Febrile infection-related epilepsy syndrome (FIRES) is a severe postinfectious epileptic encephalopathy in previously healthy children and has three phases: the initial phase with a simple febrile infection, a few days later the acute phase characterized by a peracute onset of highly recurrent seizures or refractory status epilepticus often with no more fever and generally without additional neurological features (the classical pure seizure phenotype), and last, the chronic phase with a drug-resistant epilepsy and neuropsychological impairments. FIRES seems to be sporadic and very rare: we estimated the annual incidence in children and adolescents by a prospective hospital-based German-wide surveillance as 1 in 1,000,000. Because of the preceding infection and lacking evidence of infectious encephalitis, an immune-mediated pathomechanism and, therefore, a response to immunotherapies may be involved. To test the hypothesis that antibodies against neuronal structures cause FIRES, we analyzed sera of 12 patients aged 2 to 12 years (median 6 years) and cerebral spinal fluids (CSFs) of 3 of these 12 patients with acute or chronic FIRES. We studied six patients (two including CSF) 1 to 14 weeks (median 3 weeks) and six patients 1 to 6 years (median 3.5 years) after seizure onset. All samples were analyzed for antibodies against glutamate receptors of type N-methyl-D-aspartate (NMDA) and type α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), gamma-aminobutyric acid (GABA)B-receptors, voltage-gated potassium channel (VGKC)-associated proteins leucin-rich glioma inactivated 1 (LGI1) and contactin-associated protein like 2 (CASPR2), and glutamic acid decarboxylase (GAD) by a multiparametric recombinant immunofluorescence assay employing human embryonic kidney (HEK) cells transfected with cDNAs for the antigens. In addition, indirect immunohistochemistry using rat whole-brain sections was done in three patients. Finally, sera of 10 patients were tested for VGKC complex antibodies by radioimmunoprecipitation assay (RIA). None of the antibody tests were positive in any of the patients. Moreover, steroids, immunoglobulins, and plasmapheresis had no clear effect in the seven patients receiving immunotherapy. The failure of antibody-detection against the known neuronal antigens as well as the ineffectiveness of immunotherapy questions a role for autoantibodies in the epileptogenesis of classical FIRES. As we discuss, other underlying causes need to be considered including the possibility of a mitochondrial encephalopathy.

Measurements of the optic nerve sheath diameter (ONSD) by bedside ultrasound have been shown to correlate with increased intracranial pressure (ICP). Kimberly et al (Acad Emerg Med 2008) showed a correlation of ONSD >5mm with an increased ICP >20 mmH2O. Headaches are a common symptom in neuropediatric patients. Differenzial diagnosis according intracranial processes often reveals to be challenging.

The X chromosomal defect of creatine transport is a rare disease affecting boys. Clinical presentation is unspecific with developmental delay, retarded speech development and autistic behavior. The lack of the short time energy supplying molecule creatinephosphat disturbs brain development. Current therapeutic strategies focus on stimulation of local synthesis by increasing the availability of the metabolic precursor's agrinine and gycine. Case: We report about a now 4 year old German boy of healthy parents, who presented with delay in developmental mile stones, focusing on speech delay and autistic, hyperactive behavior. Mile stones: walking 20 month, no Speech until 3 years. Physical examination at age of 2 years showed slightly decreased muscle tone. EEG was normal. Cranial MRI showed hyper intensity in T2 and FLAIR bilateral in tegmentum pontis and peritrigonal. MR-Spectroscopy revealed a lack of ceratine/phosphocreatine (C/PC) in the brain. Urinary excretion of creatine was increased in two specimens but normal in two others. Molecular genetic testing of the SLC6A8 gene revealed a stop codon at position 566 of the X chromosomal, also hemizygote in the mother. Therapy was started creatine 400mg/kg, arginine 400mg/kg and glycine 400mg/kg at the age of 3 years 6 month. In the following 7 month the parents noticed positive changes and reported of increasing attention, decreasing of hyperactivity and success in speech development resulting in the first spoken words with 4 years. MRS showed a slight increase in C/PC under therapy. There were no side effects. Discussion: Creatine transporter deficiency is a rare disease, but seems to be under diagnosed, because of its unspecific clinical presentation. MRS is no routine diagnostic method and urinary excretion, as reported, is uncertain, because of the influence of dietary intake of creatine. MRI in our patient revealed lesions in the brain stem not been reported before. Treatment with arginine was reported by Fons at al. in adolescent patients having no effect and by Chilosi at al. with positive effects on behavior. The basic mechanism of disease seems to influence negatively brain development especially in first years of live, which cannot be recovered later. The early diagnosis and treatment therefore seems to have equal effects as seen in other metabolic disease like PKU or hypothyroidism.

