Treatment of Infantile Spasm Syndrome: Update from the Interdisciplinary Guideline Committee Coordinated by the German-Speaking Society of Neuropediatrics.

OBJECTIVES: The manuscript serves as an update on the current management practices for infantile spasm syndrome (ISS). It includes a detailed summary of the level of current evidence of different treatment options for ISS and gives recommendations for the treatment and care of patients with ISS. METHODS: A literature search was performed using the Cochrane and Medline Databases (2014 to July 2020). All studies were objectively rated using the Scottish Intercollegiate Guidelines Network. For recommendations, the evidence from these studies was combined with the evidence from studies used in the 2014 guideline. RECOMMENDATIONS: If ISS is suspected, electroencephalography (EEG) should be performed within a few days and, if confirmed, treatment should be initiated immediately. Response to first-line treatment should be evaluated clinically and electroencephalographically after 14 days. The preferred first-line treatment for ISS consists of either hormone-based monotherapy (AdrenoCorticoTropic Hormone [ACTH] or prednisolone) or a combination of hormone and vigabatrin. Children with tuberous sclerosis complex and those with contraindications against hormone treatment should be treated with vigabatrin. If first-line drugs are ineffective, second-line treatment options such as ketogenic dietary therapies, sulthiame, topiramate, valproate, zonisamide, or benzodiazepines should be considered. Children refractory to drug therapy should be evaluated early for epilepsy surgery, especially if focal brain lesions are present. Parents should be informed about the disease, the efficacy and adverse effects of the medication, and support options for the family. Regular follow-up controls are recommended.

The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood.

Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated phenotypes in these children and their relatives. Only a few recent larger cohort studies are on record and findings from single reports were not confirmed so far. We collected detailed genetic and phenotypic data of 40 previously unreported patients from 36 families. All patients had benign infantile epilepsy and harbored pathogenic variants in PRRT2 (core cohort). Clinical data of 62 family members were included, comprising a cohort of 102 individuals (extended cohort) with PRRT2-associated neurological disease. Additional phenotypes in the cohort of patients with benign sporadic and familial infantile epilepsy consist of movement disorders with paroxysmal kinesigenic dyskinesia in six patients, infantile-onset movement disorders in 2 of 40 individuals, and episodic ataxia after mild head trauma in one girl with bi-allelic variants in PRRT2. The same girl displayed a focal cortical dysplasia upon brain imaging. Familial hemiplegic migraine and migraine with aura were reported in nine families. A single individual developed epilepsy with continuous spikes and waves during sleep. In addition to known variants, we report the novel variant c.843G>T, p.(Trp281Cys) that co-segregated with benign infantile epilepsy and migraine in one family. Our study highlights the variability of clinical presentations of patients harboring pathogenic PRRT2 variants and expands the associated phenotypic spectrum.

Clinical features and blood iron metabolism markers in children with beta-propeller protein associated neurodegeneration.

BACKGROUND: Neurodegeneration with brain iron accumulation constitutes a group of rare progressive movement disorders sharing intellectual disability and neuroimaging findings as common denominators. Beta-propeller protein-associated neurodegeneration (BPAN) represents approximately 7% of the cases, and its first signs are typically epilepsy and developmental delay. We aimed to describe in detail the phenotype of BPAN with a special focus on iron metabolism. MATERIAL AND METHODS: We present a cohort of paediatric patients with pathogenic variants of WD-Repeat Domain 45 gene (WDR45). The diagnosis was established by targeted panel sequencing of genes associated with epileptic encephalopathies (n = 9) or by Sanger sequencing of WDR45 (n = 1). Data on clinical characteristics, molecular-genetic findings and other performed investigations were gathered from all participating centres. Markers of iron metabolism were analysed in 6 patients. RESULTS: Ten children (3 males, 7 females, median age 8.4 years) from five centres (Prague, Berlin, Vogtareuth, Tubingen and Cologne) were enrolled in the study. All patients manifested first symptoms (e.g. epilepsy, developmental delay) between 2 and 31 months (median 16 months). Seven patients were seizure-free (6 on antiepileptic medication, one drug-free) at the time of data collection. Neurological findings were non-specific with deep tendon hyperreflexia (n = 4) and orofacial dystonia (n = 3) being the most common. Soluble transferrin receptor/log ferritin ratio was elevated in 5/6 examined subjects; other parameters of iron metabolism were normal. CONCLUSION: Severity of epilepsy often gradually decreases in BPAN patients. Elevation of soluble transferrin receptor/log ferritin ratio could be another biochemical marker of the disease and should be explored by further studies.

Beneficial impact of high-field intraoperative magnetic resonance imaging on the efficacy of pediatric low-grade glioma surgery.

