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Objective To describe a new phenotype and the diagnostic workup of a vitamin-B6-dependent epilepsy due to pyridoxal 5′-phosphate-binding protein (PLPBP) deficiency in an infant with early-onset epilepsy at the age of 5 years 6 months. Methods Following immediate and impressive clinical response to treatment with pyridoxine, metabolic screening for vitamin-B6-dependent epilepsies and targeted next-generation sequencing (NGS)-based gene panel analysis were performed. Potentially pathogenic variants were confirmed by Sanger sequencing in the patient, and variants were analyzed in both parents to confirm biallelic inheritance. The clinical phenotype and course of disease were compared to the 44 cases reported in the literature, harboring variants in pyridoxal phosphate homeostasis protein (PLPHP) and with cases of vitamin-B6-dependent epilepsy due to other known causative genes. Results Levels of alpha-aminoadipic semialdehyde in urine and amino acids were normal. Two inherited pathogenic variations in PLPHP were found in compound heterozygosity, including one novel deletion. Conclusion We here describe a previously unreported individual harboring biallelic pathogenic PLPHP variants presenting with paroxysmal eye–head movements followed by epileptic spasms and an almost normal interictal electroencephalogram, thus expanding the clinical spectrum of PLPBP deficiency. This warrants consideration of vitamin-B6-dependent epilepsies in patients with early-onset epilepsy, including epileptic spasms, and eye movement disorders also beyond the neonatal period even when metabolic screening for vitamin-B6-dependent epilepsies is negative. PLPHP should be included systematically in NGS epilepsy gene panels.

Neonatal seizures are the most prevalent and distinctive sign of neurologic dysfunction in early life and pose an immense challenge for clinicians. Improvements in neonatal care have increased the survival rate of extremely premature infants, considerably changing the spectrum of underlying etiologies, and instigating a gradual shift from mortality to morbidity. Recognizing neonatal seizures can be challenging due to variability in presentation but clinical features can often provide valuable clues about etiology. Yet, the majority of neonatal seizures are subclinical. Even though conventional electroencephalography (EEG) with simultaneous video detection of seizures still represents the diagnostic gold standard, continuous monitoring using a one- to two-channel amplitude-integrated EEG with concurrent unprocessed EEG can be crucial for early recognition and intervention. Furthermore, tremendous progress has been made in neuroimaging, and all infants with seizures should have a magnetic resonance imaging (MRI) to help identify the underlying etiology. While the majority of neonatal seizures are caused by hypoxic-ischemic events, stroke, hemorrhage, or infection, approximately 15% of patients will require more sophisticated algorithms for diagnostic workup, including metabolic and genetic screening. These recent developments have led to renew interest in the classification of neonatal seizures, which aim to help identify etiology and guide appropriate therapeutic and prognostic decisions. In this review, we outline recent progress made in the etiology, diagnosis, and treatment of neonatal seizures and highlight areas that deserve further research.

Antiquitin deficiency is the most prevalent form of pyridoxine-dependent epilepsy. While most patients present with neonatal onset of therapy-resistant seizures, a few cases with late-onset during infancy have been described. Here, we describe the juvenile onset of epilepsy at the age of 17 years due to antiquitin deficiency in an Indian female with homozygosity for the most prevalent ALDH7A1 missense mutation, c.1279G > C; p.Glu427Gln in exon 14. The diagnosis was established along familial cosegregation analysis for an affected offspring, that had neonatal pyridoxine responsive seizures and had been found to be compound heterozygous for c.1279G > C; p.Glu427Gln in exon 14 and a nonsense mutation c.796C > T; p.Arg266* in exon 9. While seizures in the mother had been incompletely controlled by levetiracetam, she remained seizure-free on pyridoxine monotherapy, 200 mg/day. Her fourth pregnancy resulted in a female affected offspring, who was treated prospectively and never developed seizures with a normal outcome at age 2 years while on pyridoxine. This report illustrates that the phenotypic spectrum of antiquitin deficiency is still underestimated and that this treatable inborn error of metabolism has to be considered in case of therapy-resistant seizures even at older age. It furthermore supports prospective in utero treatment with pyridoxine in forthcoming pregnancies at risk.

Mutations of the SCN2A gene have originally been described in association with benign familial neonatal-infantile seizures (BFNIS). Recently, single patients with more severe phenotypes and persisting epileptic encephalopathies have been recognized. We report the case of a girl with severe infantile onset epileptic encephalopathy and a de novo missense mutation in the SCN2A gene (c.4025T > C/ = ; p.L1342P/ = ), who presented with a transient choreatic movement disorder, hypersomnia, and progressive brain atrophy. Whole exome sequencing did not reveal any other disease causing mutation. Our patient contributes to the expanding phenotypic spectrum of SCN2A-related disorders and underlines the importance of genetic workup in epileptic encephalopathies.