The mitochondrial phosphate carrier SLC25A3 transports inorganic phosphate into the mitochondrial matrix, which is essential for the aerobic synthesis of adenosine triphosphate (ATP). We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life. Functional investigation of intact mitochondria showed a deficiency of ATP synthesis in muscle but not in fibroblasts, which correlated with the tissue-specific expression of exon 3A in muscle versus exon 3B in fibroblasts. The enzyme defect was confirmed by complementation analysis in yeast. This is the first report of patients with mitochondrial phosphate-carrier deficiency.

Introduction: Methotrexate (MTX) is one of the most widely used chemotherapeutic agents and the major component in the treatment of acute lymphoblastic leukaemia (ALL) in childhood. In isolated cases it may cause acute neurotoxicity, the pathogenesis of which is not completely understood. From a metabolic point of view, an underlying cause may be an effect on pterine synthesis and therefore the levels of biogenic amines (neurotransmitter (NT)) could also be affected because the pterines are used as cofactors in the synthesis of biogenic amine neurotransmitters. The aim of the study was to evaluate prospectively the concentration of biogenic amine NT in CSF in patients with ALL under the therapeutic protocoll (ALL-BFM2000) to explain the hypothesis that MTX affects the synthesis of pterines and therefore the concentration of NT.

BACKGROUND Glial neoplasms can infiltrate the central nervous system extensively with relative preservation of the underlying neuronal architecture. The differential diagnosis between cerebral glioma and infective lesions can be very difficult to distinguish by MRI only. CASE REPORT We report a 7 year old boy with recurrent vomiting, fever, weakness, abdominal pain and diarrhea. Besides an expressive speech disturbance the neurological examination showed no pathological findings. The sonography revealed discrete hepatomegaly and small pericardial effusion. MRI showed a diffuse mesencephalic and pontine swelling without contrast medium enhancement possibly pointing to an infective lesion. Microbiological, serological and metabolic investigations of blood and CSF were normal. After initial improvement associated with antibiotic, antiviral and dexamethasone treatment the process relapsed progessively. The 1H-MR-spectroscopy showed elevated cholin and decreased N-acetyl-aspartate levels suspicious for a proliferating process. Brain biopsy revealed anaplastic astrocytoma (WHO III). Despite of radiation and chemotherapy the tumordisease deteriorated and the patient died because of progressive brainstem infiltration one year later. CONCLUSION This case report shows that cerebral glioma can mimick infective brain disease and that MR-spectroscopy is an important non-invasive tool in this differential diagnosis.

Background: L-2-Hydroxyglutaric aciduria is a rare inborn error of metabolism characterised clinically by ataxia, psychomotor delay and epilepsy and biochemically by increased urinary excretion of L-2-hydroxyglutaric acid. The disease was first described by Duran et al in 1980.

Ketogenic Diet is indicated in pharmacoresistent epilepsy, but seems to be contraindicated in urea cycle defects, because metabolic changes are comparable to a fast. Alternatively, administration of 3-β-Hydroxybutyrate (BHB) is discussed. D/L BHB is successfully used in few patients with hypoketotic neurometabolic disorders like Glutaric aciduria type II.

Diagnosis of muscle eye brain disease is based on clinical symptoms and grouped in congenital muscular dystrophies because of the myopathy. Recent researches showed in some patients a mutant glycosyltransferase located in the PomGnT1 gene and allowed classifying to the family of glycosylation deficiency.

Background: Mycoplasma pneumoniae (Mp) central nervous system complications are reported to be the most common extrapulmonary manifestations occuring in 0.01–4.8% of Mp infected patients.

Objectives: Protein S-100B is a brain specific protein. In case of astro-glial damage with consecutive disturbance of the haematoencephalic barrier the serum protein S-100B concentration is increased.

