Background

KCNT1 is a gene localized at chromosome 9q34.3 in humans, which encodes a sodium-gated potassium channel. It is expressed diffusely in the brain, mainly in the cerebellum, frontal cortex and hippocampus, playing an important role in the regulation of neuronal excitability [1]. KCNT1 mutations, first described in 2012, have been found in epilepsy patients with different ages of onset and cognitive outcomes [2]. KCNT1 mutations are reported to cause developmental and epileptic encephalopathies (DEE), severe autosomal dominant sleep-related hypermotor epilepsy (ADSHE), focal temporal lobe epilepsy with intellectual disability and myoclonic-atonic epilepsy [1, 3,4,5]. Among the KCNT1-related DEE cases, half of them have malignant migrating focal seizures of infancy (MMFSI).

The KCNT1-related epilepsy seizures tend to be refractory to multiple anti-seizure medicines (ASMs) and ketogenic diet (KD), which show clinical efficacy in other epileptic encephalopathies [6,7,8]. Quinidine is expected to be an effective treatment for KCNT1-related epileptic encephalopathy by blocking the KCNT1 channel [9, 10]. However, recent studies have shown that quinidine treatment has no significant effectiveness [11]. Vagus nerve stimulation (VNS) is a nonpharmacologic therapeutic option for refractory epilepsy. VNS can improve cognition and reduce seizure frequency in patients with refractory epilepsy caused by genetic mutations, but its therapeutic mechanism remains to be determined [12].

Here, we describe a boy with refractory epilepsy caused by a KCNT1 mutation, who showed reduction in seizure frequency, as well as improvement of background changes in electroencephalography (EEG) and general condition after VNS.

Case presentation

This 9-year-old boy presented with drug-resistant focal onset seizures since age 3 and had multiple types of seizure semiology. Video EEG (VEEG) monitoring recorded 13 seizures, all of which occurred during stage 2 of sleep, including 1 hypermotor seizure, 9 automatism seizures and 3 bilateral asymmetric tonic seizures. The hypermotor seizures were manifested as trunck agitation and reptation movements, lasting less than 1 min. The ictal EEG showed onset from the bifrontal regions. The second seizure type was automatism seizures. The boy opened his eyes during sleep, with bilateral hand and mouth automatisms. The ictal EEG started with high-amplitude delta waves, followed by a fast rhythmic sharp activity on the left (in 8/9 attacks) and the right temporal lobes (1/9). The last seizure type was bilateral asymmetric tonic seizures characterised by head turning (1/3) and extension of the four extremities. This type of seizure had a frequency of about 3–4 times per night and was the main seizure semiology described by the parents. No aura was reported.

Interictal VEEG showed evidence of multifocal epileptic discharges including spike, multiple-spike and short-term fast rhythm bursts. Ictal VEEG suggested a multifocal onset. The patient was refractory to ASMs, including sodium valproate, levetiracetam and lacosamide, and allergic to oxcarbazepine.

The patient had no remarkable history of febrile convulsion, head injury or encephalitis. He suffered a severe degree of cognitive disorder and was nonverbal after the onset of epilepsy. He could only understand a few single words. The patient had no physical abnormalities during routine infant and childhood health examinations. Results of auxiliary examinations were also normal.

Genetic tests were conducted with consent from the patient and his family. The genetic testing revealed a novel mutation in the KCNT1 gene (chr9:138651532; c.862G > A; p.Gly288Ser) in this patient, while his parents were negative for mutation. This mutation was predicted to be pathogenic.

Magnetic resonance imaging (MRI) showed mild diffuse cerebral atrophy and focal cortical dysplasias (FCDs) in the right temporal lobe, and fluorodeoxyglucose positron emission tomography (PET) scan showed diffuse hypometabolism (Fig. 1).

Fig. 1
figure 1

Brain imaging: MRI scan revealed mild diffuse cerebral atrophy and focal cortical dysplasias in the right temporal lobe on T1-weighted (a) and FLAIR (b) images. PET-MRI showed hypometabolism in the right temporal-parietal area (c) and the bilateral frontal lobes (d)

Full size image

VNS was applied at age 7. The VNS settings were increased slowly, to reach a stimulation current output of 1.6 mA, a frequency of 30 Hz, a pulse width of 250 μs, a signal-on time of 30 s and a signal-off time of 5 min after 3 months. After 3 months of VNS using these parameters, the patient’s seizure frequency was markedly reduced from numerous seizures per day to several a week (Fig. 2). An improvement in background EEG was confirmed (Fig. 3). His parents reported an improvement in mood; however, there was no improvement in language function.

Fig. 2
figure 2

Monthly seizure activities.  After VNS, the patient’s seizure frequency was reduced by 50% at the last follow up

Full size image
Fig. 3
figure 3

Electroencephalographic monitoring. a At 7 years, immediately before VNS implantation, EEG showed central-occipital dominant background slowing. b At 8 years, ~ 1 year after VNS initiation, EEG showed improvement in background slowing

Full size image

Discussion

The human KCNT1 gene, also known as Slack, was first molecularly described in 2000; it encodes a sodium-activated potassium channel [6]. KCNT1 is widely expressed throughout the brain, kidney and heart and is responsible for slow hyperpolarisation after action potential bursts. KCNT1 also interacts directly with fragile X-related proteins, and is involved in a highly extensive protein network, suggesting a putative role in cognitive-developmental processes [13].

