Early myoclonic encephalopathy

Early myoclonic encephalopathy[1]
SpecialtyNeurology

Early myoclonic encephalopathy (EME) is a neonatal-onset epilepsy syndrome with multiple seizure types including myoclonic seizure. The electroencephalographic recording is abnormal with a suppression-burst pattern. 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 with 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]

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 symetric or asymetric tonic spasms which may occur singly or in clusters. The symptoms may start appearing as early as two weeks 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

There are a number of reports related to genetic mutation and Ohtahara syndrome. Mutation in the syn taxin binding protein 1 (STXBP1) gene is associated with Ohtahara syndrome. It is linked with the synaptic vesicle and neuronal progenitor cell differentiation and migration, and it also releases g-aminobutyric acid and glutamate. These mutations lead to the brainstem abnormality.[8] The other genetic mutation associated with this is on the Aristaless related homeobox (ARX) gene. It is connected with regulating neuronal differentiation and proliferation, as well as the migration of neuron progenitors to the developing cortex. Mutation of this gene is correlated with the structural abnormalities (hypoplastic corpus callosum, small basal ganglia and hippocampi).[8] There were two reports explained about the mutation in solute carrier family 25 (SLC25A22) gene. They both were born to parents in consanguineous marriage. It is associated with mitochondrial glutamate transport that directed to the energy depletion during development or to function abnormality and cell death.[8] It can also be inherited and it is autosomal recessive. In epilepsy genetics, the emphasis has been solely on genes encoding membrane ion channel proteins. However, a cumulative number of mutations in genes encoding proteins other than ion channels are now being recognized.[5]

Acquired

Sometimes a metabolic disorder that affects how the brain works may lead to EME. While most of these metabolic disorders cannot be reversed, sometimes treating the underlying disorder can help. Vitamin-responsive epileptic encephalopathies are rare but significant reasons. Vitamin B12 deficiency may also lead to seizures as well as different neurological symptoms, developmental delay and hypotonia.[5]

Mechanism

The pathogenesis of the Ohtahara syndrome and EME are distinct from each other. In EME there is a diffuse process involving the brainstem and white matter, perhaps directed to differentiation hyperexcitability of the cortex.[8] 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.[9] 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]The families who are at risk, prophylactic treatment is suggested as it may stop the seizure and help in recovering the neurodevelopmental consequences.[7][10]

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] 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. In epilepsy surgery (focal resection or hemispherectomy) the part of the brain must be removed which creates the abnormal electrical current through the brain, but the surgery is very complicated and needs to be performed by expert surgeons.[8] All these treatments can slow the neonatal progression, but they do not help patients avoid long-term consequences of the disease.[8][11]

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[12].[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] In patients with reduced phenotype, if there is early treatment initiated the better developmental outcome can be observed.[7]

Epidemiology

The prevalence ranges from 2.2 to 4.5/10,000 live births. Prevalence estimates among older children have ranged from 1.4 to 2.2/10,000.[13]

References

  1. ↑ Berg, AT; Berkovic, SF; Brodie, MJ; Buchhalter, J; Cross, JH; et al. (Apr 2010). "Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009". Epilepsia. 51 (4): 676–85. doi:10.1111/j.1528-1167.2010.02522.x. PMID 20196795.
  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. 1 2 3 4 5 6 Hwang, Su-Kyeong; Kwon, Soonhak (2015). "Early-onset epileptic encephalopathies and the diagnostic approach to underlying causes". Korean Journal of Pediatrics. 58 (11): 407. 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.
  7. 1 2 3 4 5 6 7 Cornet, MC; Cilio, MR (2019). "Genetics of neonatal-onset epilepsies". Handbook of clinical neurology. 162: 415–433. doi:10.1016/B978-0-444-64029-1.00020-5. PMID 31324323.
  8. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Beal, Jules C.; Cherian, Koshi; Moshe, Solomon L. (November 2012). "Early-Onset Epileptic Encephalopathies: Ohtahara Syndrome and Early Myoclonic Encephalopathy". Pediatric Neurology. 47 (5): 317–323. doi:10.1016/j.pediatrneurol.2012.06.002. PMID 23044011.
  9. ↑ Fusco, Lucia; Pachatz, Christa; Di Capua, Matteo; Vigevano, Federico (2001-11-01). "Video/EEG aspects of early-infantile epileptic encephalopathy with suppression-bursts (Ohtahara syndrome)". Brain and Development. West Syndrome and Other Infantile Epileptic Encephalopathies. 23 (7): 708–714. doi:10.1016/S0387-7604(01)00280-7. ISSN 0387-7604.
  10. ↑ "Early Myoclonic Encephalopathy (EME)". Epilepsy Foundation. Retrieved 2021-12-10.
  11. ↑ "Early Myoclonic Encephalopathy (EME)". Epilepsy Foundation. Retrieved 2021-12-10.
  12. ↑ Yamatogi, Yasuko; Ohtahara, Shunsuke (2002-01-01). "Early-infantile epileptic encephalopathy with suppression-bursts, Ohtahara syndrome; its overview referring to our 16 cases". Brain and Development. 24 (1): 13–23. doi:10.1016/S0387-7604(01)00392-8. ISSN 0387-7604.
  13. ↑ Trevathan, Edwin; Murphy, Catherine C.; Yeargin-Allsopp, Marshalyn (June 1999). "The Descriptive Epidemiology of Infantile Spasms Among Atlanta Children". Epilepsia. 40 (6): 748–751. doi:10.1111/j.1528-1157.1999.tb00773.x. PMID 0368073.
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