Andreas van Baalen

Febrile infection–related epilepsy syndrome (FIRES): A nonencephalitic encephalopathy in childhood

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/μl (median 5 cells/μl) 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).

Febrile infection-related epilepsy syndrome (FIRES): Pathogenesis, treatment, and outcome A multicenter study on 77 children

Purpose:  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.

Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region

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.

Combination of EEG-fMRI and EEG source analysis improves interpretation of spike-associated activation networks in paediatric pharmacoresistant focal epilepsies.

Simultaneous recording of EEG and functional MRI (EEG-fMRI) is a promising tool that may be applied in patients with epilepsy to investigate haemodynamic changes associated with interictal epileptiform discharges (IED). As the yield of the EEG-fMRI technique in children with epilepsy is still unclear, the aim of this study was to evaluate whether the combination of EEG-fMRI and EEG source analysis could improve localization of epileptogenic foci in children. Six children with an unambiguous focus localization were selected based on the criterion of the consistency of ictal EEG, PET and ictal SPECT. IEDs were taken as time series for fMRI analysis and as averaged sweeps for the EEG source analysis based on the distributed linear local autoregressive average (LAURA) solution. In four patients, the brain area with haemodymanic changes corresponded to the epileptogenic zone. However, additional distant regions with haemodynamic response were observed. Source analysis located the source of the initial epileptic activity in all cases in the presumed epileptogenic zone and revealed propagation in five cases. In three cases there was a good correspondence between haemodynamic changes and source localization at both the beginning and the propagation of IED. In the remaining three cases, at least one area of haemodynamic changes corresponded to either the beginning or the propagation. In most children analysed, EEG-fMRI revealed extended haemodynamic response, which were difficult to interpret without an appropriate reference, i.e. a priori hypothesis about epileptogenic zone. EEG source analysis may help to differentiate brain areas with haemodynamic response.

Different neuronal networks are associated with spikes and slow activity in hypsarrhythmia

Purpose: West syndrome is a severe epileptic encephalopathy of infancy characterized by a poor developmental outcome and hypsarrhythmia. The pathogenesis of hypsarrhythmia is insufficiently understood.

Pediatric Herpes Simplex Virus Encephalitis A Retrospective Multicenter Experience

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.

Peri-ictal changes of cortical excitability in children suffering from migraine without aura.

ABSTRACT In adult patients with migraine, transcranial magnetic stimulation (TMS) has been used to examine cortical excitability between attacks, but there have been discrepant results. No TMS study has examined cortical excitability in children or adolescents with migraine. Here, we employed TMS to study regional excitability of the occipital (phosphene threshold [PT] and suppression of visual perception) and motor (resting motor threshold and cortical silent period) cortex in ten children suffering from migraine without aura and ten healthy age‐matched controls. Patients were studied 1–2 days before and after a migraine attack as well as during the inter‐migraine interval. The motion aftereffect was also investigated at each time‐point as an index of cortical reactivity to moving visual stimuli. Migraineurs had lower PTs compared to healthy participants at each time‐point, indicating increased occipital excitability. This increase in occipital excitability was attenuated 1–2 days before a migraine attack as indicated by a relative increase in PTs. The increase in PTs before the next attack was associated with a stronger TMS‐induced suppression of visual perception and a prolongation of the motion aftereffect. Motor cortex excitability was not altered in patients and did not change during the migraine cycle. These findings show that pediatric migraine without aura is associated with a systematic shift in occipital excitability preceding the migraine attack. Similar systematic fluctuations in cortical excitability might be present in adult migraineurs and may reflect either a protective mechanism or an abnormal decrease in cortical excitability that predisposes an individual to a migraine attack.

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

IntroductionThe objective of this study was to explore the volumetric alterations of dural sinuses in patients with idiopathic intracranial hypertension (IIH).MethodsStandardized 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.ResultsStenoses 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.ConclusionsPatients 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.

FIRES: Febrile infection responsive epileptic (FIRE) encephalopathies of school age

Okanishi et al. [1] report on a 14-year-old boy presenting with presumed acute encephalitis with refractory, repetitive partial seizures (AERRPS) after a prodromal period with 3-day fever and a 5-day remission. The authors found serum antiglutamate receptor 2 autoantibodies associated with transient multifocal cortical lesions in MRI and suggested an autoimmunemediated pathogenesis, because CSF showed pleocytosis and extensive tests for viral infection resulted in no further findings. Similar clinical courses of initial fever with nonspecific symptoms suggestive of infection followed by an acute onset of refractory seizures due to presumed encephalitis were reported worldwide [2–4], first described as acute encephalopathy of obscure origin in 1961 by Lyon et al. [5]. The manifestation was more in school age than in infancy and the outcome was disastrous in most of the previously healthy children. Despite presumption of acute central inflammation, neuropathological findings showed no evidence of inflammatory process [2,3,5]. The lack of any response to the established immunomodulatory therapy in most patients also argues against inflammatory and immunomediated pathogenesis [1–4]. One striking feature is the acute onset and long duration of the extremely refractory epilepsy. This dramatic course was also described as epileptic encephalopathy emphazing more on an unknown epileptic syndrome [2,4]. Nevertheless, the clinical course of prodromic febrile infection in our own few patients and in the rare patients published in the literature makes the hypothesis of Okanishi et al. [1] promising, that autoantibodies binding to cortical neurons cause more excitation and less inflammation. Prospective multicenter studies regarding this topic are desirable. Currently, we are initializing a European study to identify common clinical features and to clarify the proposed immunomediated pathomechanism. Therefore, and because of the different terminology [1–5],

Febrile infection–related epilepsy syndrome (FIRES): Does duration of anesthesia affect outcome?

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.