Refractory Neonatal Seizures Research Articles

Pearls & Oy-sters: Delayed Response to Pyridoxine in Pyridoxine-Dependent Epilepsy.

Inborn errors of metabolism are a diverse group of genetic disorders including many that cause neonatal-onset epilepsy such as pyridoxine-dependent epilepsy (PDE). PDE occurs secondary to biallelic pathogenic variants in ALDH7A1 and can present with refractory neonatal seizures and status epilepticus. Neonatal seizures and encephalopathy are modifiable with pyridoxine (vitamin B6) supplementation. However, the clinical response to pyridoxine supplementation can be delayed. We present the case of a full-term neonate with PDE in which seizure cessation was seen a few hours after intravenous pyridoxine load, but the improvement in EEG background and level of clinical encephalopathy occurred five days later. We share this case to provide an example in which clinical improvement in PDE was gradual and required continuation of treatment for several days illustrating the necessity of continuing vitamin B6 supplementation in suspected cases until confirmatory genetic testing is obtained or an alternate cause is found.

Comment: Amenable Treatable Severe Pediatric Epilepsies

Phillip L. Pearl Seminars in Pediatric Neurology Volume 23, Issue 2, May 2016, Pages 158-166 Vitamin-dependent epilepsies and multiple metabolic epilepsies are amenable to treatment that markedly improves the disease course. Knowledge of these amenably treatable severe pediatric epilepsies allows for early identification, testing, and treatment. These disorders present with various phenotypes, including early onset epileptic encephalopathy (refractory neonatal seizures, early myoclonic encephalopathy, and early infantile epileptic encephalop athy), infantile spasms, or mixed generalized seizure types in infancy, childhood, or even adolescence and adulthood. The disorders are presented as vitamin responsive epilepsies such as pyridoxine, pyridoxal-5-phosphate, folinic acid, and biotin; transportopathies like GLUT-1, cerebral folate deficiency, and biotin thiamine responsive disorder; amino and organic acidopathies including serine synthesis defects, creatine synthesis disorders, molybdenum cofactor deficiency, and cobalamin deficiencies; mitochondrial disorders; urea cycle disorders; neurotransmitter defects; and disorders of glucose homeostasis. In each case, targeted intervention directed toward the underlying metabolic pathophysiology affords for the opportunity to significantly effect the outcome and prognosis of an otherwise severe pediatric epilepsy.

A Rare Cause of Developmental Epileptic Encephalopathy: D-Bifunctional Protein Deficiency with a Novel Pathogenic Variant

Abstract Peroxisomal disorders are rare causes of severe neonatal encephalopathies. Here we report a two-month old infant with refractory neonatal seizures evaluated with first-step metabolic screening in the neonatal intensive care unit. The screening did not indicate the inborn error of metabolism. In a series of electroencephalography (EEG) studies, multifocal epileptic discharges and electroclinic seizures were observed, suggesting epileptic encephalopathy. The analysis of plasma very-long-chain fatty acids indicated a peroxisomal disorder. Then a next-generation DNA sequencing panel of epileptic encephalopathy provided a D-Bifunctional Protein Deficiency (D-BP) with a novel mutant gene. The epilepsy panels with next-generation DNA sequencing, after the primarily metabolic screening for the differential diagnosis of early infantile epileptic encephalopathy, provide guidance for a definitive diagnosis. Next-generation genetic studies are essential in identifying subtypes of peroxisomal disorders because they have similar very-long-chain fatty acid levels and dysmorphic findings.

Autosomal Recessively Inherited Glucose Transporter-1 Deficiency Syndrome with Acanthocytosis: A Case Report

