[Show abstract][Hide abstract] ABSTRACT: Knowledge on pediatric herpes simplex virus encephalitis is limited. Here we summarize 6 neonates and 32 children diagnosed by polymerase chain reaction (n = 37) or serological studies (n = 1), respectively. Diagnosis was difficult, as only 15 patients presented neurologic symptoms. Moreover, cerebrospinal fluid glucose, protein, and leukocytes were normal in 6 patients. Subsequently, all but 2 showed neurologic symptoms. Diffusion-weighted neuroimaging was the most sensitive early imaging method. Despite acyclovir treatment, 8 patients experienced early relapses, showing movement abnormalities, impaired vigilance, and seizures. Diffuse white matter changes, found in 3 of 5 relapse patients on neuroimaging, and a negative cerebrospinal fluid herpes simplex virus polymerase chain reaction suggested inflammatory processes. All relapse patients were again treated with acyclovir, and 3 responded to additional corticosteroid treatment. Whereas outcome after relapses was poor, overall outcome was good. No child died; 14 were asymptomatic at discharge, and neuroimaging remained normal in 7 of 30 patients studied.
Journal of child neurology 01/2013; · 1.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim Febrile infection-related epilepsy syndrome (FIRES) is an enigmatic seizure disorder in childhood with an innocuous febrile infection triggering severe and intractable multifocal epilepsy, mostly with status epilepticus. FIRES shares several phenotypic features with epilepsies seen in patients with protocadherin 19 (PCDH19), sodium channel protein type 1 subunit alpha (SCN1A), and DNA polymerase subunit gamma-1 (POLG) mutations. The aim of the study was the mutation analysis of these prime candidate genes in a cohort of patients with FIRES. Additionally, given that rare copy number variations (CNVs) have recently been established as important risk factors for epilepsies, we performed a genome-wide CNV analysis. Method We analysed the protein coding region, including splice sites of the three candidate genes in 15 patients (eight males, seven females) with FIRES (age at onset 3-15y, median 6) using Sanger sequencing. Inclusion criteria were a status epilepticus without identifiable cause and a preceding febrile infection in previously healthy children. In addition, we performed genome-wide human single-nucleotide polymorphism 6.0 arrays in a subset of 10 patients to identify pathological CNVs. Results We could not identify the most likely pathogenic mutations or CNVs in FIRES. Interpretation Mutations in PCDH19, SCN1A, POLG, or CNVs are not responsible for FIRES.
Developmental Medicine & Child Neurology 10/2012; · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Acute cerebellitis (AC) is characterized by cerebellar symptoms and magnetic resonance imaging (MRI) changes primarily confined to the cerebellum.Objective To analyze the neurological and cognitive long-term outcome of children with AC.Methods Children with AC diagnosed by typical clinical features and MRI findings were included in this retrospective study. Medical charts were reviewed and neurological deficits were assessed by neurological examination or by the expanded disability status scale telephone interview. Cognitive outcome was evaluated with a parental questionnaire (Kognitive Probleme bei Kindern und Jugendlichen).Results A total of 11 children (6 boys, 5 girls; age range: 3 years to 14 years and 10 months) were included. Of them, six children had a severe disease manifestation including mental status changes and neurological symptoms. Of the rest, two children had a moderate and three children had a mild form of AC. MRI of the cerebellum was obtained in the acute phase revealing signal alterations with different patterns. The average follow-up period was 4 years and 4 months. A complete recovery was observed in five children. Neurological sequelae were reported in five children ranging from ataxia to mild tremor. Cognitive deficits were found in six patients. The affected areas of cognition did include spatial visualization ability, language skills, and concentration.Conclusion Neurological and cognitive sequelae are common in children with AC and underline the role of the cerebellum in cognition.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: We conducted a retrospective multicenter study on children who had been included in eight studies published between November 2001 and July 2010 to explore the correlations between burst-suppression coma (BSC) with outcome in febrile infection-related epilepsy syndrome (FIRES). The 77 enrolled patients presented with prolonged refractory status epilepticus. BSC was induced in 46 patients. Cognitive levels at follow-up were significantly associated with duration of a BSC (p=0.005). The outcome of FIRES is poor. Treatment by inducing a prolonged BSC was associated with a worse cognitive outcome.
