Current and Neuroscience Reports (2020) 20:6 https://doi.org/10.1007/s11910-020-1027-7

PEDIATRIC NEUROLOGY (WE KAUFMANN, SECTION EDITOR)

EEG Monitoring of the Epileptic Newborn

Francesco Pisani1 & Carlotta Spagnoli2 & Carlo Fusco2

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract Purpose of Review Although differentiating neonatal-onset from acute symptomatic neonatal has been increasingly recognized as crucial, existing guidelines, and recommendations on EEG monitoring are mainly based on acute symptomatic seizures, especially secondary to hypoxic-ischemic . We aimed to narratively review current knowl- edge on neonatal-onset epilepsies of genetic, metabolic, and structural non-acquired origin, with special emphasis on EEG features and monitoring. Recent Findings A wide range of rare conditions are increasingly described, reducing undiagnosed cases. Although distinguishing features are identifiable in some, how to best monitor and detect less described etiologies is still an issue. A comprehensive approach considering onset, evolution, ictal semiology, clinical, laboratory, EEG, and neuroimaging data is key to diagnosis. Summary Phenotypic variability prevents precise recommendations, but a solid, consistent method moving from existing pub- lished guidelines helps in correctly assessing these newborns in order to provide better care, especially in view of expanding precision therapies.

Keywords Neonatal seizures . Newborn . , . EEG, . Monitoring

Introduction The most prevalent etiologies include hypoxic- ischemic encephalopathy (HIE) in the full-term and Distinction between Acute Symptomatic Neonatal near-term newborn, and intraventricular hemorrhage Seizures and Neonatal-Onset Epilepsies (IVH) in preterm infants. Full-term and near-term new- borns can also suffer from seizures secondary of perinatal The majority of neonatal seizures are of acute symptom- ischemic stroke. Additional, less frequent causes include atic origin [1]. They have a significant incidence [2•]and infections and transient metabolic derangements [3]. are associated with a worsening in neurological and sur- Acute symptomatic seizures typically tend to decline spon- vival outcome [1]. taneously after a high seizure burden period, which tends to be concentrated in the first days of life [4], but can be followed by This article is part of the Topical Collection on Pediatric Neurology the development of spontaneous seizures (epilepsy) later in life in a substantial proportion of cases [5]. This typical time * Carlotta Spagnoli course has been a cornerstone for the development of recom- [email protected] mendations for EEG monitoring in newborn patients [6]. Neonatal-onset epilepsies, on the contrary, are sustained by Francesco Pisani structural, genetically-driven or non-acquired, metabolic, or [email protected] genetic etiologies [7]. Historically, well-described Carlo Fusco electroclinical syndromes of early-onset have included [email protected] Ohtahara syndrome, early-onset metabolic encephalopathy, and benign (familial) neonatal-onset epilepsy, which have def- 1 Child Neuropsychiatry Unit, Medicine & Surgery Department, Neuroscience Division, University of Parma, Parma, Italy inite clinical and EEG diagnostic criteria. However, increasing availability of genetic testing has resulted in a complete para- 2 Child Neurology Unit, Presidio Ospedaliero Provinciale Santa Maria Nuova, AUSL-IRCCS di Reggio Emilia, viale Risorgimento 80, digmatic shift, and now the literature is moving towards ge- 42123 Reggio Emilia, Italy netically based or pathophysiological mechanisms-based 6 Page 2 of 17 Curr Neurol Neurosci Rep (2020) 20:6 classifications [8•, 9]. Nonetheless, precise phenotypic de- risk for neonatal seizures in the following 18–24 h, depending scription is mandatory in order to correctly interpret the huge on the background activity [17]. The rewarming phase should amounts of data coming from next generation DNA sequenc- also be monitored in hypoxic newborns undergoing therapeu- ing investigations. tic hypothermia, as it is accompanied by an increased risk of It has long been acknowledged that etiology is the most seizure recurrence [18, 19]. important determinant of outcome following neonatal seizures Recording EEG should be considered in the presence of [10] and, therefore, there is an urgent need to construct seizure risk factors, among others: fetal distress, central ner- etiology-specific clinical studies on patients, as previous study vous system infection, HIE, preterm birth, intracranial hemor- designs did not use to distinguish between these patients. In rhage, and cardiac surgery [6, 14, 20–22]. As only a small some instances, for example, KCNQ2 encephalopathy, it has percentage of neonatal seizures have a clinical correlate (es- been possible to delineate specific electroclinical phenotypes pecially in HIE) [23], video-EEG monitoring is recommended based on etiology [11]. It is becoming increasingly clear that [14]. As per American Clinical Neurophysiology Society’s these conditions have disease-specific developmental and sei- recommendations, this should be performed for 24 h [6], al- zure outcomes and therefore need to be considered as a sepa- though according to some research the increased risk period is rate group. Significantly, the International League Against extended to the first 24–36 h [17, 24, 25]. Epilepsy (ILAE) classification of the epilepsies has incorpo- EEG can be critical for differentiating seizures from parox- rated the etiologic dimension in every step of the diagnostic ysmal, abnormal non epileptic events [26]. When this is the definition [12], and this approach should apply to the neonatal indication for EEG, its duration should be guided by the abil- period as well. ity to detect multiple typical events [6]. However, treatment strategies for neonatal seizures have After seizures are diagnosed, prolonged, or continuous remained substantially unchanged due to lack of high- monitoring is used to correctly estimate the “seizure burden” quality evidence [13]. Importantly for everyday clinical prac- and to diagnose neonatal (NSE). This has tice, the distinction between epilepsies and acute seizures is relevant practical implications, in guiding treatment decisions now necessary from the beginning, because of the existence of [6] as NSE has been linked to worse neurological and survival disease-specific therapies (precision medicine), which in a few outcome and to later development of epilepsy [1]. conditions are already established as current clinical practice, EEG is then mandatory for evaluating response to an- and in many additional conditions are either under way or ticonvulsant medications. To this end, EEG monitoring might become available in the future based on clinical obser- should continue for at least 24 h after seizure freedom is vation or basic science studies. gained, and seizure recurrence should be checked during and after drug discontinuation [6]. What is Already Known on EEG Monitoring in Newborns with Seizures Structural, Genetically Caused Brain EEG monitoring in intensive care units is performed through Abnormalities two different methods: conventional EEG (c-EEG) and amplitude-integrated EEG (aEEG). In real-world clinical prac- Tuberous Sclerosis Complex tice, c-EEG is recorded as serial standard EEG or as continu- ous EEG. Conventional EEG is recognized as gold standard Epilepsy associated with tuberous sclerosis complex (TSC) for seizure diagnosis and quantification, as it allows demon- usually begins in infancy, while onset in the neonatal period stration of the seizure onset focus and propagation [6] and can is rare [27]. Resective surgery is indicated in refractory cases, provide detailed information on brain maturation, ongoing or but typically not until the early-infantile period. As TSC1/ previous brain injury, and subsequent outcome. Simultaneous TSC2 gene products act as regulators of the PI3K-AKT- videorecordingisstandardofcareinmanyinstitutions mTOR pathway, rapalogs have been evaluated as targeted [14]. Many neonatal units, however, routinely use trend therapies of TSC-related epilepsy [28]. analysis, especially a-EEG, which allows rating of back- ground activity and degree of HIE, and prognostication Malformations of Cortical Development [15], although it has to be considered as a complimentary, “screening” tool [16] for seizure evaluation. aEEG’s eas- These include disorders of cell proliferation and apopto- iness of use and readiness of interpretation can assist real- sis, disorders of cell migration, and disorders of post- time decision-making on a 24-h basis by neonatology migrational development. Early-onset refractory epilepsy staff, which can be followed by c-EEG confirmation. is common, and neonatal onset has been described in all. In newborns with hypoxic-ischemic encephalopathy, even Examples include the well-known ARX (X-linked short standard EEGs can be useful in predicting short-term aristaless-related homeobox gene) which can often be Curr Neurol Neurosci Rep (2020) 20:6 Page 3 of 17 6 present in the neonatal period, and give rise to different KCNQ2 Encephalopathy phenotypes, including severe hydrocephalus, agenesis of the corpus callosum, malformations of cortical develop- De novo mutations in KCNQ2 are associated with a neonatal- ment, but also non malformation-related phenotypes [29]. onset developmental encephalopathy, referred to as “KCNQ2 often causes refractory epilepsy with encephalopathy” [33], characterized by neonatal-onset sei- neonatal onset. Hemispherotomy is a major consideration due zures with the same clinical presentation as in benign neonatal to high refractoriness to medications. However, surgery is not epilepsy. Interictal EEG is severely abnormal (burst suppres- typically performed in the neonatal period. The use of sion, random focal attenuation, multifocal discharges) and rapalogs has not been reported, even though germinal or, most newborns present with abnormal neonatal neurologic exami- frequently, somatic disease-causing genetic variants implicate nation and develop severe to profound developmental delay the same PI3K-AKT-mTOR pathway [30]. Conventional [33–35]. Burst-suppression pattern tends to resolve within the EEG findings in these conditions include a burst-suppression first 2 months of life [36]. pattern or severely abnormal background (multifocal, asym- Seizures are highly resistant to most antiepileptic drugs; metric, deranged sleep patterns), as well as detection of alpha- however, they show good response to sodium channel like rhythms or excess rapid spindle-like activity. blockers [35], which are considered the established precision medicine treatment for KCNQ2-related epilepsies [8]. Genetically Caused Vascular Lesions KCNQ3 Encephalopathy COL4A1 (collagen type IV alpha1 chain) gene product constituting the vascular basement membrane leads to a A few reports exist documenting early-onset KCNQ3-re- well-known clinico-radiological condition in which fetal- lated epileptic encephalopathy, which can occasionally be to-neonatal intraventricular and/or intraparenchymal hem- present in the neonatal period as a pharmaco-dependent orrhage, schizencephaly, and/or occur, often epilepsy with focal seizures, hypotonia, cyanosis, and associating with ophthalmic abnormalities (cataracts, clonic jerks. EEG shows electrical seizures characterized microphthalmia, glaucoma). There is no specific EEG by central and temporal slow waves. Homozygous vari- and/or epileptic phenotype [31]. ants in the KCNQ3 gene are causative [37].

