Egan, Robert A. MD; Brown, Adam MD; Grillo, Eugenio MDEditor(s): Avery, Robert DO; Golnik, Karl C. MD; Froment, Caroline MD, PhD; Wang, An-Guor MD Author Information

I read with interest Hanes et al.'s 1 Hanes I. Kozenko M. Callen D.J. Lethal neonatal rigidity and multifocal seizure syndrome - a misnamed disorder?. Pediatr Neurol. 2015; 53: 535-540 Abstract Full Text Full Text PDF Scopus (18) Google Scholar report of a patient with atypical lethal neonatal rigidity and multifocal seizure syndrome (LNRMSS) associated with mutations in BRAT1 gene. The authors discourage using the term LNRMSS, considering that abnormalities in the same gene could lead to more or less severe phenotypes.

*Department of Pediatrics, Hospital Universitário—Universidade Federal de Santa Catarina, Florianópolis, Brazil †Department of Neurology, Hospital Infantil Joana de Gusmão, Florianópolis, Brazil e-mail: [email protected]

Objective This was a bibliographic search to address the quality of evidence in clinical reports supporting the assertion that brain MRI signal abnormalities are a direct consequence of seizures. Methods The search on PubMed was performed by applying the following inclusion criteria: a) original case reports, b) in humans, c) as single case reports or series of patients, d) of visually detected acute MRI signal abnormalities, e) attributable directly to seizures, and f) published in English. Bibliographic references of initially selected publications were reviewed for additional articles. Full texts of selected publications were read for information regarding clinical, EEG, and MRI features. Moreover, claimed evidence supporting seizure-induced excitotoxicity was assessed. Results The search resulted in 91 publications corresponding to 413 cases. There was a wide range of clinical features and EEG and MRI abnormalities. Premorbid or comorbid conditions were present in many cases, and some of them are potential causes of MRI changes. Claimed evidence for MRI signal abnormalities as a direct consequence of ictal activity was mostly based on the similarity with previous reports, animal models, reversibility, congruent EEG, MRI changes not respecting vascular territories, and ruling out other etiologies. Conclusions Evidence supporting the notion of seizure-induced excitotoxicity is questionable in the studied reports of postictal MRI abnormalities.

Sir, We thank Dr Grillo for his comments. A growing body of evidence from in vitro studies, animal models, observational studies in critically ill neonates, children and adults supports the hypothesis that electrographic seizures independently contribute to brain injury, whether they are clinically evident or not (Holmes, 2014). However, the relative contribution of seizures to brain injury clearly depends on the underlying aetiology (Hahn and Jette, 2013). In our recent study, the association between seizure burden and outcome …

The article by Armangue et al1Armangue T. Titulaer M.J. Malaga I. et al.Pediatric anti-N-methyl-D-aspartate receptor encephalitis: clinical analysis and novel findings in a series of 20 patients.J Pediatr. 2013; 162: 850-856Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar prompted us to report a patient who we treated in 2008.2Grillo E. da Silva R.J. Childhood chorea-encephalopathy and unremarkable MRI: an association suggesting parvovirus B19 infection.Dev Med Child Neurol. 2009; 51: 759-761Crossref PubMed Scopus (9) Google Scholar This previously healthy 17-month-old boy had developed a severe encephalopathy with prominent abnormal movements, preceded by cognitive disturbances that were difficult to assess given his age. A discrepancy between the presentation of severe encephalopathy and normal magnetic resonance imaging findings caught our attention. Similar cases had been reported in the United Kingdom,3Hartley L.M. Ng S.Y. Dale R.C. Church A.J. Martinez A. de Sousa C. Immune-mediated chorea encephalopathy syndrome in childhood.Dev Med Child Neurol. 2002; 44: 273-277Crossref PubMed Google Scholar, 4Fong C.Y. de Sousa C. Childhood chorea-encephalopathy associated with human parvovirus B19 infection.Dev Med Child Neurol. 2006; 48: 526-528Crossref PubMed Scopus (18) Google Scholar one of which was associated with parvovirus B19 (PVB19) infection.4Fong C.Y. de Sousa C. Childhood chorea-encephalopathy associated with human parvovirus B19 infection.Dev Med Child Neurol. 2006; 48: 526-528Crossref PubMed Scopus (18) Google Scholar Our patient also had serologic evidence of acute PVB19 infection. Oligoclonal bands and PVB19 DNA were detected in cerebrospinal fluid by polymerase chain reaction. Cytomegalovirus DNA was detected as well, but without serologic evidence of acute infection. The patient had an initial good outcome, but long-term follow-up revealed moderate cognitive and severe behavioral disturbances, possibly as a result of the encephalopathy, a form that was called chorea-encephalopathy. Anti-N-methyl-D-aspartate receptor encephalitis is an immune-mediated condition that is frequently associated with neoplasms in adults but is rare in children, in whom infection could be a trigger. Armangue et al report an association with herpes simplex virus in one case. Symptomatic and especially asymptomatic PVB19 infections are very common in children; some cases of anti-N-methyl-D-aspartate receptor encephalitis could be triggered by this virus. Pediatric Anti-N-methyl-D-Aspartate Receptor Encephalitis—Clinical Analysis and Novel Findings in a Series of 20 PatientsThe Journal of PediatricsVol. 162Issue 4PreviewTo report the clinical features of 20 pediatric patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Full-Text PDF