[Show abstract][Hide abstract] ABSTRACT: To explore the correlations between treatment modalities and selected disease parameters with outcome in febrile infection-related epilepsy syndrome (FIRES), a catastrophic epileptic encephalopathy with a yet undefined etiology.
We conducted a retrospective multicenter study on children who had been included in eight studies published between November 2001 and July 2010. Additional data were retrieved from six of the eight participating centers.
The 77 enrolled patients presented with prolonged refractory status epilepticus. A preceding febrile infection had been reported in 96% of them. Treatment modalities included antiepileptic drugs (a median of six), intravenous immunoglobulin (IVIG, 30 patients), steroids (29 patients), burst-suppression coma (BSC, 46 patients), and other less conventional agents. There was no evidence of efficacy for those treatment modalities except for IVIG (two patients), a ketogenic diet (one patient), and a prolonged cycle of barbiturate anesthesia coma (one patient). Nine patients (11.7%) died during the acute phase of FIRES. Only 12 of the 68 surviving patients (18%) retained normal cognitive level, but most of them had learning disabilities. Sixty-three patients (93%) had refractory epilepsy at follow-up. Cognitive levels at follow-up were significantly associated with duration of BSC (p = 0.005) and younger age at FIRES onset (p = 0.02).
The outcome of FIRES is poor. No therapeutic agent was efficacious in shortening the acute phase, with the possible exception of a ketogenic diet. Treatment by inducing a prolonged BSC was associated with a worse cognitive outcome.
[Show abstract][Hide abstract] ABSTRACT: Cases of severe childhood epilepsies in temporal association with vaccination have great impact on the acceptance of vaccination programs by parents and health care providers. However, little is known about the type and frequency of seizures and epilepsy syndromes following vaccination. This study aims to describe the clinical features of children presenting with seizures after vaccination using a register-based cohort.
We surveyed the national German database of adverse events following immunization (AEFI) for reported seizures and epilepsies in children aged 0-6 years. All cases reported in 2006-2008 were analyzed retrospectively; available clinical information was reevaluated and classified by seizure type and epilepsy syndrome.
In total, 328 cases reported between 2006 and 2008 were included. Data supportive of seizures or epilepsy were present in 247 (75.3%) of 328 patients with a mean interval between the vaccination and the epileptic event of 24 h and 7.5 days for inactivated and attenuated vaccines, respectively. Fifty-one (15.5%) of 328 patients presented with syncope, hypotonic-hyporesponsive episodes, or other nonepileptic events. Information was insufficient for classification into epileptic versus nonepileptic events in 30 (11.3%) of 328 patients. For cases with confirmed seizures, febrile seizures were present in 121 (49%) of 247 cases, and 38 (15.4%) of 247 patients had single afebrile seizures. Status epilepticus was described in 21 (8.5%) of 247 patients. Thirty-one (12.6%) of 247 patients presented with various pediatric epilepsy syndromes. Severe childhood epilepsies (Dravet syndrome, West syndrome, Lennox-Gastaut syndrome, or Doose syndrome) were diagnosed in 29 (11.7%) of 247 patients, with the vaccination-associated event being the first documented seizure in 15 (51.7%) of 29 patients.
Vaccination-associated seizures present in the setting of various epilepsy syndromes, including severe childhood epilepsies in >10% of cases. Early diagnosis of the corresponding epilepsy syndromes and confirmation of an underlying etiology is important for treatment decisions, genetic counseling, and public health evaluation of vaccine safety.
[Show abstract][Hide abstract] ABSTRACT: IH can alter the configuration of anatomic structures of the central nervous system. We determined the sensitivity and specificity of MR imaging to detect these changes in patients with secondary IH.
Patients (n = 36) with IH were prospectively investigated with MR imaging and were matched to 36 controls. MR images were evaluated for elongation and edema of the optic nerves, protrusion of the optic disc, flattening of the posterior sclera, height of the pituitary gland, and width of the optic nerve sheath. On MRV, we recorded venous sinus abnormalities and measured the luminal width of the superior ophthalmic veins. A grading score was introduced to define cranial venous outflow obstruction.