SCN2A-Related Neonatal Epilepsies Genetic Non-Structural Conditions SCN2A channelopathy causes a spectrum of epilepsies and neurodevelopmental disorders, also of neonatal onset, ranging In this group of disorders, neuroimaging findings can be from benign familial neonatal-infantile epilepsy (BFNIE) to either negative or nonspecific. Details on each condition epileptic encephalopathy and even to severe hypotonia with arereportedinTable1. developmental delay and autistic features without epilepsy. BFNIE is a self-limited condition with good neurodev CHANNELOPATHIES elopmental outcome, with typical onset between the first days of life and infancy. Seizures are mainly focal tonic or clonic. Benign Neonatal Epilepsy Interictal EEG is either normal or shows focal spikes. Epileptic/developmental are characterized Benign neonatal epilepsy, caused by pathogenic variants in by refractory epilepsy (focal tonic, tonic-clonic, and spasms) the potassium channel genes KCNQ2 or KCNQ3, may occur with onset in the first months of life and severely abnormal as autosomal dominant epilepsies with incomplete penetrance EEG (burst-suppression or multifocal interictal abnormali- or less often as a sporadic condition. They carry favorable ties). Neonatal-onset SCN2A-related epilepsy (typically seizures and neurodevelopmental outcomes. Clusters of sei- sustained by gain-of-function, missense variants) also re- zures occur within the first days of life and are characterized sponds well to sodium channel antagonists, while later-onset by asymmetric tonic posturing evolving into unilateral or cases (usually deriving from loss-of-function variants) are asynchronous bilateral clonic movements, frequently with as- worsened or respond poorly to these medications [38]. sociated vegetative symptoms (namely apnoea and desaturation). Rapid response to carbamazepine has been doc- Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) umented in KCNQ2-related cases, regardless of time of initi- ation [32]. However, prompt administration is associated with Epilepsy of infancy with migrating focal seizures (EIMFS) shorter intensive care stay. Interictal EEG is normal and pa- typically begins in the infantile period, although neonatal on- tients have a normal neurological evaluation between seizures. set has been occasionally described. The hallmark of this 6 Table 1 Genetic Nonstructural Neonatal Epilepsies and Epileptic Encephalopathies

