Early myoclonic encephalopathy

Early myoclonic encephalopathy (EME) is a developmental and epileptic encephalopathy (DEE) with onset in the neonatal period or during the first three months of life.[2] It is marked by the presence of myoclonic seizures but multiple seizure types may occur.[2] The electroencephalographic recording is abnormal with a suppression-burst pattern or other significantly abnormal patterns.[2] On most occasions the seizures are drug-resistant. After several months, the seizure pattern may develop into infantile spasms syndrome (West syndrome). The neurological exam is abnormal and there is a significant risk of early death.[2] Various genetic and metabolic disorders are responsible.[3] At present, EME and Ohtahara syndrome are recorded as distinct patterns in the categorization of epilepsies but both neonatal-onset epilepsy syndromes are considered to be merged in one unique entity.[4] It is a severe type of epilepsy syndrome associated with high level of resistance to treatment and a high risk for cognitive impairment.[5]

Early myoclonic encephalopathy[1]
SpecialtyNeurology

The myoclonic seizures could be seen in other epilepsy syndromes. Multiple types of childhood epilepsies are usually mentioned as myoclonic epilepsies when the myoclonic seizures are a predominant feature.

Signs and symptoms

It is characterized by neonatal-onset myolconic seizures with also other seizure types such as symmetric or asymmetric tonic spasms which may occur singly or in clusters. The symptoms may start appearing as early as a few hours after birth and up to three months of age.[6] Around three-fourths of affected children present with neonatal seizure.[7] The distinctive feature of the phenotypes is severe progressive encephalopathy which develops a few hours to a few days after birth. It is also associated with clonic seizures, jerks, hiccups and vomiting. Sometimes neonates with apnea require ventilator support.[7] Abnormal neurological behavior could be observed before the seizure onst in some patients. Head circumference is usually normal at onset but microcephaly may develop over time.

Causes

There are varied etiologies related with Ohtahara syndrome. Most of the cases are associated with structural brain abnormality, though there are also cases related to genetic abnormalities (mutations).[8] EME has variable pathogenesis and structural metabolism.[8] Another common reason rather than structural brain abnormality is inborn metabolic defects.[5]

Genetics

A growing number of genetic aetiologies have been linked to the phenotype of EME and Otahara syndrome and diagnosis by genetic testing can nowadays be achieved in around 50 percent of cases.[9] Some examples of well described genetic aetiologies include: KCNQ2- DEE,[9] SCN2A-DEE,[10] STXBP1-DEE,[11] CDKL5-DEE,[12] KCNT1-DEE[13] and UBA5-DEE.[14]

Acquired

No acquired etiology is known for EME although etiology remains unknown for a small percentage of patients after genetic, metabolic, and imaging workups.[15]

Mechanism

Pathology results in EME consist of multifocal changes in white matter, imperfect lamination of the deep cortical layers, astrocytic proliferation, and demyelination.[8]

Diagnosis

EEG

Electroencephalogram (EEG) is characterised by burst suppression pattern.[16] Subsequently it may transition to hypsarhythmia, a chaotic pattern on EEG.[8][5]

MRI

Neuroimaging is useful in assessing the underlying structural causality of these syndromes.[8] These changes might cause EME. Later follow-up MRI can show atrophy of the brain in comparison to the initial MRI.

Prevention

Early identification of metabolism error is very essential in prevention as the traditional antiepileptic drug are usually not very effective, proper treatment aiming to the conditions can prevent neurological worsening.[7] Genetic counselling is critical but early genetic testing also helps to control in unnecessary procedure and unsuccessful treatment.[7]

Management

Antiepileptic drugs are used to treat EME, but it is difficult to control seizures with anti-epileptic drugs alone.[5] Phenobarbital, valproate, pyridoxine, zonisamide, and benzodiazepines have all established inadequate usefulness in seizure control.[8] Some patients show favorable response to sodium channel agents, often at high dose.[17] There are various means to add on the treatment. A ketogenic diet can be useful in controlling seizures.[8] Surgery is also a treatment option.[8] In epilepsy surgery (focal resection or hemispherectomy) the part of the brain which creates the abnormal electrical current through the brain must be resected, but the surgery is very complicated and needs to be performed by expert surgeons in epilepsy reference centers.[8] None of these treatments, with the exception of some metabolic disorders with specific treatments available, have shown any efficacy at avoid long-term consequences of the disease.[8]

Prognosis

The prognosis is usually poor. Mortality rate is high during early infancy and almost half of the children die by 2 years of age.[18][8] Most of the survivors suffer from psychomotor impairment.[8] In the patient with severe phenotype, even when optimal treatment is initiated promptly the prognosis remains poor.[7]

Epidemiology

The prevalence ranges from <1 / 1 000 000 live births.[19]

References
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  2. Richardson S, Alarcon G, Nashef L, Cross H, Nightingale J. Epilepsy (Oxford Specialist Handbooks in Neurology). Oxford University Press;2009. p.82. ISBN 0-19-857073-2
  3. Djukic A, Vigevano F, Plouin P, Moshé S. Early Myoclonic Encephalopathy. In: Dichter MA, Engel J, Pedley TA, Aicardi J, editors. Epilepsy: a comprehensive textbook. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2008. ch. 224. ISBN 0-7817-5777-0
  4. "Proposed classification: Syndromes in Neonates and Infants // International League Against Epilepsy". www.ilae.org. Retrieved 2022-01-29.
  5. Hwang, Su-Kyeong; Kwon, Soonhak (2015). "Early-onset epileptic encephalopathies and the diagnostic approach to underlying causes". Korean Journal of Pediatrics. 58 (11): 407–414. doi:10.3345/kjp.2015.58.11.407. PMC 4675920. PMID 26692875.
  6. Beal, Jules C.; Cherian, Koshi; Moshe, Solomon L. (2012-11-01). "Early-Onset Epileptic Encephalopathies: Ohtahara Syndrome and Early Myoclonic Encephalopathy". Pediatric Neurology. 47 (5): 317–323. doi:10.1016/j.pediatrneurol.2012.06.002. ISSN 0887-8994. PMID 23044011.
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  9. Pisano, T; Numis, AL; Heavin, SB; Weckhuysen, S; Angriman, M; Suls, A; Podesta, B; Thibert, RL; Shapiro, KA; Guerrini, R; Scheffer, IE; Marini, C; Cilio, MR (May 2015). "Early and effective treatment of KCNQ2 encephalopathy". Epilepsia. 56 (5): 685–91. doi:10.1111/epi.12984. PMID 25880994. S2CID 44459702.
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  12. Bahi-Buisson, N; Nectoux, J; Rosas-Vargas, H; Milh, M; Boddaert, N; Girard, B; Cances, C; Ville, D; Afenjar, A; Rio, M; Héron, D; N'guyen Morel, MA; Arzimanoglou, A; Philippe, C; Jonveaux, P; Chelly, J; Bienvenu, T (October 2008). "Key clinical features to identify girls with CDKL5 mutations". Brain : A Journal of Neurology. 131 (Pt 10): 2647–61. doi:10.1093/brain/awn197. PMID 18790821.
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  14. Chitre, M; Nahorski, MS; Stouffer, K; Dunning-Davies, B; Houston, H; Wakeling, EL; Brady, AF; Zuberi, SM; Suri, M; Parker, APJ; Woods, CG (December 2018). "PEHO syndrome: the endpoint of different genetic epilepsies". Journal of Medical Genetics. 55 (12): 803–813. doi:10.1136/jmedgenet-2018-105288. PMID 30287594. S2CID 52920593.
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  19. RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Early myoclonic encephalopathy". www.orpha.net.
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