Cranial venous outflow obstruction and ONS hydrops were the most valid signs indicating IH with a sensitivity of 94% and 92% and a specificity of 100% and 89%, respectively. Sensitivities and specificities were 56% and 97% for reduced pituitary height, 64% and 78% for flattening of the posterior sclera, 31% and 97% for widening of the superior ophthalmic veins, 33% and 100% for optic disc protrusion, 14% and 100% for optic nerve edema, and 6% and 100% for elongation of the optic nerve. At least 2 MR imaging findings could be demonstrated in each patient but in none of the controls. The number of positive MR imaging findings correlated with CSF pressure (r = 0.62, P = .01).
The combination of cranial and orbital MR imaging and MRV can be highly sensitive and specific in the diagnosis of patients with IH.
American Journal of Neuroradiology 06/2011; 32(6):1021-9. · 3.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to explore the volumetric alterations of dural sinuses in patients with idiopathic intracranial hypertension (IIH).
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: Craniospinal hyper- or hypotension leads to morphologic changes in certain intracranial structures. We tested the hypothesis that the amount of CSF in the ONS visible in MR imaging is reduced in patients with CSH.
Nineteen patients with CSH were prospectively studied. Three readers assessed the width of the peri-optical CSF rim at 4 different anatomic positions by using coronal STIR sequences from a 3T MR imaging scanner. The height of the pituitary gland was also measured. Results were compared with normal values obtained with the same imaging technique. Qualitative signs of CSH also recorded were engorgement of venous sinuses, dural enhancement, subdural effusion, narrow ventricles, and sagging brain.
CSF signal intensity surrounding the optic nerves was diminished in at least 2 of the 4 positions used for measurements so that decreased diameters of the ONSs were observed in all patients (sensitivity, 100%; specificity, 97%). The height of the pituitary gland was above normal limits in 12 of 19 patients (sensitivity, 63%; specificity, 97%). Frequencies of qualitative signs of CSH varied from 32% to 81%.
The ISSON in patients with CSH is partially or fully collapsed due to reduced CSF content. In comparison with other anatomic markers, this sign showed the highest sensitivity for the diagnosis of patients with CSH in this study.
American Journal of Neuroradiology 10/2010; 31(9):1752-7. · 3.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Seizure disorders of the rolandic region comprise a spectrum of different epilepsy syndromes ranging from benign rolandic epilepsy to more severe seizure disorders including atypical benign partial epilepsy/pseudo-Lennox syndrome,electrical status epilepticus during sleep, and Landau-Kleffner syndrome. Centrotemporal spikes are the unifying electroencephalographic hallmark of these benign focal epilepsies, indicating a pathophysiologic relationship between the various epilepsies arising from the rolandic region. The etiology of these epilepsies is elusive, but a genetic component is assumed given the heritability of the characteristic electrographic trait. Herein we report on three patients with intellectual disability, various dysmorphic features, and epilepsies involving the rolandic region, carrying previously undescribed deletions in 16p13. The only gene located in the critical region shared by all three patients is GRIN2A coding for the alpha-2 subunit of the neuronal N-methyl-D-aspartate(NMDA) receptor.
[Show abstract][Hide abstract] ABSTRACT: P>Encephalitis is generally presumed, even when seizures follow banal febrile infection, and pathogen detection in cerebrospinal fluid fails. This retrospective multicenter case series reports on 22 previously healthy children aged 3-15 years (median 6.5 years) with prolonged or recurrent seizures occurring 2-14 days (median 5 days) after fever onset (19 children with respiratory or nonspecific infections). Cerebrospinal fluid studies revealed 2-42 cells/mu l (median 5 cells/mu l) and no pathogens. Electroencephalography showed diffuse slowing or multifocal discharges. Neuroimaging demonstrated normal findings in 10 children. Brain biopsies were performed in seven children showing gliosis but no inflammation. Anesthetic barbiturates were used in 14 children with refractory status epilepticus, and immunotherapy in 9. Two children died, eight remained in a state of impaired consciousness, eight developed therapy-refractory epilepsies, two had behavioral disturbances, and two recovered. The lack of evidence for encephalitis suggests another infection-related pathogenesis of this disastrous epileptic encephalopathy. Therefore, we propose the term "febrile infection-related epilepsy syndrome" (FIRES).