Category Inheritance Gene Ictal semiology EEG Interictal state Rep Neurosci Neurol Therapy, Curr response “Precision Outcome References 17 of 4 Page Phenoty- and additional therapy” pe findings

Channelopathies KCNQ2 benign AD (incomplete BFNE KCNQ2 Asymmetric tonic Interictal: normal Normal interictal Carbamazepine Yes (carbamazepine) Favorable [32] neonatal epilepsy penetrance)/- posturing ➔ neurological sporadic unilateral/bilateral examination asynchronous clonic, apnoea and desaturation KCNQ2 De novo / rarely DE/EE KCNQ2 asymmetric tonic Interictal: severely Abnormal Sodium channel Yes (carbamazepine) Severe to profound [8, 33–36] encephalopathy mosaicism posturing ➔ abnormal (burst neonatal blockers, especially DD, unilateral/bilateral suppression, neurologic carbamazepine: Some asynchronous random focal examination effective dystonic-spastic clonic, apnoea, and attenuation, Severe resistance to syndrome, desaturation multifocal other drugs Epilepsy may cease discharges) within 24 months of age KCNQ3 benign AD (incomplete BFNE KCNQ3 Focal Interictal: normal Normal interictal carbamazepine no Favorable [32] neonatal epilepsy penetrance)/- asymmetric tonic neurological sporadic posturing ➔ examination unilateral/bilateral asynchronous clonic, apnoea, and desaturation KCNQ3 AR DE/EE KCNQ3 focal, hypotonia, cyanosis, Interictal: severely Abnormal pharmaco-dependent no ID (mild to severe) [37] encephalopathy clonic jerks abnormal neonatal epilepsy Ictal: central and neurologic temporal slow examination waves Sporadic cases with severe clinical presentations (DD with or without refractory seizures or CVI) SCN2A-related AD BFNIE SCN2A focal tonic or clonic Interictal: normal / normal Neonatal-onset (GoF, Yes (carbamazepine good [38] epilepsy focal spikes missense and sodium neurodevelopmen- variants) respond to channel blockers, tal outcome sodium based on age at channel blockers onset and functional consequence of PV) (2020)20:6 SCN2A-related De novo DE/EE SCN2A focal tonic, tonic-clonic, severely abnormal Abnormal Refractory Yes (carbamazepine Severe ID, hypotonia, [38] encephalopathy and spasms (burst-- (hypotonia, Neonatal-onset (GoF, and sodium MD suppression / movement missense channel blockers, multifocal disorder) variants) respond to based on age at interictal sodium onset and abnormalities) channel blockers functional consequence of PV) EIMFS De novo DE/EE KCNT1 unilateral motor Interictal: possibly Severely Highly refractory to Inconsistent results Severe to profound ID [9, 11, SCN2A, SCN1A, (alternating side) with negative or abnormal antiseizure with quinidine despite seizure 39–41] SLC25A22, versive component, nonspecific (KCNT1) control urNuo ersiRep Neurosci Neurol Curr Table 1 (continued)

Category Inheritance Gene Ictal semiology EEG Interictal state Therapy, response “Precision Outcome References Phenoty- and additional therapy” pe findings

PLCB1, myoclonic (early phase), drugs, steroids, TBC1D24, jerks, hypertonia, abnormal, with .

GABRB3, possibly focal / Bromide. (2020)20:6 QARS autonomic features multifocal paroxysmal activity, B-S. Ictal: seizure migration from one focus to another and simultaneous seizures GABAR-related De novo DE/EE GABRA1, OS phenotype Markedly Severely refractory no broad phenotypic [9, 42, 43] epileptic GABRB2, abnormal (B-S) abnormal, range of severe encephalopathies GABRB3, multifocal severe delayed EE, DD GABRG2 myelination CACNA1A AR DE/EE CACNA1A Polymorphic (more often Severely markedly refractory no Moderate to severe ID [42, 44] infantile onset with IS) abnormal, hypotonic, progressive , multifoca, no absent deep progressive sleep-wake tendon reflexes cerebral, differentiation diffuse cerebellar, and hypomyelinati- optic atrophy are on frequent CACNA1C De novo DE/EE CACNA1C Subtle / prolonged tonic Interictal: diffuse multiple refractory no Profound DD, [45, 46] and fast, lack of congenital profound tonic-myoclonic. normal abnormalities, hypotonia, organization hypotonia, inability to visually optic nerve track or fixate dysplasia DEND syndrome De novo DE/EE KCNJ11 IS in infancy; non-specified B-S intractable refractory yes hypotonia, profound [47] neonatal phenotype hyperglycemia, sulphanyl-urea DD very low insulin secretion, undetectable islet cell antibodies causing neonatal diabetes hypotonia Growth factors FGF12 . De novo DE/EE FGF12 versive tonic seizures with Interictal: cerebellar atrophy Possible response to no Early cases with [48] apnoea, multifocal carbamazepine progressive course and possibly twitching spikes / and early death,

of the limbs background Single cases with 17 of 5 Page suppression and milder phenotype: multifocal n = 1 normal (11 mo) spikes n = 1 autism, Ictal: independent moderate ID, bi-frontal foci epilepsy (15y) Nuclear gene expression 6 PACS2 De novo DE/EE PACS2 polymorphous Interictal: focal neonatal-onset Controlled with no DD [49] spikes, normal DE/EE, facial difficulty 6 Table 1 (continued)