KCNT1 gene mutations have been detected in various epileptic encephalopathies, such as West Syndrome, Lennox–Gastaut syndrome and MMFSI [14]. Sleep-related hypermotor epilepsy (SHE) with KCNT1 mutations was observed to have an earlier age of seizure onset and a severe intellectual disability. The mean age at seizure onset in KCNT1-related SHE was 60 months, while in non-KCNT1-related SHE it was more than 10 years. The KCNT1-related SHE usually has negative MRI findings and predominant hypermotor seizures [6]. Our case showed characteristic features of SHE: all of the seizures occurred during stage-2 sleep and the clinical expression consists of “hypermotor” events. However, the patient’s most common seizure type was automatisms, and MRI scan showed a lesion at the right temporal lobe. The temporal lobe epilepsy caused by KCNT1 mutations with a late onset has been reported recently [4]. The patient’s clinical features were partially compatible with both SHE and temporal lobe epilepsy. So he was more accurately diagnosed as KCNT1-related epileptic encephalopathies based on seizure symptoms and the clinical course [15]. Children with KCNT1-related epilepsy usually have an early onset, are nonverbal and refractory to ASM, and MRI findings include brain atrophy and FCD. A recent study showed that the p.Gly288Ser mutation can also cause SHE and MMFSI phenotypes [2], which means that there is no clear specific correlations between genotype and phenotype.

To date, at least 7 different genes have been shown to be associated with SHE, including KCNT1 [16]. Understanding the genetic aetiology could help us find new treatments [16]. Recent studies revealed that quinidine could block the KCNT1 channel and improve the electrophysiological abnormalities caused by KCNT1 mutations [17]. However, the reported efficacy of quinidine therapy has been contradictory [18]. A recent study showed that only 20% of patients have good response (> 50% reduction in seizures) [14]. The response to quinidine therapy may be age-dependent, as a study showed that only patients younger than 4 years have good response to quinidine treatment [19].

The MRI scan revealed mild diffuse cerebral atrophy and FCD at the right temporal lobe in the case. In KCNT1-related epilepsies, thin corpus callosum and brain atrophy are the most common findings from brain MRI. FCD induced by KCNT1 is rarely reported. FCD is commonly caused by gene mutations in components of the mTOR pathway. The exact mechanism of KCNT1-related FCD remains unclear to date. One study reported that patients with KCNT1-related focal refractory epilepsy have poor surgery outcomes despite having lesions (FCD I) on MRI [20]. KCNT1 mutations and FCD might reciprocally influence each other in the development of pathophysiology. In our patient, the MRI scan showed FCD at the right temporal lobe, but the PET scan showed more diffuse hypometabolism in the bilateral frontal lobes and the right temporal-parietal area. The PET abnormalities suggest that the gene is expressed diffusely in the central nervous system [21]. The functional imaging may help us assess the brain network in patients with KCNT1 mutations.

KCNT1-related epilepsy is often refractory to ASMs. KD is the most frequently reported treatment to reduce KCNT1-related seizures [6, 8], but it is difficult to implement in older children due to poor compliance. Sudden unexpected death in epilepsy (SUDEP) has been reported in patients with KCNT1-related ADSHE and MMFSI [7], which may be caused by the gene mutation in the heart.

VNS is a safe and effective neuromodulatory therapy for pediatric drug-resistant epilepsy, with a responder rate (> 50% seizure reduction) of around 35% to 50% after 2 years of follow up and higher rate after 5-year or longer follow-up [22, 23]. In children, the responder rate is higher than that in adults with drug-resistant epilepsy with any etiology [24]. The precise mechanism of VNS treatment remains unknown, although several hypotheses have been offered by previous studies [25]. Obviously, the mechanism is different from ASMs, which directly affect the ionic conductivity of neuronal membranes or affect the function of neurotransmitters.

Patients with genetic aetiology of drug-resistant epilepsy can also achieve significant outcomes after VNS. In tuberous sclerosis complex (TSC) patients, about 40% patients could acquire seizure freedom and the responder rate was 68% [24]. In contrast to TSC patients, the responder rate of Dravet syndrome with SCN1A mutation was only 41% and none were seizure free [12]. In Rett and Angelman syndrome, few cases respond to VNS [26].

The VNS therapy also improves the comorbidity of epilepsy such as cognitive and/or behavioral disorder, mental retardation, autism and attention deficit-hyperactivity disorder, independent of whether or not their seizures are controlled [27]. VNS may also reduce the rate of SUDEP. Ishii reported successful treatment of seizures with KCNT1-related MMFSI by VNS [28]. Our patient also responded to VNS, with 50% seizure reduction at the last follow up; however, whether it can benefit children with KCNT1-related epilepsy remains unknown.

Conclusions

Children with KCNT1-related epilepsy usually have an early onset, are nonverbal, and are refractory to ASMs. KCNT1-related focal refractory epilepsy has poor surgery outcomes. In this paper, we describe a boy with lesional drug-resistant KCNT1-related epilepsy, who showed significant improvement in seizure frequency after the initiation of VNS. Our report may provide reference for management of KCNT1-related epilepsy.