AbstractGlucose transporter-1 deficiency syndrome (GLUT-1DS) is a rare, autosomal dominantly inherited disorder due to a heterozygous mutation in the gene solute channel 2A1 (SLC2A1).This gene encodes the glucose transporter protein-1. Autosomal recessive inheritance is extremely rare. Similarly, only very few reports are found in the literature of hematological manifestations in this syndrome. We report an autosomal recessively inherited GLUT-1DS, due to a de novo mutation, with the classical infantile presentation associated with concomitant acanthocytosis. In this case report, the second child born to consanguineous parents with initial refractory neonatal seizures and subsequent poorly controlled epilepsy and developmental regression is discussed. The most notable investigation findings supportive of his underlying diagnosis were very low cerebrospinal fluid (CSF) glucose and CSF lactate levels. His CSF:plasma glucose ratio was 1:7.6. He was anemic with a hemoglobin of 8.8 g/dL with his blood film showing marked acanthocytosis. His elder brother who also had refractory epilepsy and developmental regression had similar hypoglycorrhachia, low CSF:plasma glucose ratio, and mild anemia with acanthocytosis, and he died before establishment of a diagnosis. Our patient was diagnosed to have a novel mutation SLC2A1 c.184A > G p.(Thr62Ala), for which both parents were heterozygous, confirming autosomal recessive inheritance. Commencement of a ketogenic diet resulted in improvement of his seizures and slow gain in development. It also resulted in gradual disappearance of acanthocytes from his peripheral blood. This case describes a rare case of classical GLUT-1DS, autosomal recessively inherited, due to a novel mutation. The acanthocytosis in his blood smear is another rare association minimally reported in GLUT-1DS. The cause of his abnormal red blood cell morphology is unclear. It is possibly related to cation leakage reported in some rare mutations of the SLC2A1 gene needs reference.

Tolerability and Safety of Lacosamide in Neonatal Population.

Lacosamide is a newer antiepileptic medication used in refractory neonatal seizures with limited safety and efficacy data. This case series spans 4 years and includes 38 neonates cared for in the neonatal, pediatric, and cardiovascular intensive care units, who received lacosamide for refractory seizures. Because lacosamide affects atrioventricular node function in adults, among other metrics, electrocardiogram (ECG) changes were monitored closely in these neonates. Within this cohort, 2 neonates were found to have atrial bigeminy on ECG and telemetry. Otherwise, lacosamide was generally well tolerated with sleepiness being the most common symptom noted. This case series reports data on the tolerability of lacosamide and emphasizes the importance of monitoring key cardiac intervals with ECG before and after the use of lacosamide in this population.

Early Myoclonic Infantile Encephalopathy in Neonate Caused by 5-Oxoprolinuria, a Rare Metabolic Entity: A Case Report

Neonatal encephalopathy is a common entity encountered by treating physicians in any neonatal intensive care unit. Though hypoxic ischaemic encephalopathy is the most frequent cause in developing countries, metabolic causes should also be looked for in refractory neonatal seizures with sibling death and parental consanguinity. Early myoclonic infantile encephalopathy, considered under the broad spectrum of infantile encephalopathy, is a rare syndrome in infants with onset within 3 months of age. It is characterized by myoclonic seizures, features of encephalopathy and caused by underlying metabolic diseases, nonketotic hyperglycinemia being the most common cause. On contrary its close mimicker, Ohtahara syndrome or early infantile epileptic encephalopathy is most likely associated with structural neurological lesions. We report a 12-day term Indian male neonate, born of second degree consanguinity with multiple sibling death history, presented with refractory myoclonic seizures in spite of uneventful birth history. Myoclonic seizures, refractory to intravenous phenobarbitone, phenytoin and infusion Midazolam, persisted after ruling out hypoglycemia, dyselectrolytemia, and neonatal sepsis. EEG showed typical burst suppression pattern pointing towards diagnosis of early myoclonic infantile encephalopathy. Further metabolic causes were looked for but tandem mass spectrometry for dried blood sample was normal. Lastly, urinary GCMS revealed 5-oxoprolinuria, an autosomal recessive condition, characterized by acidosis, jaundice, and severe hemolytic anemia among neonates, primarily due to glutathione synthetase enzyme deficiency. In severe form of 5-oxoprolinuria, neurological complications in form of seizures, ataxia have been documented in earlier studies; however, its association with myoclonic encephalopathy is yet to be reported in the literature and this report may be the first of its kind.

Suspected SCN1A gain of function mutation causing refractory neonatal seizures responsive to sodium channel blocking antiepileptics (P6-8.006)

Suspected SCN1A gain of function mutation causing refractory neonatal seizures responsive to sodium channel blocking antiepileptics (P6-8.006)

Multicystic Brain and Refractory Neonatal Seizures

Multicystic Brain and Refractory Neonatal Seizures

Topiramate Is Safe for Refractory Neonatal Seizures: A Multicenter Retrospective Cohort Study of Necrotizing Enterocolitis Risk