Category Inheritance Gene Ictal semiology EEG Interictal state Rep Neurosci Neurol Therapy, Curr response “Precision Outcome References 17 of 6 Page Phenoty- and additional therapy” pe findings

focal or bilateral tonic, background / dysmorphisms, in the first year Improved seizure clonic, excess cerebellar control in early focal with tonic discontinuity dysgenesis childhood stiffening and excessive atypical social and and autonomic features, multifocal sharp behavioral myoclonic, clonic with waves features, ASD eye deviation Ictal: clear focal onset (often multifocal) or diffuse attenuation with later focal features Synaptopathies STXBP1 De novo DE/EE STXBP1 tonic spasms, frequently severely abnormal Severely refractory no Profound DD [11, 50] with (B-S / abnormal focal component multifocal) neurological examination, associated movement disorder SPTAN1 De novo DE/EE SPTAN1 Early-onset spasms hypsarrhythmia spastic refractory no poor [51, 52] (3w-3mo) quadriplegia progressive progressive brain, , brainstem and severe DD and cerebellar hypotonia, severe atrophy, with hypomyelination hypomyelinati- on in most PRRT2 AD BFIE PRRT2 Behavioral arrest normal NA NA no Seizure-free [53–55] off-medications, permanent and severe ID (single case report with neonatal onset) TBC1D24 De novo DE/EE TBC1D24 Polymorphous, No consistent Neonatal-onset More commonly no Commonly [56] frequently including features EE, hypotonia, refractory hypotonia, DD, ID myoclonic (abnormal, DD in early-onset cases Frequent SE multifocal) Additional (facial, cranial, acral, or other organ) abnormalities deafness, (2020)20:6 onychodystro- phy, osteodystrophy,

mental retardation, and seizures (DOORS) syndrome SIK1 De novo DE/EE SIK1 severe neonatal-onset B-S / Severe refractory no Profound/severe DD, [57] seizures discontinuous neonatal-onset refractory epilepsy, (EME, OS) or IS EE risk of early death urNuo ersiRep Neurosci Neurol Curr Table 1 (continued)

Category Inheritance Gene Ictal semiology EEG Interictal state Therapy, response “Precision Outcome References Phenoty- and additional therapy” pe findings

in infancy (respiratory

failure) (2020)20:6 Cell signaling CDKL5 De novo DE/EE CDKL5 tonic, spasms, Interictal: initially Abnormal: Refractory no Moderate/severe DD, [58–60] “hypermotor-tonic- normal, hypotonic, stereotypies, spasm” sequence progressive poor eye hypotonia, deterioration contact breathing abnormalities, severe ID with absent speech, head growth deceleration GNAO1 De novo DE/EE GNAO1 Mainly infantile-onset B-S, slow severe motor and Refractory / controlled no DD, MD, epilepsy / [61] Focal, spasms, GTCS background cognitive on medications EE impairment, marked choreoathetosi- s, epileptic encephalopa- thy BRAT1 AR “lethal BRAT1 Polymorphous (eye Severely neonatal onset Often refractory No Profound DD, [62, 63] neona- blinking, tonic, abnormal, B-S, hypertonia, autonomic tal myoclonic, focal excessively intractable instability, and rigidity clonic, apnea, discontinuous, seizures, apneic early death and desaturation, multifocal episodes, (cardiopulmonary multi- and increased tone) discharges microcephaly arrest), focal and stagnant head progressive atrophy seizure growth, lack of of the cerebral syn- developmental hemispheres, drom- progress, mild brainstem, and e” frontal lobe cerebellum hypoplasia, Mild cases: cerebral, and pharmaco-- cerebellar responsive atrophy epilepsy Intermediate cases: refractory epilepsy, survival beyond infancy

AD autosomal dominant, AR autosomal recessive, ASD autism spectrum disorder, B-S burst-suppression, CVI cortical visual impairment, DD developmental delay, GTCS generalized tonic-clonic seizures, ID , DE developmental encephalopathy, EE epileptic encephalopathy, MD movement disorder, NA not available, PV pathogenic variant, SE status epilepticus ae7o 17 of 7 Page 6 6 Page 8 of 17 Curr Neurol Neurosci Rep (2020) 20:6 condition is migration of medically intractable seizures from 1C subunit of the long lasting (L-type) voltage gated calcium one focus to another. Multiple seizures can evolve simulta- channel [45]. neously. The most common cause is de novo gain of function mutation of KCNT1, encoding a sodium activated potassium channel [39]. Additional genes implicated in a subset of cases Developmental Delay, Epilepsy, Neonatal Diabetes: DEND include SCN2A [38], SCN1A, SLC25A22, PLCB1, TBC1D24 [9], GABRB3 [40]andQARS [11]. Seizures are highly This is a potassium channelopathy characterized by in- refractory. tractable hyperglycemia, very low insulin secretion and At onset, unilateral motor seizures with alternating side, undetectable islet cell antibodies causing neonatal diabe- versive component, myoclonic jerks, and hypertonia usually tes and neonatal seizures which may evolve to infantile occur, possibly with associated autonomic component. Of spasms. EEG shows bursts suppression pattern. It is note, interictal EEG might be negative in the early phase, or caused by pathogenic variants in the KCNJ11 (potassium only show nonspecific diffuse slowing, but subsequently ab- voltage-gated channel subfamily J member 11) gene. normal background with focal or multifocal paroxysmal ac- Patients are hypotonic, with profound developmental de- tivity and periods of burst-suppression develop. As mentioned lay. Early treatment with sulphanyl-urea has been reported above, ictal EEG showing seizure migration from one focus to to result not only in better diabetes control but also in another, changing focuses between seizures and the presence improved control of epilepsy [47]. of different simultaneous seizures are the neurophysiologic hallmarks of this condition [9], which fully develops in the second phase of the disorder. Infants have normal neurological Growth Factors examination before seizure onset. Following promising in vitro studies [41], reports on the FGF12 Mutation clinical administration of quinidine have published, with in- consistent results [64]. A de novo variant (c.G155A) in the fibroblast growth factor 12 (FGF12) gene has been associated with early-onset epilep- GABA Receptors sy in two patients with versive tonic seizures with apnoea, and possibly twitching of the limbs, beginning in the first month of Pathogenic variants in GABA receptors genes (GABRA1, life. Interictal EEG shows multifocal spikes or background GABRB2, GABRB3, and GABRG2) are associated with suppression and multifocal spikes, while ictal EEG shows neonatal-onset epileptic encephalopathies. EEG is markedly multiple independent left and right frontal seizures. In one abnormal, consistent with Early Myoclonic Encephalopathy case seizure responded to sodium channel blockers develop- (EME), Ohtahara or non-syndromic early-onset epileptic en- ment is normal at 11 months, while the second patient, now cephalopathy [9, 42]. aged 15 years, has treatment-resistant focal epilepsy, moderate intellectual disability, and autism. Carbamazepine (sodium channel blocker) was tried later and discontinued due to drug CACNA1A reaction [48].

