Multicenter retrospective study of patients with PCDH19-related epilepsy: The first Hungarian cohort.

OBJECTIVE: PCDH19-related epilepsy occurs predominantly in girls and is caused by pathogenic variant of the protocadherin-19 gene. The initial seizures usually develop in association with fever, begin on average at 15 months of age, and often occur in clusters. Autistic symptoms, intellectual disability, and sleep disturbance are often associated. METHODS: In our retrospective, multicenter study, we reviewed clinical data of nine children with epilepsy genetically confirmed to be associated with PCDH19. RESULTS: In the Hungarian patient population aged 0-18 years, the prevalence of PCDH19-related epilepsy was found to be lower (1/100000 live births in females) than the reported international data (4-5/100000 live births in females). Four of our nine patients had positive family history of epilepsy (cousins, sister, and mother). We assessed brain anomalies in three patients (in one patient focal cortical dysplasia and left anterior cingulate dysgenesis, and in two children right or left hippocampal sclerosis) and in another three cases incidentally identified benign alterations on brain MRI were found. The first seizure presented as a cluster in seven out of nine children. In seven out of nine cases occurred status epilepticus. Six out of nine children had autistic symptoms and only one child had normal intellectual development. Seven of our patients were seizure free with combined antiseizure medication (ASM). The most effective ASMs were levetiracetam, valproate, and clobazam. SIGNIFICANCE: The prevalence of PCDH19-related epilepsy is presumably underestimated because of the lack of widely performed molecular genetic evaluations. Molecular genetic testing including PCDH19 pathogenic variants is recommended for female patients with an onset of seizures before the age of 3 years.

Classification of events contributing to postneonatal cerebral palsy: Development, reliability, and recommendations for use.

AIM: This paper introduces the Surveillance of Cerebral Palsy in Europe (SCPE) classification of events contributing to postneonatally acquired cerebral palsy, presents its interrater reliability, and describes the cases identified in the SCPE database. METHOD: The development of the classification, based on literature review and expert discussions, resulted in six main categories and 19 subcategories. The first chronological event designated as the primary event was mainly reported. Interrater reliability was assessed through online exercise providing 24 clinical vignettes representing single/complex pathways. Percent agreement and Gwet's AC1 index of reliability were estimated. Primary events were described using data of 221 children born between 2008 and 2012. RESULTS: Thirty-nine professionals (21 registries) participated in the reliability exercise. Substantial overall agreement was reached (0.75), with some contrast between complex (0.48, moderate agreement) and single events involved (0.89, almost perfect). The distribution of primary events showed that 32.1% were infections (category A), 23.1% head injuries (B), 15.4% related to surgery or medical interventions (C), 13.1% cerebrovascular accidents (D), 9.1% hypoxic brain damaging events of other origins (E), and 7.2% miscellaneous (F). INTERPRETATION: This classification allows all the events involved to be recorded while consistently reporting the primary event, and may be used in different settings. WHAT THIS PAPER ADDS: A standardized classification enables the description of the events contributing to postneonatal cerebral palsy (CP). The first chronological event in complex pathway leading to CP is coded. Category choice and coding of the primary event identify preventable situations. The detailed 2-level classification is easy to use in various settings. Substantial overall interrater reliability shows that main categories can be consistently differentiated.

Anti-N-methyl-D-aspartate receptor encephalitis and drug abuse - the probable role of molecular mimicry or the overstimulation of CB receptors in a 17-year-old adolescent - case report.

Anti-N-methyl-D-aspartate encephalitis is an autoimmune disorder characterized by autoantibodies produced against NMDA receptors. We report the case of a 17-year-old drug user teenager who presented with altered mental scale, psychiatric symptoms and autonomic dysfunction. In the background we diagnosed NMDA encephalitis. We supposed that synthetic cannabinoids/drugs may have lead to the of trigger NMDA encephalitis via the altered activation of the immune system and molecular mimicry mechanism.

Does vigabatrin treatment for infantile spasms cause visual field defects? An international multicentre study.

AIM: The aim of this study was to examine whether vigabatrin treatment had caused visual field defects (VFDs) in children of school age who had received the drug in infancy. METHOD: In total, 35 children (14 males, 21 females; median age 11y, SD 3.4y, range 8-23y) were examined by static Humphrey perimetry, Goldmann kinetic perimetry, or Octopus perimetry. The aetiologies of infantile spasms identified were tuberous sclerosis (n=10), other symptomatic causes (n=3), or cryptogenic (n=22). RESULTS: Typical vigabatrin-attributed VFDs were found in 11 out of 32 (34%) children: in one out of 11 children (9%) who received vigabatrin for <1 year (group 1), in three out of 10 children (30%) who received vigabatrin for 12 to 24 months (group 2), and in seven out of 11 children (63%) who received vigabatrin treatment for longer than 2 years (group 3). VFDs were mild in five and severe in six children. Patients with tuberous sclerosis were at higher risk of VFDs (six out of 10 children). The mean cumulative doses of vigabatrin were 140.5, 758.8, and 2712g in group 1, 2, and 3, respectively. INTERPRETATION: VFDs were found in 34% of the cohort of children in this study. The rate of VFD increased from 9% to 63% as duration of treatment increased. The results of this study showed that the risk-benefit ratio should always be considered when using vigabatrin.

[Anti-NMDA-receptor encephalitis: description of the syndrome in connection with the first Hungarian patient]. / Anti-N-metil-D-aszpartát-receptor-encephalitis: a szindróma ismertetése az elsõ magyar beteg leírása kapcsán.