BackgroundA previously published, single-institution, case series suggested an association between topiramate administration in neonates and subsequent development of necrotizing enterocolitis (NEC). This contradicted our more extensive experiences using topiramate in this population. We therefore studied safety and tolerability of topiramate for treating refractory neonatal seizures, hypothesizing that the risk of developing NEC following topiramate exposure was low and that most infants tolerate topiramate. MethodsThis multicenter retrospective cohort study included seventy-five neonates who received topiramate to treat seizures from January 2011 to October 2019 at three geographically diverse level IV neonatal intensive care units affiliated with pediatric tertiary hospitals. Data included demographics, birth history, seizure etiology, treatment response, side effects, and occurrence and details of NEC. ResultsThree of seventy-five infants (4%) developed NEC following topiramate exposure. These infants did not differ in gestational age, birth weight, seizure etiology, postmenstrual age, weight when topiramate was initiated, or dosing of topiramate. Topiramate was well tolerated. Only three infants (4%) discontinued due to side effects. The most common side effect (20%) was weight loss (typically <5%). Topiramate was felt to be efficacious (61%). Most infants (72%) continued topiramate when discharged. ConclusionsOur multicenter, 75-infant study demonstrated that development of NEC after treatment with topiramate was rare (4%) and refutes prior literature suggesting an association. Topiramate was felt to be efficacious and was well tolerated. Although limited by retrospective design, study data are broadly applicable and support thoughtful use of topiramate as a safe, reasonable option for treating refractory neonatal seizures.

Targeting ischemia-induced KCC2 hypofunction rescues refractory neonatal seizures and mitigates epileptogenesis in a mouse model.

Neonatal seizures pose a clinical challenge in their early detection, acute management, and long-term comorbidities. They are often caused by hypoxic-ischemic encephalopathy and are frequently refractory to the first-line antiseizure medication phenobarbital. One proposed mechanism for phenobarbital inefficacy during neonatal seizures is the reduced abundance and function of the neuron-specific K+/Cl− cotransporter 2 (KCC2), which maintains chloride homeostasis and promotes GABAergic inhibition upon its phosphorylation during postnatal development. Here, we investigated whether this mechanism is causal and whether it can be rescued by KCC2 functional enhancement. In a CD-1 mouse model of refractory ischemic neonatal seizures, treatment with the KCC2 functional enhancer CLP290 rescued phenobarbital efficacy, increased KCC2 abundance, and prevented the development of epileptogenesis, as quantified by video electroencephalogram monitoring. These effects were prevented by knock-in expression of nonphosphorylatable mutants of KCC2 (S940A or T906A and T1007A), indicating that KCC2 phosphorylation regulates both neonatal seizure susceptibility and CLP290-mediated KCC2 functional enhancement. Our findings therefore validate KCC2 as a clinically relevant target for refractory neonatal seizures and provide insights for future drug development.

TrkB agonists prevent postischemic emergence of refractory neonatal seizures in mice.

Refractory neonatal seizures do not respond to first-line antiseizure medications like phenobarbital (PB), a positive allosteric modulator for GABAA receptors. GABAA receptor-mediated inhibition is dependent upon electroneutral cation-chloride transporter KCC2, which mediates neuronal chloride extrusion and its age-dependent increase and postnatally shifts GABAergic signaling from depolarizing to hyperpolarizing. Brain-derived neurotropic factor-tyrosine receptor kinase B activation (BDNF-TrkB activation) after excitotoxic injury recruits downstream targets like PLCγ1, leading to KCC2 hypofunction. Here, the antiseizure efficacy of TrkB agonists LM22A-4, HIOC, and deoxygedunin (DG) on PB-refractory seizures and postischemic TrkB pathway activation was investigated in a mouse model (CD-1, P7) of refractory neonatal seizures. LM, a BDNF loop II mimetic, rescued PB-refractory seizures in a sexually dimorphic manner. Efficacy was associated with a substantial reduction in the postischemic phosphorylation of TrkB at Y816, a site known to mediate postischemic KCC2 hypofunction via PLCγ1 activation. LM rescued ischemia-induced phospho-KCC2-S940 dephosphorylation, preserving its membrane stability. Full TrkB agonists HIOC and DG similarly rescued PB refractoriness. Chemogenetic inactivation of TrkB substantially reduced postischemic neonatal seizure burdens at P7. Sex differences identified in developmental expression profiles of TrkB and KCC2 may underlie the sexually dimorphic efficacy of LM. These results support a potentially novel role for the TrkB receptor in the emergence of age-dependent refractory neonatal seizures.

Oral Levetiracetam as Add-On Therapy in Refractory Neonatal Seizures.

