The seasonality of new-onset refractory status epilepticus (NORSE).

The etiology of new-onset refractory status epilepticus (NORSE), including its subtype with prior fever known as FIRES (febrile infection-related epilepsy syndrome), remains uncertain. Several arguments suggest that NORSE is a disorder of immunity, likely post-infectious. Consequently, seasonal occurrence might be anticipated. Herein we investigated if seasonality is a notable factor regarding NORSE presentation. We combined four different data sets with a total of 342 cases, all from the northern hemisphere, and 62% adults. The incidence of NORSE cases differed between seasons (p = .0068) and was highest in the summer (32.2%) (p = .0022) and lowest in the spring (19.0%, p = .010). Although both FIRES and non-FIRES cases occurred most commonly during the summer, there was a trend toward FIRES cases being more likely to occur in the winter than non-FIRES cases (OR 1.62, p = .071). The seasonality of NORSE cases differed according to the etiology (p = .024). NORSE cases eventually associated with autoimmune/paraneoplastic encephalitis occurred most frequently in the summer (p = .032) and least frequently in the winter (p = .047), whereas there was no seasonality for cryptogenic cases. This study suggests that NORSE overall and NORSE related to autoimmune/paraneoplastic encephalitis are more common in the summer, but that there is no definite seasonality in cryptogenic cases.

Clinical Course, Myopathology and Challenge of Therapeutic Intervention in Pediatric Patients with Autoimmune-Mediated Necrotizing Myopathy.

(1) Background: Immune-mediated necrotizing myopathy (IMNM) is a rare form of inflammatory muscle disease which is even more rare in pediatric patients. To increase the knowledge of juvenile IMNM, we here present the clinical findings on long-term follow-up, myopathological changes, and therapeutic strategies in two juvenile patients. (2) Methods: Investigations included phenotyping, determination of antibody status, microscopy on muscle biopsies, MRI, and response to therapeutic interventions. (3) Results: Anti-signal recognition particle (anti-SRP54) and anti- 3-hydroxy-3-methylglutarly coenzyme A reductase (anti-HMGCR) antibodies (Ab) were detected in the patients. Limb girdle presentation, very high CK-levels, and a lack of skin rash at disease-manifestation and an absence of prominent inflammatory signs accompanied by an abnormal distribution of α-dystroglycan in muscle biopsies initially hinted toward a genetically caused muscle dystrophy. Further immunostaining studies revealed an increase of proteins involved in chaperone-assisted autophagy (CASA), a finding already described in adult IMNM-patients. Asymmetrical muscular weakness was present in the anti-SRP54 positive Ab patient. After initial stabilization under therapy with intravenous immunoglobulins and methotrexate, both patients experienced a worsening of their symptoms and despite further therapy escalation, developed a permanent reduction of their muscle strength and muscular atrophy. (4) Conclusions: Diagnosis of juvenile IMNM might be complicated by asymmetric muscle weakness, lack of cutaneous features, absence of prominent inflammatory changes in the biopsy, and altered α-dystroglycan.

Whole-Exome Sequencing in NF1-Related West Syndrome Leads to the Identification of KCNC2 as a Novel Candidate Gene for Epilepsy.

Patients with neurofibromatosis type 1 (NF1) have an increased risk for West syndrome (WS), but the underlying mechanisms linking NF1 and WS are unknown. In contrast to other neurocutaneous syndromes, intracerebral abnormalities explaining the course of infantile spasms (IS) are often absent and the seizure outcome is usually favorable. Several studies have investigated a potential genotype-phenotype correlation between NF1 and seizure susceptibility, but an association was not identified. Therefore, we identified three patients with NF1-related WS (NF1-WS) in a cohort of 51 NF1 patients and performed whole-exome sequencing (WES) to identify genetic modifiers. In two NF1 patients with WS and good seizure outcome, we did not identify variants in epilepsy-related genes. However, in a single patient with NF1-WS and transition to drug-resistant epilepsy, we identified a de novo variant in KCNC2 (c.G499T, p.D167Y) coding for Kv3.2 as a previously undescribed potassium channel to be correlated to epilepsy. Electrophysiological studies of the identified KCNC2 variant demonstrated both a strong loss-of-function effect for the current amplitude and a gain-of-function effect for the channel activation recommending a complex network effect. These results suggest that systematic genetic analysis for potentially secondary genetic etiologies in NF1 patients and severe epilepsy presentations should be done.

Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood.

Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins. Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. Introduction of the identified PMPCB variants into the homologous S. cerevisiae Mas1 protein resulted in a severe growth and MPP processing defect leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of iron-sulfur clusters, which are indispensable for a broad range of crucial cellular functions. Analysis of biopsy materials of an affected individual revealed changes and decreased activity in iron-sulfur cluster-containing respiratory chain complexes and dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes. We conclude that biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood.

Intravenous lacosamide in clinical practice-Results from an independent registry.

PURPOSE: This non-interventional study was conducted to evaluate the efficacy and tolerability of intravenous lacosamide (LCM-iv) under routine conditions in daily clinical practice as a prospective registry. METHODS: Patients with any type of seizure or epilepsy syndrome were recruited in 16 neurological and neuropediatric centers in Germany if the treating physician decided to administer LCM-iv for any reason. Observation time per patient was 10 days with daily documentation of LCM-iv administration, type and frequency of seizures, currently used drugs and doses, and adverse events. Treatment efficacy, tolerability, and handling of LCM-iv were assessed using a five-step scale. RESULTS: In 119 patients treating physicians classified epilepsies as focal in 66.1% and generalized in 17.4% (16.5% unclassifiable). Most common etiologies of seizures were tumors (36.1%) and cerebrovascular diseases (21.8%). Reasons for LCM-iv treatment included preparation for surgery (25.2%), convulsive (24.4%) and non-convulsive (18.5%) status epilepticus (SE), series of seizures (16.0%), gastrointestinal causes (5.9%), and acute seizures (4.2%). The median dose of LCM-iv was 300mg per day. In 45 of 64 patients (70.3%) with SE or series of seizures, epileptic activity ceased during observation time. Five patients showed abnormalities in ECG prior to the infusion and one patient afterwards, but during infusion no abnormalities were reported. Treating physicians rated efficacy and tolerability as very good or good in 77.6% and 93.1% of patients, respectively. CONCLUSIONS: This large and independent multicenter registry on the use of LCM-iv in clinical practice demonstrates that LCM-iv is well-tolerated and highly efficacious when given in emergency situations, including patients experiencing SE. It is advisable to perform an electrocardiogram prior to LCM-iv administration.

Early muscle and brain ultrastructural changes in polymerase gamma 1-related encephalomyopathy.

Mutations affecting the mitochondrial DNA-polymerase gamma 1 (POLG1) gene have been shown to cause Alpers-Huttenlocher disease. Ultrastructural data on brain and muscle tissue are rare. We report on ultrastructural changes in brain and muscle tissue of two sisters who were compound heterozygous for the c.2243G>C and c.1879C>T POLG1 mutations. Patient 1 (16 years) presented with epilepsia partialis continua that did not respond to antiepileptic treatment. Neuroimaging showed right occipital and bithalamic changes. Light microscopy from a brain biopsy performed after 3 weeks suggested chronic encephalitis showing astro- and microgliosis as well as perivascular CD8-positive T-cells. However, immunosuppressive therapy failed to improve her condition. When her 17-year-old sister (patient 2) also developed epilepsy, an intensified search for metabolic diseases led to the diagnosis. On electron microscopy mitochondrial abnormalities mainly affecting neurons were detected in the brain biopsy of patient 1, including an increase in number and size, structural changes and globoid inclusions. In patient 2, light and electron microscopy on a muscle biopsy confirmed a mitochondrial myopathy, also revealing an increase in mitochondrial size and number, as well as globoid inclusions. Neurons may be the primary target of mitochondrial dysfunction in brains of patients with Alpers disease related to POLG1 mutations. During early disease stages, brain histopathology may be misleading, showing reactive inflammatory changes.

Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES.

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.

The entire dural sinus tree is compressed in patients with idiopathic intracranial hypertension: a longitudinal, volumetric magnetic resonance imaging study.

