients had tonic seizures, and clinical signs of brainstem anomalies were present in all of them.

Genetic mapping of an autosomal-recessive form of EME to chromosome 11p15.5 led to the identification of a missense mutation (p.Pro206Leu) in the gene encoding GCI, a protein in the mitochondrial inner membrane that cotransports glutamate with H⁺.²¹ Expression of this protein has an age-specific distribution: At 20 weeks of gestation, the highest gene expression is identified in the cortex, brainstem, and cerebellum. A moderate to high level of expression is observed within the brainstem in the red nuclei, the substantia nigra, and the olivary complexes and the dentate nucleus in the cerebellum. It is interesting that many of these structures, especially the substantia nigra pars reticulata and its output circuits, play a prominent role in the control of seizures as a function of age and gender.³⁷ The observation that EME results from a defect in GC1 suggests a role for either glutamate metabolism, mitochondrial pathology, or both in EME.

Early myoclonic encephalopathy and Ohtahara syndrome share many common clinical and EEG characteristics such as onset in the first few months of life, suppression-burst pattern on EEG, and grave prognosis. The boundary between the two syndromes unfortunately is not always clear,^18,33,40 and the classification is sometimes questionable even among the published cases.⁴ Once tonic seizures occur in patients with EME, the differential diagnosis becomes even more difficult, perhaps implying common pathogenetic mechanisms as discussed earlier. Perhaps the term neonatal epileptic encephalopathy is more appropriate to encompass both conditions.

The critical difference between EME and EIEE appears to be in the presumed etiologies and the prevailing seizure type at the onset of the clinical seizures. EIEE typically manifests with tonic seizures at onset, whereas EME is most associated with myoclonic seizures. However, erratic myoclonus may be absent even in the most frequently identified cause of EME: glycine encephalopathy (J. Aicardi, personal communication). In its classification, the International League Against Epilepsy emphasizes the symptomatic nature and nonspecific etiology of both syndromes.¹⁶ The majority of cases of EIEE are associated with structural brain anomalies, whereas the majority of EME cases are associated with metabolic disorders.^{4,9,19,26,38,40} There is an overlap, however, and often the underlying etiology
remains unclear.⁴² The observation that under some circumstances multiple etiologies can produce either syndrome suggests that EIEE and EME may represent a continuum.

The initial differentiation of EIEE and EME based on the presence or absence of myoclonic or tonic seizures at onset may better indicate the stage of the progression of the brainstem pathology/dysfunction than a phenotype specific to one syndrome or another. A major differentiating point is the absence of myoclonias in EIEE. A common unifying feature is the eventual appearance of tonic seizures. As the brainstem disease burden approaches the threshold for tonic seizures, EME patients become less distinguishable clinically from patients with EIEE.

The EEG pattern and persistence of “burst-suppression” distinguishes EME and EIEE from other conditions that produce neonatal burst-suppression, such as hypoxic–ischemic encephalopathy and neonatal convulsions.

With the exception of cases with pyridoxine dependency, there is no effective management for EME. Neither the conventional antiepileptic medications nor adrenocorticotropic hormone or corticosteroids alter the progressive nature of the disease and improve the poor outcome. Treatments directed at correcting the underlying metabolic deficit may improve the outcome. A trial of treatment with pyridoxine is justified in all cases with EME because it is still the only efficient treatment for the small subgroup of patients in whom it is effective.

EME is a malignant epileptic syndrome with typical onset during the neonatal period. The main seizure type at onset is erratic myoclonus, but as the disease progresses, other seizure types develop, including tonic seizures at 3 to 4 months of age. The EEG is characterized by a suppression-burst pattern and often evolves into hypsarrhythmia. The etiology of EME is diverse: Congenital errors of metabolism are the most frequently identified, followed by cryptogenic and cases with structural brain malformations. Except in rare cases responsive to treatment with pyridoxine, control of seizures is poor. Prognosis is grave, with high early mortality and severe neurologic handicap in survivors.

It is possible that EME presents a continuum with EIEE and the phenotypic differences reflect the severity of the underlying pathologic process. In the future, a systematic approach including comprehensive evaluations (morphometric and functional imaging studies, neurophysiologic evaluations with multimodal evoked potentials, and possibly CSF neurotransmitter studies) performed during different stages of the diseases and especially during periods of clinical transitions could help to provide a better understanding of the underlying pathophysiologic processes. Shifting the goal of the diagnostic evaluation from detecting a specific abnormality to detecting a progressive pathologic change might permit the identification of more subtle changes before they become significant and allow the introduction of new treatments.