Pyridoxal-5'-phosphate oxidase (PNPO) deficiency is a rare autosomal recessive, vitamin-responsive metabolic disorder causing refractory neonatal seizures that respond to the administration of pyridoxal-5'-phosphate (PLP). There are currently few case studies that have documented the functional outcome in PNPO deficiency, which remains poor in the majority of cases. We present the case of a male infant born at 35 weeks gestation who promptly responded to oral administration of PLP, following resistance to common anticonvulsive therapy and to a pyridoxine trial. Neurological outcome at 21 months is favorable and illustrates the importance of standardized vitamin trials in the acute setting of "therapy-resistant" neonatal seizures. Early recognition of PNPO deficiency and appropriate intervention might be associated with a more favorable outcome than initially considered.

As only 10 - 30 % of patients with a Pelizaeus Merzbacher disease (PMD) phenotype carry mutations of the proteolipid protein (PLP) gene, we were interested if the degree and time-dependent progression of abnormal MRI and MRS findings would discriminate patients with mutations of the PLP gene (Pelizaeus Merzbacher disease, PMD) from patients without a defect of the PLP gene (Pelizaeus Merzbacher-like disease, PMLD). For a standardised intraindividual follow-up and for comparison of the degree of hypomyelination, we have applied a newly developed semiquantitative myelination score on a total of 18 MRI series of 4 PMD and 4 PMLD patients. We found severe hypomyelination (50 % of normal) in 2 PMD and in 2 PMLD patients, moderate hypomyelination (75 % of normal) in 2 PMD and mild hypomyelination (75 % of normal) in 2 PMLD patients. Our score revealed a clear correlation between the degree of hypomyelination and the severity of clinical handicap in PMD but not in PMLD patients. MRS showed heterogeneous cerebral metabolite patterns in both patient groups and seems to reflect a mixture of unspecific changes due to primary hypomyelination and secondary gliosis and demyelination. Neither by MRI nor by MRS were patterns found that would allow differentiation between PMD and PMLD patients.

We report a neonate with brainstem disconnection. Only five similar cases have previously been described, the longest survival was 7 weeks. The newborn exhibited muscular hypertonia, absent suction, insufficient breathing, and seizures. Magnetic resonance imaging showed a disconnection between the upper pons and the medulla oblongata and cerebellar hypoplasia. The basilar artery was not visible. These neuroimaging findings are clearly different from other midbrain or hindbrain malformations with cerebellar hypoplasia. This pattern and a previously reported autopsy point to a malformation, not a disruption.

Rhino-orbito-cerebral mucormycosis is a rare fulminant opportunistic fungal infection that particularly occurs in immunocompromised patients. We present a case of fatal invasive rhino-orbito-cerebral mucormycosis complicated by bilateral thrombotic occlusion of the internal carotid artery with consequent cerebral infarction in a 5-year-old boy after hematopoietic stem cell transplantation for acute pre-B-cell lymphoblastic leukemia.

Introduction: In the general population the incidence of arteriovenous malformations (AVM) is ˜1 per 100.000 per year. About 9% of patients with cerebral vascular lesions suffer from multiple AVMs. Multiple AVMs often become evident during the course of disease. Some patients with multiple AVMs can be assigned to Rendu-Osler-Weber or Parkes-Weber-Syndrom (RASA I). Case report: A 13 y old male patient presented with a swirring noise over the left A. carotis and puls-synchronized tinnitus. CE- angiography revealed a combined durale-piale AVM in the region of the right basal ganglia and brainstem. There were signs of increased intracranial pressure with enlarged lateral ventricles, compressed 4th ventricle and herniation of the cerebellar tonsills. Within a period of 4 years the patient underwent 10 sessions of endovascular therapy (embolisation by coiling). After his 3rd embolisation, a cerebellar AVM became apparent. The 8th embolization was complicated by retroperitoneal bleeding and scrotal hematoma necessitating surgical intervention. Aside from transient hypasthesia of his right upper leg, he was free of neurological symptoms over the following 3 years. At the age of 17y he presented with acute left-sided hemiparesis due to an intracranial bleeding within the basal ganglia of the right hemisphere. He developed posthemorrhagic hydrocephalus needing extracranial drainage followed by a ventriculo-peritoneal shunt. Shunt revision was complicated by subdural and subarachnoidal bleeding and neurologic deterioration. In addition he developed a difficult to treat focal epilepsy. Molecular analysis of the RASA I gene was normal. Conclusion: Despite repeated embolisation this patient with multiple AVMs developed spontaneous intracranial bleeding, posthemorrhagic hydrocephalus and severe neurologic sequelea. Beside this endovascular therapy neurosurgery and stereotactic radiosurgery (e.g. gamma knife) or a combination of these have to be considered to prevent hemorrhages in patients with multiple AVMs.