Seizure is the most common signs of nervous system disease in neonates. The first line of treatments in neonatal seizures (after ruling out and emergency treatment of electrolyte imbalance and hypoglycemia) are phenobarbital and phenytoin. We aimed to evaluate drugs that are more effective on neonatal seizure. Patients admitted to neonatal wards & NICUs (level IIa&IIb) in Qom hospitals (2015-2017), central Iran with presentation of seizure, were enrolled in this clinical trial study. After ruling out electrolyte imbalance and hypoglycemia these neonates were managed by intravenous phenobarbital, then if no response was seen we added intravenous phenytoin and for remaining neonates with refractory seizure we applied oral levetiracetam as add on therapy. The study was registered as code number of IRCT2016051527896N1. Initially, 245 neonates were enrolled. According to exclusion criteria, 12 cases were excluded, and phenobarbital was prescribed to the remaining patients. Out of these, 86 patients did not respond, and phenytoin was prescribed for them. Forty two patients who were not responding to phenytoin were finally treated with oral levetiracetam. Finally, 95.3% of seizures were controlled with oral levetiracetam but 4.7% were not cured. When the intravenous form of levetiracetam is not available and neonatal seizure does not respond to first line classic drugs, oral levetiracetam as add on therapy maybe effective.

A Review on Pharmacokinetics of Levetiracetam in Neonates.

Neonatal seizures are the most common clinical manifestation of Central Nervous System (CNS) dysfunction and are associated with various neurological sequelae. There are currently no evidence-based guidelines for the management of neonatal seizures and currently used drugs such as phenobarbital, and phenytoin have limited efficacy and potential toxicities. Newer second line anticonvulsant, levetiracetam, has been used in refractory neonatal seizures despite limited data and off-label use. In this review, we will discuss various pharmacological properties of levetiracetam when used in neonatal population. A PubMed search for MEDLINE was undertaken to look for studies using the terms "Levetiracetam", AND "Neonates" as key words from year 1995 to January 2017. Relevant articles were selected and information was extracted about pharmacokinetics, pharmacodynamics and clinical uses of levetiracetam in neonates. Levetiracetam is an active, water-soluble S-enantiomer of racemic pyrrolidine acetamide which exerts its antiepileptic action by binding to the synaptic vesicle protein within the brain. Metabolism of levetiracetam does not include the CYP P450 system and it is mainly eliminated through kidneys after rapid absorption. Also, no significant interactions with other drugs have been identified. Unlike other commonly used antiepileptic drugs, levetiracetam is not bound to plasma proteins, thereby, reducing the chances of toxicity and severe, life threatening side effects have not been reported. In fact, it has been shown to prevent neuro-degeneration after hypoxia/ischemia in rodent models of epilepsy. Levetiracetam has been emerging as a potential therapeutic option for refractory neonatal convulsions owing to its non-hepatic elimination, linear pharmacokinetics, low protein binding and better safety profile.

Punctate white matter lesions in full-term infants with neonatal seizures associated with SLC13A5 mutations.

Early-onset epileptic encephalopathy caused by biallelic SLC13A5 mutations is characterized by seizure onset in the first days of life, refractory epilepsy and developmental delay. Little detailed information about the brain MRI features is available in these patients. Observational study describing the neuro-imaging findings in eight patients (five families) with mutations in the SLC13A5 gene. Seven infants had an MRI in the neonatal period, two had a follow-up MRI at the age of 6 and 18 months and one only at 13 months. One patient had follow-up MRIs at 11 and 16 months and 3 and 6 years of age, but no neonatal MRI. All patients presented with refractory neonatal seizures on the first day of life after an uncomplicated pregnancy and term delivery. Six out of seven infants with a neonatal MRI had a characteristic MRI pattern, with punctate white matter lesions (PWML), which were no longer visible at the age of 6 months, but led to gliotic scarring visible on MRI at the age of 18 months. The same pattern of gliotic scarring was seen on the MRIs of the infant without a neonatal scan. One infant had signal abnormalities in the white matter suspected of PWML on T2WI, but these could not be confirmed on other sequences. In infants presenting with therapy resistant seizures in the first days after birth, without a clear history of hypoxic-ischemic encephalopathy, but with PWML on their neonatal MRI, a diagnosis of SCL13A5 related epileptic encephalopathy should be considered.