INTRODUCTION: The objective of this study was to explore the volumetric alterations of dural sinuses in patients with idiopathic intracranial hypertension (IIH). METHODS: Standardized cranial magnetic resonance imaging (MRI) was used in 17 patients prior to and following treatment of IIH and in seven controls. Magnetic resonance venographies (MRV) were employed for (a) judgement of circumscript dural sinus stenoses and (b) computation of sinus volumes. Cross-sectional areas (CSA) of the superior sagittal sinuses (SSS) were measured on T2-weighted images. Results of the initial MRIs were compared to those on follow-up MRIs and to results of controls. RESULTS: Stenoses of the transverse sinuses (TS) resulting in cranial venous outflow obstruction (CVOO) were present in 15/17 (88%) patients, normalizing in 7/15 cases (47%) after treatment of IIH. CVOO was not detected in the control group. Segmentation of MRV revealed decreased dural sinus volumes in patients with IIH as compared to controls (P = 0.018). Sinus volumes increased significantly with normalization of intracranial pressure independent from disappearing of TS stenoses (P = 0.007). The CSA of the SSS were normal on the initial MRIs of patients with IIH and increased on follow-up after treatment (P < 0.001). However, volumetries displayed overlap in patients and controls. CONCLUSIONS: Patients with IIH not only exhibit bilateral stenoses of the TS as has been reported, but volume changes of their entire dural sinus system also occur. The potential etiopathological and diagnostic roles of these changes are discussed.

Dyschromatosis ptychotropica: an unusual pigmentary disorder in a boy with epileptic encephalopathy and progressive atrophy of the central nervous system-a novel entity?

The skin and the central nervous system are tissues of common ectodermal origin and share a close ontogenetic relationship. Genetic diseases primarily affecting both organ systems are regularly encountered in both dermatological and neurological settings. Here, we report on a boy with epileptic encephalopathy, severe intellectual disability, optic atrophy, and progressive cerebellar and supratentorial atrophy, reminiscent of progressive encephalopathy with edema and hypsarrythmia (PEHO) syndrome displaying a previously undescribed dyschromatosis in the form of progressive reticulate and mottled hyper- and hypopigmentation of the neck and the inguinal and axillary regions. We hypothesised that this combination of neurological and cutaneous findings has a common aetiology and represents a novel recognisable entity. Because of the unusual dermatological findings, we suggest the term dyschromatosis ptychotropica. Recognition of further cases may help elucidate the aetiology of this condition and give insight into the pathophysiology of both pigmentation disorders and epileptic encephalopathies.

Anterior choroid plexus cysts: distinction from germinolysis by high-resolution sonography.

BACKGROUND: The aim of the present paper was to develop criteria identifying anterior choroid plexus cysts (ACPC) and distinguish these from germinolytic pseudocysts. METHODS: Cerebral sonography was performed in 2200 neonates with mean gestational age 40 completed weeks (range 23-42 weeks) and mean birthweight of 3450 g (range 340-4610 g). In the last 300 neonates cystic formations in the caudothalamic groove were studied prospectively using a high-resolution ultrasound system with linear scanhead, and the previous results were re-evaluated. RESULTS: In 22 neonates choroid plexus cysts outside the typical location in the choroid plexus glomus could be attributed to the anterior part of the choroid plexus in the lateral ventricles (prospectively analyzed in 16 of 300 neonates: 5% prevalence on high-resolution sonography). ACPC were located medial and behind germinolytic pseudocysts and best realized during sweep of the scanhead through the caudothalamic groove. In contrast to germinolytic pseudocysts, they had a spherical form, no septation and a thick, partial double wall. Larger cysts seemed to bounce. CONCLUSIONS: ACPC are not rare and are identified by their location, form, and movement.

Flexible and floating choroid plexus cyst of the third ventricle: an ultrasonographic video documentation.

INTRODUCTION: Choroid plexus cysts can lead to isolation of the lateral ventricles and distension of the third ventricle. We present an ultrasonographic video documentation of an infant with variably shaped and localized choroid plexus cyst of the third ventricle. CASE REPORT: An infant had periods of increased intracranial pressure with changing dilatation of the first to third ventricle. Cerebral ultrasonography of the not crying boy demonstrated a choroid plexus cyst limply hanging down from the roof of the third ventricle to the beginning of the aqueduct of Sylvius. During crying, the cyst prolapsed from the third into left lateral ventricle and was strangled by the foramen of Monro. Endoscopic cyst fenestration and third ventriculostomy continuously solved the problem of intermittent hydrocephalus occlusus. CONCLUSION: Depending not only on localization and size but also on cyst form and cerebrospinal fluid pressure, a single choroid plexus cyst can cause various obstructions of cerebrospinal fluid pathways.