Electroclinical phenotypes in genetic epilepsy Focus on EEG aspects

Abstract

This thesis explores the role of EEG as a biomarker for diagnosis, treatment response and prognosis in four specific genetic epilepsies. The subject is important, as the feasibility of precision therapy targeting pathophysiological mechanisms is increasing in this group of disorders. Juvenile myoclonic epilepsy is the most common form of idiopathic generalized epilepsy. The cause is usually polygenic. The main EEG feature is generalized spike-wave and polyspike-wave complexes. Appropriate medication is usually effective, but the vulnerability to seizure provoking factors may represent an obstacle. We assessed nearly 400 EEG recordings in 40 patients with follow-up over 30 years. Prolonged ≥3 s epileptiform runs were associated with uncontrolled seizures. This pattern may represent an EEG biomarker for poor prognosis. Juvenile neuronal ceroid lipofuscinosis (CLN3 disease) is a rare autosomal recessive and progressive neurodegenerative disorder. Pathogenic variants in the CLN3 gene lead to intracellular accumulation of lipopigments in lysosomes. Progressive visual and cognitive decline are the presenting symptoms, followed by seizures usually at age 10-11 years. Options for precision treatment are in the pipeline. Twenty-four patients were included via the Norwegian JNCL parent association. We studied the evolution of EEG and clinical features. The seizure disorder is complex and can be classified as a combined focal and generalized epilepsy. In the late stage, heart block and dysautonomic events may be misinterpreted as seizures. ADCK3-related mitochondrial disease is also an autosomal recessive disorder. Epilepsy and spinocerebellar ataxia may mimic the more common POLG-related disease. Variants in the ADCK3 gene cause abnormal Q10 metabolism and treatment with Q10 can be useful. In three of four identified patients, we demonstrated unusual and almost continuous spikes and spike-waves over posterior regions. We believe that this peculiar EEG pattern might represent a biomarker for this very rare type of mitochondrial disease. Pyridoxine dependent epilepsy is an uncommon recessive genetic-metabolic epilepsy caused by a disturbed degradation of the amino acid lysine. The availability of pyridoxine is blocked. The most common cause is a variant in the ALDH7A1 gene. The classic form presents with neonatal seizures. Respiratory distress and asphyxia are common. Antiseizure medications are ineffective, but pyridoxine provides seizure control, and a lysine restriction diet can be beneficial. We identified 13 Norwegian patients, of whom five were adults, and explored the diagnostic role of EEG. An early EEG “burst suppression” is common, but not specific. Eleven patients had EEG recordings during i.v. pyridoxine administration. Clinical effect and EEG changes were often delayed, and transient worsening was seen in some. All achieved seizure control after a few days with pyridoxine treatment. We concluded that EEG during pyridoxine injection contributes little to the diagnostic assessment. The patients presented varying degrees of cognitive disability, but one adult had normal development. EEG follow-up in adulthood showed only slight abnormalities without progression. Conclusion: Further systematic and long-term EEG studies in the rapidly growing number of epileptic disorders with genetic etiology are warranted in the search for electroclinical characteristics, which may promote identification and decisions on optimal tailored treatment.