“Breath holding spells” in a child with SCN8A-related epilepsy: Expanding the clinical spectrum

Abstract

A 14-month-old, developmentally-normal girl presented with daily events since 6-months of age. The events were characterized by crying (provoked by fall/anger) followed by cessation of crying, peri-oral cyanosis, and tonic stiffening of the limbs and jerking. She also had a microcytic/ hypochromic anemia. Initially she was diagnosed with breath-holding spells with reflex-anoxic seizures and started on iron with no effect. Subsequently, these episodes started happening without crying. On suspicion of seizures, she received phenobarbital and levetiracetam (minimal response) and then oxcarbazepine. After adding oxcarbazepine, the episodes markedly reduced (once/month) and she is now seizure free for 2 months.Magnetic-resonance-imaging (MRI) of the brain demonstrated high T2 signal in the white matter of the left anterior temporal lobe, suspicious for focal cortical dysplasia type I. Positron-Emission-Tomography was concordant. Video-EEG captured generalized seizures (induced by breath-holding and spontaneous) with unclear lateralization (Video 1). Rarely, sharply contoured slow waves were seen in the left temporal region. Magneto-encephalography revealed occasional spike dipoles (without EEG spikes) over the left posterior insula and posterior portion of left superior temporal gyrus. Targeted epilepsy gene panel revealed a de novo previously described pathogenic variant [c.5630 A > G, p.Asn1877Ser (N1877S)] in the SCN8A gene, which has been associated with milder phenotypes [1]. She is being managed medically at the moment. Epilepsy surgery may be considered in future if she develops drug-resistant focal seizures. DiscussionSCN8A-related epilepsy presents with a variable phenotype from benign infantile seizures to a severe epileptic encephalopathy. The epilepsy is usually drug-refractory, although response to sodiumchannel blockers has been described [2].Gardella et al. [2] reported nine (40.9%) patients with SCN8A mutation with tonic-clonic seizures preceded by cyanosis and autonomic features. Our patient presented with a brief breath-holding spell (with perioral cyanosis) followed by behavioral-arrest, and then generalized tonic-clonic seizures. These events were consistently triggered by "breath-holding" before oxcarbazepine. The sequence of provoked crying, breath-holding, bluish discoloration of lips followed by behavioral arrest, and then tonic-clonic limb movements, in a developmentally normal child, was mistaken as isolated breath holding spells with possible reflex-anoxic-seizures. However, video-EEG monitoring proved these events were generalized epileptic seizures following breath-holding spells and prompted the search for a cause. Yamamoto [3] described three developmentally-normal infants with normal neuro-imaging with generalized tonic-clonic seizures induced by crying who were thought to have "breath-holding spells." Inter-ictal EEG showed frontal spike-waves and ictal-onset was generalized. No

Breath-holding Spells: Etiological Factors, Laboratory Findings, and Rates of Response to Iron Therapy

“…In addition, when given iron supplementation, patients with BHS without IDA could show similar or even better response, as reported in previous studies (8,10). In contrast to the study of Jain et al (20), the present study found a significantly higher rate of complete remission with iron therapy in patients with a greater BHS frequency. The complete remission rate was 39.5% (53 patients).…”

“…MRI revealed focal cortical dysplasia type I. Video-EEG revealed generalized seizures (both spontaneous and induced by breath-holding) with unclear lateralization. Targeted epilepsy gene panel revealed a de novo previously described pathogenic variant in the SCN8A gene linked to milder phenotypes (20). Our patient had no spontaneous episodes.…”

SCN8A self‐limited infantile epilepsy: Does epilepsy resolve?

“…For 22, the age at seizure offset was not provided, so they were excluded from subsequent analysis. [8][9][10][11][12][13][14][15][16][17] The remaining 29 cases were combined with our nine individuals (38 total) to assess natural history of seizure progression (Table S1).…”

Early-Onset Developmental and Epileptic Encephalopathies of Infancy: An Overview of the Genetic Basis and Clinical Features

“…61 The EEG findings are variable and depend on the phenotype and include a slow background, multifocal, frontal, temporo-occipital, and generalized epileptiform discharges. 61,63,64 A posterior predominance of epileptiform activity has been observed in some patients. 61 Neuroimaging may show both cortical and subcortical atrophy as well as restricted diffusion in the optic radiations.…”

“…63,65 Seizure control may improve in those with gain-offunction mutations (i.e., self-limited familial infantile epilepsy, EIEE) with high doses (supratherapeutic) of sodium channel blockers, such as oxcarbazepine, carbamazepine, or phenytoin. 61,64 The ketogenic diet may also be effective, and in severe cases, levetiracetam may worsen seizures. 61 Synaptic proteins…”