Dystonia is a common neurological disorder, but its pathophysiological basis is poorly understood. Primarily dystonic movement disorders seem to be related to basal ganglia and the biogenic amine system of neurotransmission. Pharmacological therapy is governed by personal experience, often resulting in drug cocktails. The use of gabapentin has been sporadically reported for the treatment of dystonia. Patients: We report on two patients with severe Levodopa non-responsive torsion dystonia as a symptom of an underlying neurodegenerative disorder. Both patients demonstrated impressive improvement on gabapentin treatment with a decrease in dystonia attacks from hundreds per day to remission. The CSF amino acid pattern of both patients revealed an increased concentration of glutamine and decreased concentrations of branched chain amino acids (BCAA). Discussion: These results may indicate an increased central nervous system glutamine/glutamate synthesis at the expense of BCAA via the major synthesizing pathway, the astrocytal branched chain aminotransferase, an enzyme which is inhibited by gabapentin. While both patients had a drug history including GABAergic substances like vigabatrin and baclofen with no effect on the dystonia, we suggest that gabapentin is effective by decreasing glutamate/glutamine synthesis. This is supported by the normalization of glutamine and BCAA in CSF during gabapentin treatment. Based on these observations, we conclude that analysis of CSF glutamine and BCAA may be useful in monitoring gabapentin treatment in patients with dystonia.

Patients with propionic acidemia (PA) suffer from recurrent metabolic crisis presenting with metabolic acidosis and hyperammonemia. Therefor the neurological presentation with somnolence/coma mostly is related to acute metabolic decompensation. Damaging of the basal ganglia can happen during these episodes. Besides toxicity of ammonia and organic acids secundary mitochondrial dysfunction is discussed to play a role in this neurotoxicity of the basal ganglia.

In patients with propionic aciduria, the accumulating metabolite propionyl-CoA causes a disturbance of the urea cycle via the inhibition of N-acetylglutamate synthesis. Lack of this allosteric activator results in an inhibition of carbamoylphosphate synthase (CPS). This finally leads to hyperammonaemia. In two patients with decompensated propionic aciduria the CPS activator carbamylglutamate was tested for its ability to antagonize the propionyl-CoA associated hyperammonaemia. Oral carbamyl glutamate administration resulted in a significant increase in ammonia detoxification and could avoid further dialysis therapy. Safe, fast and easy to administer, carbamyl glutamate improves the acute therapy of decompensated propionic aciduria by increasing ammonia detoxification and avoiding hyperammonaemia.

In the central nervous system (CNS) the glucoplastic amino acid glutamate (Glu) functions as the major excitatory neurotransmitter. Besides this Glu also reveals excitotoxic effects that are discussed in the pathogenesis of several neurometabolic diseases. In CNS Glu is carefully compartmentalized and inactivated to glutamine (Gln) which is found in high amounts in CSF. CNS Glu synthesis occurs in astrocytes where it is connected to the Krebs cycle and the branched chain amino acids (BCAA) via BCAA amino transferase.

Epidermoid cyst in the spinal cord is a rare condition. The majority arise in the cerebellopontine angle or parasellar. They are considered malformations due to incorporation of ectoderm into the folds of the developing nervous system at the time of closure of the neural tube (3.-5. gestational week). They consist of delicate connective-tissue capsule lined by laminated squamous epithelium filled with keratin. In the majority they are associated by further dysrhaphic malformations like dermalsinus, which can be the cause for secondary infection.

Deficiency of 3-methylcrotonyl-CoA carboxylase (MCC) results in elevated excretion of 3-methylcrotonylglycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA). MCC is a heteromeric mitochondrial enzyme comprising biotin-containing alpha subunits and smaller beta subunits, encoded by MCCA and MCCB, respectively. Mutations in these genes cause isolated MCC deficiency, an autosomal recessive disorder with a variable phenotype that ranges from severe neonatal to asymptomatic adult forms. No reported patients have responded to biotin therapy. Here, we describe two patients with a biochemical and, in one case, clinical phenotype of MCC deficiency, both of whom were responsive to biotin. The first patient presented at 3 months with seizures and progressive psychomotor retardation. Metabolic investigation at 2 years revealed elevated excretion of 3-MCG and 3-HIVA, suggesting MCC deficiency. High-dose biotin therapy was associated with a dramatic reduction in seizures, normalization of the electroencephalogram, and correction of the organic aciduria, within 4 weeks. MCC activity in fibroblasts was 25% of normal levels. The second patient, a newborn detected by tandem-mass-spectrometry newborn screening, displayed the same biochemical phenotype and remained asymptomatic with biotin up to the age of 18 months. In both patients, sequence analysis of the complete open reading frames of MCCA and MCCB revealed heterozygosity for MCCA-R385S and for the known polymorphic variant MCCA-P464H but revealed no other coding alterations. MCCA-R385S is unusual, in that it has a normal amount of MCC alpha protein but confers no MCC activity. We show that MCCA-R385S, but not other MCCA missense alleles, reduces the MCC activity of cotransfected MCCA-wild-type allele. Our results suggest that MCCA-R385S is a dominant negative allele and is biotin responsive in vivo.