Disease-causing variants in the CACNA1A (alpha-1 subunit of the Cav2.1P/Q type calcium channel) gene are associated with Nuclear Gene Expression prenatal or neonatal-onset of epileptic encephalopathies, with polymorphic , and ensuing intellectual disability PACS2 (Phosphofurin Acidic Cluster Sorting Protein 2) [42, 44]. Recurrent de novo PACS2 heterozygous missense variant CACNA1C c.607C > T (p.Glu209Lys) has been linked to neonatal-onset developmental epileptic encephalopathy, facial A single case of neonatal onset epileptic encephalopathy was dysmorphisms, and cerebellar dysgenesis. Neonatal EEG reported in association with a missense variant in the characteristics range from focal spikes on a normal back- CACNA1C gene, in the context of multiple congenital abnor- ground to excess discontinuity and excessive multifocal sharp malities, hypotonia, optic nerve dysplasia. Ictal semiology is waves. Seizures are focal or bilateral tonic, clonic, focal with described as subtle tonic as well as prolonged tonic and tonic- tonic stiffening and autonomic features, myoclonic, and clonic myoclonic seizures. Neonatal EEG is described as diffuse fast with eye deviation. PA CS 2 gene product is a multifunctional activities and lack of normal organization. The CACNA1C sorting protein involved in nuclear gene expression and path- gene encodes multiple isoforms of the pore-forming alpha- way traffic regulation [49]. Curr Neurol Neurosci Rep (2020) 20:6 Page 9 of 17 6