In the majority of cases, anti-NMDA (N-methyl-D-aspartate) receptor encephalitis is a severe, but treatable disorder, therefore early diagnosis and adequate therapy are very important. It should be suspected in children and young women, who develop acute psychiatric symptoms and seizures. During the course of the disease severe encephalopathy, agitation, hallucinations, orofacial dyskinesias, prolonged cognitive disturbance, autonomic symptoms can be observed and akinetic mutism develops. EEG shows diffuse slowing. Brain MRI is normal or unspecific. Elevated protein, pleiocytosis and oligoclonal bands can be present in the CSF Detection of NMDA-receptor antibodies in sera or CSF confirms diagnosis. We present the case of a 15-year-old girl, who fully recovered within two months after steroid treatment and repeated plasma exchange. Ovarian teratoma has not been detected.

Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway.

Various syndromes of the Ras-mitogen-activated protein kinase (MAPK) pathway, including the Noonan, Cardio-Facio-Cutaneous, LEOPARD and Costello syndromes, share the common features of craniofacial dysmorphisms, heart defect and short stature. In a subgroup of patients, severe muscle hypotonia, central nervous system involvement and failure to thrive occur as well. In this study we report on five children diagnosed initially with classic metabolic and clinical symptoms of an oxidative phosphorylation disorder. Later in the course of the disease, the children presented with characteristic features of Ras-MAPK pathway-related syndromes, leading to the reevaluation of the initial diagnosis. In the five patients, in addition to the oxidative phosphorylation disorder, disease-causing mutations were detected in the Ras-MAPK pathway. Three of the patients also carried a second, mitochondrial genetic alteration, which was asymptomatically present in their healthy relatives. Did we miss the correct diagnosis in the first place or is mitochondrial dysfunction directly related to Ras-MAPK pathway defects? The Ras-MAPK pathway is known to have various targets, including proteins in the mitochondrial membrane influencing mitochondrial morphology and dynamics. Prospective screening of 18 patients with various Ras-MAPK pathway defects detected biochemical signs of disturbed oxidative phosphorylation in three additional children. We concluded that only a specific, metabolically vulnerable sub-population of patients with Ras-MAPK pathway mutations presents with mitochondrial dysfunction and a more severe, early-onset disease. We postulate that patients with Ras-MAPK mutations have an increased susceptibility, but a second metabolic hit is needed to cause the clinical manifestation of mitochondrial dysfunction.

Transverse myelitis as a rare, serious complication of Mycoplasma pneumoniae infection.

We report on the first published case of a Mycoplasma pneumoniae-associated transverse myelitis appearing in childhood and leading to persistent paraplegia and bowel and bladder dysfunctions. Magnetic resonance imaging of the spinal cord indicated extensive transverse myelitis extending from T(5)-T(12). A repeated scan established spinal cord atrophy in the affected area. Various therapies (methylprednisolone pulse therapy, plasmapheresis, and roxythromycine) produced no clinical effect.

Staged bilateral stereotactic pallidothalamotomy for life-threatening dystonia in a child with Hallervorden-Spatz disease.

Hallervorden-Spatz disease (HSD) is a rare disorder characterized by progressive motor dysfunction and dementia. Dystonia is the most prominent and disabling symptom, responding only to a modest extent to pharmacological therapy. At the moment, only a few cases have been reported to improve dystonia and even fewer to resolve status dystonicus for a longer period in children. The authors present the case of a 10-year-old boy who had progressive generalized dystonia, resulting in spontaneous femur fracture and life-threatening swallowing and respiratory disability. As a rescue solution, staged bilateral pallidothalamotomy was performed. Postoperatively, Burke-Fahn-Marsden Dystonia Rating Scale and Dystonia Disability Rating Scale improved (from 116 and 30 points to 41 and 18 points, respectively) and painful dystonia was resolved, which was still continuous 4 years later (47 and 20 points). Stereotactic staged bilateral pallidothalamotomy should be considered as a potential treatment in the management of life-threatening generalized dystonia related to HSD.

Maternally inherited deafness and unusual phenotypic manifestations associated with A3243G mitochondrial DNA mutation.

The mitochondrial DNA A3243G transition is a fairly common mutation which often associates with a MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) phenotype, however, a broad variety in the associated clinical picture has also been described. The patient reported here developed a generalized seizure at age 12, which was followed by bilateral hearing loss and occasional fatigue. The maternal inheritance pattern of hearing loss pointed to a possible mitochondrial origin, which was confirmed by molecular analysis of the mitochondrial DNA, revealing a heteroplasmic A3243G transition. Interestingly, muscle biopsy showed ragged-red fibers in the proband, which is unusual in the deafness-associated forms of this mitochondrial disorder. In addition to hearing impairment in four generations of the family, fatal cerebral embolization in the mother and fatal heart attack in the maternal grandmother (both at age 33) also occurred. On the contrary, diabetes, which usually accompanies the hearing loss variant, was specifically absent in all generations. The unusual manifestations associated with this mutation somewhat differentiate this family from the already known variants.

Tel Hashomer camptodactyly syndrome: 12-year follow-up of a Hungarian patient and review.

Tel Hashomer camptodactyly syndrome (THCS) was diagnosed in a 4-month-old boy whom we have followed for 12 years. In addition to the characteristic clinical findings, he had preductal coarctation of the aorta, persistent ductus arteriosus, and multiple ventricular septal defects. The electron-microscopic evaluation of his muscle biopsy showed anomalies of the sarcoplasmic reticulum and mitochondria; the organization of the myofibrils was normal. The morphological findings suggested primary or secondary involvement of neuromuscular signal transduction and involvement of mitochondria in the development of the myopathy in this child.