OBJECTIVE: Intraoperative MRI (iMRI) is assumed to safely improve the extent of resection (EOR) in patients with gliomas. This study focuses on advantages of this imaging technology in elective low-grade glioma (LGG) surgery in pediatric patients. METHODS: The surgical results of conventional and 1.5-T iMRI-guided elective LGG surgery in pediatric patients were retrospectively compared. Tumor volumes, general clinical data, EOR according to reference radiology assessment, and progression-free survival (PFS) were analyzed. RESULTS: Sixty-five patients were included in the study, of whom 34 had undergone conventional surgery before the iMRI unit opened (pre-iMRI period) and 31 had undergone surgery with iMRI guidance (iMRI period). Perioperative data were comparable between the 2 cohorts, apart from larger preoperative tumor volumes in the pre-iMRI period, a difference without statistical significance, and (as expected) significantly longer surgeries in the iMRI group. According to 3-month postoperative MRI studies, an intended complete resection (CR) was achieved in 41% (12 of 29) of the patients in the pre-iMRI period and in 71% (17 of 24) of those in the iMRI period (p = 0.05). Of those cases in which the surgeon was postoperatively convinced that he had successfully achieved CR, this proved to be true in only 50% of cases in the pre-iMRI period but in 81% of cases in the iMRI period (p = 0.055). Residual tumor volumes on 3-month postoperative MRI were significantly smaller in the iMRI cohort (p < 0.03). By continuing the resection of residual tumor after the intraoperative scan (when the surgeon assumed that he had achieved CR), the rate of CR was increased from 30% at the time of the scan to 85% at the 3-month postoperative MRI. The mean follow-up for the entire study cohort was 36.9 months (3-79 months). Progression-free survival after surgery was noticeably better for the entire iMRI cohort and in iMRI patients with postoperatively assumed CR, but did not quite reach statistical significance. Moreover, PFS was highly significantly better in patients with CRs than in those with incomplete resections (p < 0.001). CONCLUSIONS: Significantly better surgical results (CR) and PFS were achieved after using iMRI in patients in whom total resections were intended. Therefore, the use of high-field iMRI is strongly recommended for electively planned LGG resections in pediatric patients.

Treatment of Infantile Spasms: Report of the Interdisciplinary Guideline Committee Coordinated by the German-Speaking Society for Neuropediatrics.

Objectives This report aims to define treatment goals, to summarize the evidence level (EL) of different treatment options for infantile spasms (IS), both in terms of efficacy and adverse effect, and to give recommendations for the management of IS. Methods The Cochrane and Medline (1966-July 2014) databases were searched. Literature known to the guideline working group and identified through citations was also considered. The results of previously published guidelines were taken into account in our analysis. Rating the level of evidence followed the Scottish Intercollegiate Guidelines Network. Recommendations If IS are suspected, electroencephalogram (EEG) should be performed within a few days and, if confirmed, treatment should be initiated immediately. Response to first-line treatments should be evaluated clinically and electroencephalographically after 14 days.Adrenocorticotropic hormone, corticosteroids, and vigabatrin are the first-line drugs for the treatment of IS. In children with tuberous sclerosis complex, vigabatrin is the treatment of first choice. Ketogenic diet, sulthiame, topiramate, valproate, zonisamide, and benzodiazepines can be used when first-line drugs have proved ineffective. Children refractory to drug therapy should be evaluated for epilepsy surgery, especially if focal brain lesions are present.Regular follow-up controls, including EEG (preferably sleep EEG) and standardized developmental assessment are recommended.

Holocord pilocytic astrocytoma--case report and review of the literature.

Intramedullary glial neoplasms affecting the entire cord from the cervicomedullary junction to the conus are termed "holocord tumors" and those diagnosed as pilocytic astrocytoma are rare. Herein, we present a 13-year-old girl with a tumor extending from the cervicomedullary junction to the conus which was partially resected in a four-stage approach. Histopathological examination of all specimens resulted in diagnosis of a pilocytic astrocytoma. Although no signs of atypia were present, an elevated proliferative activity of endothelial vessels was noted. Residual parts of the tumor showed progress making additional surgery necessary. Therapy and its consequences are discussed and an overview of the literature of these rare longitudinally extensive intramedullary lesions is given.

Multifocal dysembryoplastic neuroepithelial tumor with signs of atypia after regrowth.

We report the case of a multifocal dysembryoplastic neuroepithelial tumor (DNT) in a 7-year-old girl with local tumor regrowth 6 years later. The tumor was localized in the right parietal lobe extending from the cortex into the periventricular white matter. After subtotal resection of a histopathologically confirmed DNT we observed unexpected tumor progression in long-term follow-up. Therefore, a second surgery was performed when the patient was 14 years of age. In neuropathological examination of the second specimen the tumor showed an increased cellularity and pleomorphism, microvascular proliferations, an elevated proliferative activity (MIB1-index focally up to 10%) and cellular atypia not typical for WHO grade I DNT. Furthermore, MRI studies showed additional supratentorial and infratentorial lesions which remained stable over years and are also well consistent with DNTs. Thus, an unusual form of a DNT with multifocal lesions, local regrowth and morphological transformation is supposed.

Disseminating anaplastic brainstem oligodendroglioma associated with allelic loss in the tumor suppressor candidate region D19S246 of chromosome 19 mimicking an inflammatory central nervous system disease in a 9-year-old boy.

We report the case of a 9-year-old boy clinically presenting with severe headache, vomiting, head retroflexion, nystagmus, and ataxia. Magnetic resonance imaging showed brainstem enlargement leading to the diagnosis of an inflammatory process. In addition, the clinical picture, a monocytic cerebrospinal fluid pleocytosis with elevated protein and lactate and serum IgM antibodies to Mycoplasma pneumoniae favored this diagnosis. Subsequently, corticosteroid treatment rapidly improved clinical symptoms, and lesions declined in subsequent neuroradiological examinations. However, 2 months later, fulminant disease progression led to brain death. Final neuroradiological examination favored meningoencephalitis. The autopsy revealed brain swelling and brainstem softening with a superficial gelatinous mass extending along the spinal cord. Finally, a disseminating anaplastic oligodendroglioma with allelic loss of the D19S246 tumor suppressor candidate locus of chromosome 19 was diagnosed. To our knowledge, this is the first case of a disseminating anaplastic brainstem oligodendroglioma associated with this specific allelic loss occurring in childhood.