Synaptic Vesicle Docking and Release resistant seizures since the first weeks of life, associated with hypotonia and developmental delay. Seizures are polymor- STXBP1 Encephalopathy phic, including the “hypermotor-tonic-spasm” sequence [58]. Hypotonia and poor visual tracking typically associate, De-novo pathogenic variants in STXBP1 (syntaxin binding while only a subset displays microcephaly. EEG findings are protein 1) gene cause an early-onset developmental encepha- nonspecific and interictal EEG can even be normal at onset lopathy with seizure onset often immediately after birth, with [59]. In some instances, seizure control can be achieved after tonic spasms, frequently with a focal component and high several weeks to months, but EEG deteriorates progressively. refractoriness. EEG is severely abnormal (burst-suppression The typical three-stage electroclinical course has been de- or multifocal abnormalities) [50]. Disease-causing variants scribed in [60]. in this gene explain up to one third of non-malformation Ohtahara syndrome [11]. Importantly, it is associated with a GNAO1 neonatal-onset movement disorder. Epilepsy onset may be relatively early, developmental delay is often profound. Heterozygous GNAO1 (G protein subunit alpha o1) gene var- iants cause early-onset epileptic encephalopathy or Ohtahara SPTAN1 syndrome with refractory tonic seizures and an associated movement disorder. Nonetheless, early-onset movement dis- SPTAN1 (spectrin alpha, non-erythrocytic 1) pathogenic vari- order can also occur without epilepsy (GNAO1 encephalopa- ants cause early-onset , beginning between thy), which has been associated with gain-of-function vari- 3weeksand3monthsofage[51]. ants, opposed to loss-of-function ones. Background EEG is severely abnormal (burst-suppression/multifocal) [61]. TBC1D24 BRAT1 Aside from a minority of cases of epilepsy of infancy with migrating focal seizures (EIMFS), TBC1D24 (TBC1 domain Biallelic pathogenic variants in the BRAT1 (BRCA1 associat- family member 24) gene variants have been rarely associated ed ATM activator 1) gene cause a rare but severe clinical with neonatal-onset epileptic encephalopathy, in the context of syndrome initially reported as “rigidity and multifocal seizure hypotonia and developmental delay and a high rate of status syndrome, lethal neonatal”, featuring neonatal-onset focal sei- epilepticus [56]. zures, rigidity/hypertonia, autonomic instability with cardio- pulmonary arrest in infancy [62], although milder (non-lethal) SIK1 cases have also been reported [63]. Little is known on the neonatal characteristics of this rare condition. The responsible SIK1 (salt-induced kinase 1) pathogenic variants cause a se- gene is implicated in mitochondrial function, but also in DNA vere neonatal-onset epileptic encephalopathy (EME or repair and cell growth. Ohtahara phenotype) with poor outcome and a risk of early death in infancy [57]. Inborn Errors of Metabolism PRRT2 Pyridoxine-Dependent Epilepsy (PDE) A single report of onset of seizures in the neonatal period is and Pyridoxal-5-Phosphate-Dependent Epilepsy present in the literature [53] for this gene (proline-rich trans- membrane protein 2), whose mutations causes benign familial PDE is an autosomal recessive disorder characterized by re- and non-familial infantile onset seizure, paroxysmal sponse to vitamin B6 despite pharmacoresistance to conven- kinesigenic dyskinesia, paroxysmal kinesigenic dyskinesia tional antiepileptic drugs. Seizure types are polymorphic (ton- with infantile convulsions, hemiplegic migraine [54], and be- ic, myoclonic, tonic-clonic, or epileptic spasms), with nign non-epileptic [55]. antenatal/ neonatal onset. EEG shows asynchronous bursts of epileptiform activity, multifocal discharges or burst-sup- Cell Signaling pression. Its leading cause is the presence of pathogenic var- iants in the gene encoding alpha-aminoadipic semialdehyde CDKL5 Encephalopathy (AASA) dehydrogenase (ALDH7A1 or antiquitin –ATQ- gene) [65]. CDKL5 (cyclin dependent kinase like 5) encephalopathy is Pyridoxal 5′-phosphate sensitive seizures are a form of ep- another developmental encephalopathy with early-onset ileptic encephalopathy resistant to conventional antiepileptic 6 Page 10 of 17 Curr Neurol Neurosci Rep (2020) 20:6 drugs and pyridoxine but responsive to pyridoxal 5′-phos- oxidase deficiency. Two-thirds of cases are due to mutation phate (PLP) [66]. There is clinical overlap with PDE. The of MOCS1 (molybdenum cofactor synthesis 1) gene, which defect is located in the pyridox(am)ine 5′-phosphate oxidase catalyzes the first step in synthesis of molybdenum cofactor. (PNPO), converting pyridoxamine 5′-phosphate, and pyridox- Recently, successful treatment of seizures and encephalopathy ine to pyridoxal 5′-phosphate (PLP). Pyridoxal-phosphate was reported with daily infusions of cyclic pyranopterin [72, levels in CSF have been proposed as a diagnostic marker in 73]. Early recognition and treatment are necessary to prevent PNPO deficiency, although with limitations. Consequently, irreversible damage (Table 2). definite diagnosis requires genetic testing. More recently de- scribed forms of vitamin B6-related epilepsies include: Sulfite Oxidase Deficiency PROSC (pyridoxyl homeostasis protein) gene variants [67] and ALPL (tissue non-specific alkaline phosphatase) which Sulfite oxidase deficiency is caused by biallelic variants in the is associated with vitamin B6-responsive epilepsy associated SUOX (sulfite oxidase) gene. Sulfite oxidase is a mitochon- with congenital hyperphosphataemia [68](Table2). drial enzyme implicated in the final step of sulfur-containing amino acids (methionine, homocysteine) metabolism. Presentation is with intractable seizures and encephalopathy, which can mimic hypoxic-ischemic encephalopathy. Cystic Glycine encephalopathy is an inborn error of metabolism due encephalomalacia is the typical neuroimaging finding. to a defect in the glycine cleavage system (GCS). CSF glycine Outcome is grim, with early death [74](Table2). concentration and CSF-to-plasma glycine ratio are raised. Presentation is in the first hours or days of life, with lethargy, Mitochondrial Disorders hypotonia, and myoclonic jerks leading to apnea and death. Neonatal EEG lacks organization and physiological features, Nearly one third of mitochondrial disorders can present in the usually presenting with a burst-suppression pattern with mul- neonatal period, and approximately 15% of these have tifocal sharps and spikes, later evolving into hypsarrhythmia neonatal-onset seizures. Myoclonic seizures and spams usual- and/or multifocal discharges in the early-infantile period. ly predominate, although semiology can vary considerably The three known genetic defects leading to glycine enceph- [76]. alopathy are: GLDC (encoding the P-protein component of the GCS complex), AMT (encoding the T-protein component of the GCS complex), and GCSH (encoding the H-protein Disorders of Glycosylation component of the GCS complex). Although treatment is not effective in severe cases, out- These can present with various systemic and neurologic come might be improved in patients with residual GCS en- symptoms, including neonatal-onset epilepsies. SLC35A2 zyme activity by aggressive treatment in the first 2 years of life (encoding for a Golgi-located uridine diphosphate-galactose with sodium benzoate and N-methyl D-aspartate (NMDA) transporter) causes a phenotype associating epileptic enceph- receptor site antagonists, such as dextromethorphan [69] alopathy, developmental delay, cerebral, and cerebellar atro- (Table 2). phy, thin corpus callosum, delayed myelination [77]. PIGA (phosphatidylinositol glycan anchor biosynthesis class A) Amino Acidopathies gene mutation is associated with EME, Ohtahara syndrome, and non-specific early-onset epileptic encephalopathy with Serine synthesis and transport disorders and asparagine neonatal-infantile onset [78]. PIGT (phosphatidylinositol- synthethase deficiency are also associated with neonatal- glycan biosynthesis class T) mutations give rise to a pheno- onset epileptic encephalopathy and at times microcephaly, type combining profound/severe intellectual disability and ep- along with a pyramidal syndrome and severe developmental ileptic encephalopathy of neonatal/infantile onset (myoclonic delay [9]. Early-onset epileptic encephalopathies with burst- and/or tonic, often with apnea, subtle focal). EEG in the neo- suppression pattern have also been associated with a patho- natal period is severely abnormal, with a burst-suppression genic variant in the selenocysteine formation pathway pattern [79](Table2). (SEPSECS) [70](Table2). SLC13A5-Related Epileptic Encephalopathy Molybdenum Cofactor Deficiency SLC13A5 gene encodes for a sodium-dependent citrate trans- Molybdenum cofactor deficiency is an autosomal recessive porter. Pathogenic variants have been associated with the de- condition presenting in the first days of life with abrupt onset velopment of refractory early-onset epilepsy, with frequent of encephalopathy and refractory seizures, similar to sulfite status epilepticus and early death. EEG in the early stages urNuo ersiRep Neurosci Neurol Curr Table 2 Neonatal Epilepsies and Epileptic Encephalopathies Secondary to Inborn Errors of Metabolism

Disorder Gene Phenotype Ictal EEG Interictal state and Metabolic profile Therapy Outcome References Inherita- semiology additional findings nce