[Show abstract][Hide abstract] ABSTRACT: It has been hypothesized that abnormalities of information processing in migraine may be attributed to impairment of cerebral maturation. However, the most evidences for this hypothesis have come from cross-sectional studies during childhood. We performed a longitudinal study and recorded contingent negative variation (CNV), an event-related slow cortical potential, in migraine children (n = 27) and age-matched healthy individuals (n = 23) in 1998 and 8 years later (2006). Amplitudes of all CNV components were reduced and habituation of the initial CNV (iCNV) increased in the observed time. However, the reduction of the iCNV amplitude was more pronounced in migraine patients who were in remission in 2006 and in healthy subjects and less pronounced in migraineurs with persisting headaches. Patients with the worsened migraine demonstrated the most pronounced loss of iCNV habituation in 1998 and significantly increased iCNV amplitudes in 2006. This longitudinal study supports the hypothesis of impaired cerebral maturation in migraine and shows that migraine manifestation is a key factor interfering with the natural maturation process of central information processing.
The Journal of Headache and Pain 12/2009; 11(2):105-13. · 2.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bei anamnestischen Infektionshinweisen wird regelhaft eine Enzephalitis als Ursache für akut aufgetretene epileptische Anfälle
vermutet, selbst wenn diese banalen Infektionen folgen und ein Erregernachweis im Liquor nicht gelingt. Die im Folgenden vorgestellte
retrospektive Multizenterstudie analysierte die Daten von 23Kindern im Alter von 3 bis 15Jahren (Median 6Jahre) mit ungewöhnlich
refraktären Anfällen 2 bis 14Tage (Median 5Tage) nach Beginn einer fieberhaften Infektion (20Kinder mit Luftwegs- oder
unspezifischen Infektionen). Im Liquor waren 2–42Zellen/µl (Median 5Zellen/µl), aber keine Erreger nachweisbar. Die Elektroenzephalogramme
zeigten diffuse Verlangsamungen oder multifokale Entladungen. Die kraniellen Magnetresonanztomographien in der Frühphase ergaben
überwiegend Normalbefunde und lediglich leicht erhöhte Signalintensitäten mit hippocampaler oder temporaler Prädilektion bei
10Kindern. Im Verlauf entwickelten 48% der überlebenden Kinder ausgeprägte Hirnatrophien. Hirnbiopsien wurden bei 7Kindern
durchgeführt und zeigten reaktive Gliosen, aber keine entzündlichen Veränderungen. Barbituratnarkosen wurden bei 15Kindern
und Immuntherapien bei 10Kindern angewendet. Zwei Kinder starben, 8Kinder entwickelten das Bild eines apallischen Syndroms
bzw. eines „minimally responsive vegetative state“, 9Kinder entwickelten refraktäre Epilepsien und 2Kinder Gedächtnis- oder
Verhaltensstörungen. Nur 2Kinder erholten sich vollständig und ohne neuropsychologische Defizite. Das Fehlen von Belegen
für eine Enzephalitis als Ursache dieser überwiegend schwer verlaufenden Enzephalopathie mit refraktären Anfällen bei Kindern
weist auf einen immunvermittelten Pathomechanismus hin. Deshalb wird hierfür der Begriff „febrile infection responsive epilepsy
syndrome (FIRES)“ vorgeschlagen.
Encephalitis is generally presumed, even when severe seizures follow banal febrile infection and pathogen detection in cerebrospinal
fluid fails. This retrospective, multicenter study analyzed the data from 23 children aged 3–15years (median 6years) with
prolonged or recurrent seizures occurring 2–14days (median 5days) after fever onset (20children with airway or non-specific
infections). Cerebrospinal fluid studies revealed 2–42cells/µl (median 5cells/µl), but no pathogens. Electroencephalograms
showed diffuse slowing or multifocal discharges. Magnetic resonance imaging demonstrated slightly increased signal intensities
with hippocampal or temporal predilection in 10children. During the course, 48% of the children who survived developed pronounced
brain atrophy. Brain biopsies, performed in 7children, showed gliosis but no inflammation. Anesthetic barbiturates were used
in 15children, immunotherapy in 10. Two children died, 8 remained in a minimally responsive vegetative state, 9 developed
therapy-refractory epilepsy and 2 developed memory or behavioral disturbances, while only 2 children recovered completely
and without significant neuropsychological deficits. The lack of evidence for encephalitis suggests an immune-mediated pathomechanism
of this predominantly severe encephalopathy with refractory seizures in children. Therefore, the term “febrile infection responsive
epilepsy syndrome (FIRES)” is proposed.
Zeitschrift für Epileptologie 11/2009; 22(4):256-259.