KCNQ2 encephalopathy: Delineation of the electroclinical phenotype and treatment response

Abstract

Neonatal-onset epilepsies are rare conditions, mostly genetically determined, that can have a benign or severe phenotype.^1,2 There is recent recognition of de novo KCNQ2 mutations in patients with severe neonatal-onset epilepsy with intractable seizures and severe psychomotor impairment, termed KCNQ2 encephalopathy.^3,4 This is a rare condition and all patients reported so far were diagnosed well after the neonatal period.^3,4 We report on 3 new cases of KCNQ2 encephalopathy diagnosed in the neonatal period and studied with continuous video-EEG recording. We describe a distinct electroclinical phenotype and report on efficacy of antiepileptic drug (AED) therapies.

Neonatal-onset epilepsies are rare conditions, mostly genetically determined, that can have a benign or severe phenotype.^1,2 There is recent recognition of de novo KCNQ2 mutations in patients with severe neonatal-onset epilepsy with intractable seizures and severe psychomotor impairment, termed KCNQ2 encephalopathy.^3,4 This is a rare condition and all patients reported so far were diagnosed well after the neonatal period.^3,4 We report on 3 new cases of KCNQ2 encephalopathy diagnosed in the neonatal period and studied with continuous video-EEG recording. We describe a distinct electroclinical phenotype and report on efficacy of antiepileptic drug (AED) therapies.

Classification of evidence.

This study provides Class IV evidence that oxcarbazepine/carbamazepine is effective in reducing seizures in newborns with neonatal epileptic encephalopathy associated with heterozygous de novo missense mutations in the KCNQ2 gene.

Methods.

We reviewed the clinical details and video-EEG monitoring of patients with neonatal epileptic encephalopathy who, on genetic testing, demonstrated disease-causing mutations in KCNQ2. Details of genetic testing are found in appendix e-1 on the Neurology® Web site at www.neurology.org.

Standard protocol approvals, registrations, and patient consents.

Parents gave informed consent to this study, which was approved by the local human research committee.

Results.

We identified 3 newborns with neonatal epileptic encephalopathy associated with novel heterozygous de novo missense mutations in the KCNQ2 gene (appendix e-1). Family histories were all negative for epilepsy or mental retardation. We describe in detail the clinical characteristics; genetic, EEG, and MRI findings; and trialed AEDs (table).

Table.

Genetic, clinical, and EEG characterization in KCNQ2 encephalopathy in the neonatal period

In all infants, neurologic examination was abnormal from the very first days of life, even prior to seizure onset, and demonstrated lack of visual fixation, decreased spontaneous movements, and axial hypotonia. Seizures began in the first week of life in all cases. Semiology was characterized by tonic head, conjugate eye, and mouth deviation, associated with unilateral tonic abduction of the limbs, apnea, and desaturation requiring oxygen administration (videos 1 and 2, video legend). Ictal and interictal EEGs are shown in figures e-1 and e-2.

After several treatments had failed, oxcarbazepine/carbamazepine was initiated at 3 months, 13 months, and 4 months of life in cases 1, 2, and 3, respectively. Patients 1 and 2 experienced a dramatic reduction of seizure frequency, with seizure freedom within 2 weeks of treatment. Patient 3 was treated with carbamazepine for 10 days with no clear improvement and died shortly after of respiratory failure in the setting of infection. Patients 1 and 2 remained seizure-free on follow-up at 12 and 30 months of age, respectively. However, both infants showed severe psychomotor delay, quadriplegia, axial hypotonia with appendicular hypertonia, and a tendency to opisthotonic posturing.

Discussion.

Prolonged video-EEG monitoring is a useful tool in the diagnosis of neonatal-onset epileptic encephalopathies, allowing for accurate recognition of electroclinical syndromes. A precise diagnosis often has implications for management and prognosis. We observed a similar electroclinical pattern in 3 newborns with KCNQ2 encephalopathy characterized by focal tonic seizures affecting alternatively both sides of the body and ictal discharges involving the left or right hemisphere, with a severely abnormal background characterized by multifocal epileptiform abnormalities and random attenuations. A similar seizure type is reported in benign familial neonatal seizures (BFNS), which also can be associated with KCNQ2 mutations. However, in comparison to BFNS, these infants were severely neurologically impaired from birth with axial hypotonia and lack of visual tracking, and their EEG was severely abnormal from onset.⁵ Differently from Ohtahara syndrome and early myoclonic encephalopathy, we did not observe myoclonic jerks or tonic spasms at presentation or during several months of follow-up. Moreover, while EEG demonstrated transient periods of discontinuity after phenobarbital loading, it lacked the invariable and regular periodicity of the suppression-burst pattern of Ohtahara syndrome.⁶ MRI abnormalities similar to those observed in our cases have been reported in KCNQ2 encephalopathy, but also in subjects with STXBP1 mutations and during treatment with vigabatrin.¹

The electroclinical findings in this report help to recognize a distinct neonatal phenotype and may guide the diagnostic workup, which should include KCNQ2 testing.

We found a dramatic response with seizure freedom to carbamazepine. This was unlikely attributable to evolution of the syndrome, as just 1 of 8 infants with KCNQ2 encephalopathy had seizure freedom by 3 months of age.⁴ Carbamazepine stabilizes the inactive state of voltage-gated sodium channels, while KCNQ2 mutations decrease the inhibitory potassium current on membranes.² Seemingly disparate, voltage-gated sodium channels and KCNQ potassium channels colocalize and are bound at critical locations of the neuronal membrane⁷; modulation of one channel may significantly affect the function of the channel complex. Accordingly, retigabine, which increases potassium current through the KCNQ channels, may also be of benefit in KCNQ2 encephalopathy. Therefore, these patients could benefit from a trial of carbamazepine, followed by consideration of retigabine. Studies investigating the efficacy of these agents in KCNQ2 encephalopathy and whether their early use is potentially of benefit in improving neurodevelopmental outcomes are warranted.