Vitamin AR PDE: antenatal/ polymorphic PDE: asynchronous Hypotonia/hypertonia, ALDH7A1: elevated PDE: vitamin B6 ALDH7A1: [65–68] B6-related ALDH7- neonatal onset (tonic, bursts of irritability ± urinary AASA, PNPO: PLP, GDD/ ID epilepsies and A1, of epileptic myocloni- epileptiform lethargy, P6C, pipecolic acid possible PROSC: (2020)20:6 PLP-DE PROSC, encephalopathy c, activity, multifocal encephalopathy ± hypoglycaemia, reposnse to normal to ALPL tonic-- discharges, B-S ALPL: defective bone lactic acidosis pyridoxine or slight DD, PLP-DE: clonic, and teeth PROSC: nonspecific riboflavin in a good E PNPO spasms) mineralization, CSF AA and NT subset of outcome congenital profile patients ALPL: high hyperphosphataemi- ALPL: very low mortality a, respiratory (absent) serum PNPO: fatal complications, ALP, low PTH, if premature normal 25-hydroxy untreated, craniosynostosis and on PLP: 1,25-dihydroxy ranging vitamin D, from hypercalcemia, normal to hyperphosphatemi- varying a, hypercalciuria degree of PNPO: CSF PLP ID, E levels Glycine AR GLDC, AMT, Severe myoclonic B-S with multifocal lethargy, hypotonia, Raised CSF glycine sodium benzoate, unfavorable [69] encephalopathy GCSH neonatal-onset sharps and spikes apnea, death concentration and dextromethor- EE (EME) CSF-to-plasma phan glycine ratio Amino AR PSPH, neonatal-onset EE Tonic, B-S microcephaly, Low serine levels Supplementation Severely [9, 70, 71] acidopathies PHGDH, myocloni- B-S, MFD pyramidal (plasma, CSF) Supportive abnormal Serine synthesis PSAT1, c, syndrome, severe Low asparagine levels therapy progres- and transport SLC1A4 focal-- DD in all conditions (plasma, CSF) sive disorders ASNS onset hyperekplexia in high plasma and CSF Asparagine SEPSECS spasms ASD lactate synthethase microcephaly, deficiency hypotonia, (ASD) cerebellar > cerebral Selenocysteine atrophy formation pathway Molybdenum AR MOCS1 Neonatal-onset poorly B-S Encephalopathy, Low serum and Frequently unfavorable: [36, 17 of 11 Page cofactor MOSC2 EE described exaggerated startle urinary uric acid, refractory profound 71–73] deficiency GPHN (myoclon- reaction, axial positive urinary cyclic ID, poor ic/ hypotonia, limb sulfite test, pyranopterin feeding,

tonic-- hypertonia, feeding elevated urinary daily infusion early 6 clonic) difficulties xanthine, death[ 6 Table 2 (continued)

Disorder Gene Phenotype Ictal EEG Interictal state and Rep Neurosci Neurol Curr Metabolic profile Therapy Outcome References 17 of 12 Page Inherita- semiology additional findings nce

(progressively hypoxanthine, and worsening) S-sulfocysteine Sulfite oxidase AR SUOX Onset: first hours poorly B-S Severely abnormal positive urinary sulfite Frequently unfavorable: [74, 75] deficiency to days of life. described (progressively dipstick, high refractory profound Frequent and (myoclon- worsening) urinary thiosulfate Dietary therapy ID, poor refractory. ic or and might improve feeding, tonic-- S-sulfocysteine, late-onset form early clonic) low urinary organic death sulfate, markedly reduced plasma homocysteine Mitochondrial High genetic Relevant Myoclonic, Often severely high phenotypic Skin/muscle biopsy Depending on Often [76] disorders Men- heteroge- pleiotropy spasms, abnormal heterogeneity for respiratory specific unfavor- delia- neity focal Lethargy, chain activity, diagnosis able n- encephalopathy, CSF/plasma lactate /- hypotonia, matri- hypoglycaemia, linear possible liver, heart or kidney involvement Disorders of De novo SLC35A2 EE, DD, cerebral Spasms, Severely abnormal facial dysmorphism, Isoelectric focusing of Often refractory Severe ID [77–80] glycosylation hemi- PIGA and cerebellar subtle skeletal transferrins Severely hypotonia, zygo- PIGT atrophy, thin Tonic/ abnormalities, refractory severe us CC, delayed myoclonic congenital cardiac DD, E De novo myelination or disease, CVI hemi- EME, OS and nonspecif- zygo- nonspecific ic us EOEE with myoclonic neonatal onset and/or profound/- tonic, severe often with intellectual apnea, disability and subtle

epileptic focal (2020)20:6 encephalopathy of neonatal/- infantile onset SLC13A5-related AR SLC13A5 EOE, with NA Negative/excessively GDD Increased plasma and refractory GDD [81] epileptic frequent SE and discontinuous CSFcitrate anecdotal data on Severe E encephalopathy early death (early stages) elevated CSF efficacy of 2-methylcitrate and GABA N6-succinyladenosine Curr Neurol Neurosci Rep (2020) 20:6 Page 13 of 17 6

AR can either be negative or excessively discontinuous [81] GLDC

PROSC (Table 2). epileptic EE sulfite oxidase

phosphoglycerate Discussion epilepsy, SUOX E Sep (O-phosphoserine) The increased diagnostic rate offered by Next-Generation PHGDH aminomethyltransferase, -phosphate oxidase, ′ Sequencing techniques and the emerging role for precision AMT

SEPSECS medicine have created an impetus for differentiation between neonatal-onset epilepsies and acute symptomatic seizures, al-

glycine cleavage system protein H, though knowledge on the optimal management probably is sodium channel blockers and acetazolamide

developmental delay, still incomplete. modifying drugs, pyridox(am)ine 5 ohtahara syndrome, GCSH DD The range of potential differential diagnoses is very wide, OS

aline phosphatase, while the main categories of electroclinical presentations can PNPO be successfully subdivided into big categories, based on the solute carrier family 35 member A2, presence/absence of malformations, presence/absence of an

phosphoserine phosphatase, early-onset epileptic encephalopathy, and seizure semiology.