Introduction: Childhood stroke has an estimated incidence of about 10:100000 per year. Nevertheless stroke is one of the 10 most common causes for death in childhood. We were interested in the mean diagnostic delay and presenting symptoms of pediatric patients referred to our University Hospital. Method: We retrospectively analyzed the history of 16 patients (9 girls, 7 boys) with childhood stroke. Age at presentation varied from 2 months to 17.8 years. Initial symptoms were unspecific with vomiting in 4, collaps 2, headache1 and followed by specific signs of hemiparesis 12, aphasia 3, central facial palsy 2, seizure2, nystagmus 1, vertigo 1. Time delay from onset of symptoms to diagnosis by MRI ranged from 2h to 18 days (mean 58.7h±116). All patients were imaged by a 1.5 Tesla MRI, only 1 child had a CT due to orthodontic therapy. With respect to the vascular territory 9 had ischemic stroke of the medial cerebral artery, 4 of the posterior cerebral artery, 2 of the cerebellar artery. 1 had cerebral sinus venous thrombosis (CSVT). As underlying etiology we identified: heart disease 4, dissection 2, chemotherapy with lung cancer 1, chronic inflammatory bowel disease 1, otitis media 1 (CSVT), post varicella zoster vasculitis 1. Screening for thrombophilia revealed homozygosity for MTHFR(677T) in 2, heterozygosity in 3, positive lupus inhibitor in 2. Conclusions: As illustrated by this cohort the diagnosis of childhood stroke is still associated with marked diagnostic delay despite specific and acute neurologic deficits. Though in childhood stroke the option of lysis is only considered on an individual basis, the critical time window is often elapsed before a diagnosis was made. This illustrates that broader general awareness and logistic guidelines are needed to improve medical care of childhood stroke in pediatric centers.

Propionic acidemia (PA) is an autosomal recessively inherited defect of propionyl-CoA carboxylase with an incidence of approximately 1:50 000. There are few reports on the occurrence of EEG findings and development of epilepsy in patients with PA. Retrospectively, the data of 17 patients with PA from one Italian and four Austrian centers were evaluated concerning EEG findings and the development of epilepsy. Nine patients showed a disturbance of background activity, as well as epileptiform discharges. All nine patients with pathological EEG discharges developed seizures compatible with the definition of symptomatic epilepsy. Five of these nine patients showed fever induced seizures at the beginning. Two of them suffered from symptomatic absence epilepsy. Six of the nine patients with seizures were treated with antiepileptic drugs (AED), which were tolerated without side-effects. Four patients showed photosensitivity, which so far has never been reported in PA. We hypothesize that patients with PA are prone to cortical dysfunction caused by one or several pathological metabolites - leading to changes in background and epileptiform activity with a high manifestation rate of clinical seizures.

We report on a male proband with pyridoxine-dependent epilepsy (PDE) and neonatal seizure onset. At the age of 31 months, a prolonged status epilepticus led to severe neurological regression with cortical blindness, loss of speech and muscular hypotonia with slow recovery over the following 3 months. At 33 months of age pyridoxine therapy was initiated with excellent response and the boy remained seizure-free on pyridoxine monotherapy, except for two occasions with seizure recurrence 10 days after accidental pyridoxine withdrawal. alpha-aminoadipic semialdehyde dehydrogenase (antiquitin) deficiency was indicated by elevated pipecolic acid concentrations in plasma and alpha-aminoadipic semialdehyde excretion in urine. Molecular analysis of the antiquitin gene revealed a novel missense mutation c.57insA, while the mutation of the other allele remained unidentified so far. Despite the delay in diagnosis and prolonged status epilepticus, neuropsychological evaluations at the ages of 11 and 18 years demonstrated full-scale IQ of 93 and 92, respectively, with better verbal IQ (103 and 101) than performance IQ (85 and 82).

Introduction: In the diagnostic work-up of unclear neurologic diseases many biochemical tests are routinely performed in the metabolic screening. Among these homocysteine is less well established and hyperhomocysteinemia is not detected by newborn screening programs. Nevertheless hyperhomocysteinemia serves as a reliable diagnostic marker for a variety of treatable enzyme defects in folate- cobalamin- and methionine metabolism, which may present with a broad spectrum of neurologic and haematologic symptoms. We report on a patient with a rare remethylation defect. Case history: 2nd child of a healthy, consanguineous couple from Austria. Pregnancy and delivery were uneventful. By the end of the 1st year ataxic gait was evident. A cranial MRI was normal. In the 3rd year of life the child exhibited acute neurologic deterioration in the course of pneumonia, leading to respiratory failure and mechanical ventilation. Cranial MRI showed global brain atrophy and a non-recent thrombosis of the saggital sinus, while the myelon was normal. Due to pancytopenia and macrocytic anemia plasma folic acid and cobalamin were measured but gave normal results, methylmalonic acid in urine was normal. Plasma homocysteine in serum was markedly elevated to 188µmol/l. Plasma methionine was as low as 3µmol/l, pointing towards a remethylation defect. Treatment with daily injections of hydroxycobalamin, 1mg and oral supplementation of folate, 10mg and betaine, 200mg/kg/day lead to rapid normalisation of blood count, plasma homocysteine and plasma aminoacids. Also from the neurologic point of view the child showed continuous improvement but 6 weeks after initiation of specific treatment, is still not able to walk independently. Conclusions: In view of the clinical and biochemical findings our patient suffers from a remethylation defect (most likely cobalamine E/G deficiency); biochemical and complementation studies are pending. Despite treatment options with cofactor- and betaine supplementation diagnostic delay bears the risk of irreversible brain damage and spinal cord d egeneration.