Amenable Treatable Severe Pediatric Epilepsies

Vitamin-dependent epilepsies and multiple metabolic epilepsies are amenable to treatment that markedly improves the disease course. Knowledge of these amenably treatable severe pediatric epilepsies allows for early identification, testing, and treatment. These disorders present with various phenotypes, including early onset epileptic encephalopathy (refractory neonatal seizures, early myoclonic encephalopathy, and early infantile epileptic encephalopathy), infantile spasms, or mixed generalized seizure types in infancy, childhood, or even adolescence and adulthood. The disorders are presented as vitamin responsive epilepsies such as pyridoxine, pyridoxal-5-phosphate, folinic acid, and biotin; transportopathies like GLUT-1, cerebral folate deficiency, and biotin thiamine responsive disorder; amino and organic acidopathies including serine synthesis defects, creatine synthesis disorders, molybdenum cofactor deficiency, and cobalamin deficiencies; mitochondrial disorders; urea cycle disorders; neurotransmitter defects; and disorders of glucose homeostasis. In each case, targeted intervention directed toward the underlying metabolic pathophysiology affords for the opportunity to significantly effect the outcome and prognosis of an otherwise severe pediatric epilepsy.

Pyridoxine responsive epilepsy caused by a novel homozygous PNPO mutation

We report a patient with anti-epileptic treatment refractory neonatal seizures responsive to pyridoxine. Biochemical analysis revealed normal markers for antiquitin deficiency and also mutation analysis of the ALDH7A1 (Antiquitin) gene was negative. Mutation analysis of the PNPO gene revealed a novel, homozygous, presumed pathogenic mutation (c.481C>T; p.(Arg161Cys)). Measurements of B6 vitamers in a CSF sample after pyridoxine administration revealed elevated pyridoxamine as the only metabolic marker for PNPO deficiency. With pyridoxine monotherapy the patient is seizure free and neurodevelopmental outcome at the age of 14months is normal.

EPILEPSY IN INBORN ERRORS OF METABOLISM

Epilepsy is a frequent and sometimes leading symptom in inborn errors of metabolism, especially in neonatal or infantile ones. Early myoclonic encephalopathy and myoclonus as a seizure type are the prototypes of epilepsy in inherited metabolic diseases. But clinical presentation also includes refractory neonatal seizures, Ohtahara syndrome, infantile spasms and progressive myoclonic epilepsy. Clinical manifestations seems to be similar in different etiology and in majority of cases look like unspecific epileptic encephalopathy. Selected treatable inborn errors of metabolism are discussed alongside with diagnostic approach to inherited metabolic epilepsies. Probably it’s better to avoid the treatment with valproic acid in clinical situations when etiology is unclear. Alternative use of levetiracetam is recommended. Besides the antiepileptic drugs we can also make pyridoxine, pyridoxal-5-phosphate and folinic acid consequent trials for 3-5 days before our diagnostic quest succeed.

Neonatal Seizures and Inborn Errors of Metabolism: An Update

Early identification of an underlying inborn error of metabolism in newborns with otherwise unexplained seizures may address appropriate disease-specific treatment and provide important tools about the choice of the antiepileptic drugs. Neonatal seizures usually present as prolonged or recurrent, often configuring epileptic status. Striking features of an underlying metabolic disorder include abnormal neurological examination, lethargy and/ or symptoms of acute decompensation. Ex adiuvantibus, trial with intravenous pyridoxine administration could be attempted in refractory unexplained neonatal seizures. Peculiar EEG patterns such as Suppression Burst may address diagnosis and laboratory work-up being most frequently associated to specific metabolic disorders.

Valproate-induced hyperammonaemic encephalopathy in a neonate: Treatment with carglumic acid

Valproate-induced hyperammonemic encephalopathy (VHE) is an unusual and serious complication of valproate (VA) treatment. When an early diagnosis is made, it can be reversed with VA withdrawal and early treatment for hyperammonemia. We describe the case of a 20 days old male, who developed a serious VHE after receiving VA for refractory neonatal seizures. The VHE was resolved with VA withdrawal in association with carglumic acid and other measures for hyperammonemia treatment.

Pyridoxine or pyridoxal-5′-phosphate for neonatal epilepsy

The discovery of the cause of pyridoxine-dependent epilepsy (PDE), a unique autosomal recessive and treatable cause of refractory neonatal seizures, came 50 years after its first description with the identification of ALDH7A1 mutations leading to deficiency of the enzyme α-aminoadipic semialdehyde dehydrogenase (antiquitin).1 Dysfunction of this enzyme interferes with lysine degradation and leads to accumulation of a carboxylate product that irreversibly inactivates pyridoxal-5′-phosphate (PLP), the biologically active form of vitamin B6.