SLC35A2 Correct differentiation starts from accurate history taking Metabolic profile Therapy Outcome References PSPH neurotransmitters, and phenotypic characterization. This can be helped by the use NT tissue non-specific alk

cortical visual impairment, of video-EEG. Ictal data on seizure semiology and informa- global developmental delay, tion from interictal and ictal EEG have to be interpreted in the CVI ALPL

GDD context of pre/perinatal, family history, and overall clinical presentation, especially with respect to neurologic and general

not available, examination of the affected newborn. Neuroimaging can also NA

additional findings assist differential diagnosis [7]. Doing so, in some cases, key features can be obtained, even if the phenotypic spectrum is cerebrospinal fluid, broad and further complicated by genetic and phenotypic het- solute carrier family 13 member 5,

CSF erogeneity [11]. phosphoserine aminotransferase 1, In some of the rarest, more recently described conditions, the gamma-amino-butyrric acid, phosphatidylinositol glycan anchor biosynthesis class T,

SLC13A5 neonatal presentation is still not well characterized; therefore, a PSAT1

mutlifocal discharges, high index of suspicion is necessary. On the other hand, even EEG Interictal state and PIGT GABA though genetic testing can be resource- or time-consuming, and corpus callosum, MFD not straightforward, the clinical tools leading to the major dis- CC tinction between suspected neonatal-onset epilepsies versus aldehyde dehydrogenase 7 family member A1, acute symptomatic seizures are available to a high number of semiology clinicians, and can be sufficient to avoid unnecessary investiga-

early-onset epilepsy, tions or prioritize treatment strategies (e.g., to perform a treat- ALDH7A1 ment trial with sodium channel blockers or vitamins in drug- EOE burst-suppression, movement disorder,

solute carrier family 1 member 4, resistant seizures with no definite acquired risk factor), which is B-S MD the ultimate goal of differential diagnostics. There has been renewed interest in the semiological classifica- SLC1A4 pyridoxal-phosphate dependent epilepsy,

c semialdehyde, tion of seizures and into the possible links between ictal semiology ncephalopathy, and etiology, as a way to guide accurate and timely diagnosis. In a recent review of previously published papers, although PLP-DE

Gene Phenotype Ictal with under-represented hypoxic-ischemic encephalopathy intellectual disability, asparagine synthethase, cases, an association was found between hemorrhage and au- ID alpha-aminoadipi phosphatidylinositol glycan anchor biosynthesis class A,

early myoclonic e tonomic seizures, and metabolic/vitamin-dependent disorders ASNS Inherita- nce and inborn errors of metabolism with myoclonic seizures AASA EME PIGA [82•]. Focal clonic seizures can indicate a focal cortical lesion (stroke, intracranial hemorrhage, and focal cortical dysplasia, (continued) or central nervous system infection) [7, 82•]. Tonic seizures

amino acids, point to a genetic epilepsy syndrome or to a cortical malfor- dehydrogenase, Table 2 Disorder glycine decarboxylase, tRNA:Sec (selenocysteine) tRNA synthase, AA pyridoxyl homeostasis protein, encephalopathy, autosomal recessive, mation, if the history does not suggest acute symptomatic 6 Page 14 of 17 Curr Neurol Neurosci Rep (2020) 20:6

Fig. 1 Diagnostic flow chart etiology [7]. As outlined above, tonic seizures followed by a occurring in the first day of life. On the contrary, in a neuro- myoclonic or clonic phase are the hallmarks of KCNQ2- logically healthy newborn with seizure onset towards the end related epilepsy. Finally, the rare occurrence of epileptic of the first week, genetic benign neonatal-onset epilepsy spasms can indicate a metabolic disorder such as vitamin B6 might be suspected, especially if family history is positive. dependent epilepsy, a cortical malformation, or an early-onset In metabolic/genetic disorders the maximum seizure bur- epileptic encephalopathy [7]. den tends to develop later than in HIE and the last seizure Correct EEG interpretation and pattern recognition is cru- occurs later than in moderate HIE (while the period with on- cial, and some correlations can be made between focal ictal going seizures is longer in severe HIE). Therefore, the differ- discharges and vascular disorders or electrolyte derangements, ent time evolution of seizures in neonatal epilepsies versus multifocal discharges and vitamin-related disorders, and final- acute symptomatic seizures might prompt a more extended ly burst-suppression with genetic disorders. Clonic and auto- diagnostic work-up. In a recent paper, it was suggested that nomic seizures are more frequently present with focal EEG if seizures persist beyond 96 h, additional investigations abnormalities, while tonic and myoclonic seizures with burst- should be performed [83]. suppression [82•]. In the conditions we reviewed, it is relevant At this stage, it seems that there is no disease-specific way to note that not all of the neonatal-onset epileptic encephalop- of monitoring newborns with suspected or confirmed athies are accompanied by severely abnormal EEG since the neonatal-onset epilepsies, nor a timeline for EEG monitoring onset. Serial recordings are mandatory in order to detect pro- that would optimize detection rate in all of these conditions. gressive deterioration (as seen in KCNT1, CDKL5, SLC13A5). However, we think that some general conclusions might be The timing of seizure onset can also provide a first clue to drawn: EEG (and possibly video-EEG) should be started as seizure etiology, and also guide decisions on EEG monitoring. soon as seizures are suspected; age at onset and time evolution Seizures occurring in the first 72 h of life are mainly acute of seizures are factors helping prioritize the list of differential symptomatic, and HIE accounts for the majority of those diagnoses; a full cycle of wakefulness, quiet and active sleep Curr Neurol Neurosci Rep (2020) 20:6 Page 15 of 17 6 have to be recorded in order to have a full picture of the References background and behavioral states organization; typical clini- cal events should be detected, if possible multiple times (as per Papers of particular interest, published recently, have been American Clinical Neurophysiology Society guidelines) [6]in highlighted as: order to get consistent, solid information; EEG data always • Of importance have to be necessarily combined with the overall clinical im- pression on the newborn (normal versus abnormal neurologic 1. 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