I read with interest the article “Seizure-induced brain lesions: A wide spectrum of variably reversible MRI abnormalities”, by Cinfoni et al. [ [1] Cianfoni A. Caulo M. Cerase A. et al. Seizure-induced brain lesions: a wide spectrum of variably reversible MRI abnormalities. Eur J Radiol. 2013; Google Scholar ]. They accept the complete or partial reversibility of the MRI abnormalities as evidence for the hypothesis that they are consequence rather than cause of the seizures. Every brain lesion that is not associated to death or to a progressive condition evolves to partial or complete resolution, as occurs is vascular, infectious, immune-mediated or metabolic conditions. It is not rare in our everyday practice. Seizure-induced brain lesions: A wide spectrum of variably reversible MRI abnormalitiesEuropean Journal of RadiologyVol. 82Issue 11PreviewIntroduction MRI abnormalities in the postictal period might represent the effect of the seizure activity, rather than its structural cause. Material and Methods Retrospective review of clinical and neuroimaging charts of 26 patients diagnosed with seizure-related MR-signal changes. All patients underwent brain-MRI (1.5-Tesla, standard pre- and post-contrast brain imaging, including DWI-ADC in 19/26) within 7 days from a seizure and at least one follow-up MRI, showing partial or complete reversibility of the MR-signal changes. Full-Text PDF Response to: ‘Comment on: Seizure-induced excitotoxicity: Just considering it could be a fallacy’European Journal of RadiologyVol. 82Issue 12PreviewWe thank Dr. Grillo, for his interest and stimulating comments on our article [1]. Full-Text PDF

In the large group of genetically undetermined infantile-onset mitochondrial encephalopathies, multiple defects of mitochondrial DNA-related respiratory-chain complexes constitute a frequent biochemical signature. In order to identify responsible genes, we used exome-next-generation sequencing in a selected cohort of patients with this biochemical signature. In an isolated patient, we found two mutant alleles for EARS2, the gene encoding mitochondrial glutamyl-tRNA synthetase. The brain magnetic resonance imaging of this patient was hallmarked by extensive symmetrical cerebral white matter abnormalities sparing the periventricular rim and symmetrical signal abnormalities of the thalami, midbrain, pons, medulla oblongata and cerebellar white matter. Proton magnetic resonance spectroscopy showed increased lactate. We matched this magnetic resonance imaging pattern with that of a cohort of 11 previously selected unrelated cases. We found mutations in the EARS2 gene in all. Subsequent detailed clinical and magnetic resonance imaging based phenotyping revealed two distinct groups: mild and severe. All 12 patients shared an infantile onset and rapidly progressive disease with severe magnetic resonance imaging abnormalities and increased lactate in body fluids and proton magnetic resonance spectroscopy. Patients in the 'mild' group partially recovered and regained milestones in the following years with striking magnetic resonance imaging improvement and declining lactate levels, whereas those of the 'severe' group were characterized by clinical stagnation, brain atrophy on magnetic resonance imaging and persistent lactate increases. This new neurological disease, early-onset leukoencephalopathy with thalamus and brainstem involvement and high lactate, is hallmarked by unique magnetic resonance imaging features, defined by a peculiar biphasic clinical course and caused by mutations in a single gene, EARS2, expanding the list of medically relevant defects of mitochondrial DNA translation.

To the Editors: Studying risk factors for recurrence after antiepileptic drug (AED) withdrawal in patients treated with anterior temporal lobectomy (ATL) in mesial temporal lobe epilepsy (MTLE), Rathore et al. found, in univariate analysis, that surgery at age of 30 years or older and duration of epilepsy before surgery of 20 years or more were significant risk factors. They conclude “these results reemphasize the need to consider epilepsy surgery at earlier age” (Rathore et al., 2011). As a child neurologist, it called my attention for its practical implications. The authors did not mention an important selection bias: the older patients and the longer epilepsies were those more untreatable along the years. In multivariate analysis, Rathore et al. found that older age at surgery and longer epilepsy before surgery lost statistical significance, whereas absence of hippocampal sclerosis (HS) as a postsurgical pathologic finding remained a significant risk factor (Rathore et al., 2011). It is reasonable to suppose that surgery should be indicated as soon as possible in refractory MTLE considering its adverse effects in, for example, social life and employment (Engel, 2004). It has been suggested that epilepsy leads to cognitive impairment and behavioral abnormalities. However, confounders, as AEDs, do not allow one to assess if ictal activity itself along the years could have some deleterious cumulative effect on temporal or extratemporal cortex (Vingerhoets, 2006), thereby worsening prognosis after surgery and AED withdrawal. This paper raised this issue. Little is known about natural history of MTLE in population-based studies (Berg, 2008) and it is possible that, in some patients, epilepsy becomes less refractory over the years. With study of less-selected series of patients and not only those in epilepsy surgery centers, it has been observed that in the heterogeneous group of MTLE, even with HS, many patients have favorable outcomes and remission with and without AEDs (Labate et al., 2006; Aguglia et al., 2011). Most of these patients respond to the first AED and are not candidates for surgery (Labate et al., 2011), but a few of them require a second AED (Aguglia et al., 1998), and it is possible that these patients who would improve even without surgery, were included in this and other series of patients submitted to ATL, misleading to the view that earlier surgeries are responsible for better results regarding postsurgical AED withdrawal. Finally, what is known as MTLE in tertiary centers, where ATL is performed, probably represents the final outcome of multiple etiologies. Recognizing different pathogenic processes leading to this epilepsy will improve decisions about the best age for surgery. I have no conflicts of interest to disclose. I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

SIR–Parvovirus B19 (PVB19) is the only known member of the family parvoviridae linked to disease in humans. It demonstrates special tropism to erythroid progenitor cells but there is a wide spectrum of diseases linked to this virus in other tissues. Asymptomatic infection is common in children and adults and erythema infectiosum is the best recognized condition related to PVB19. Arthropathy, transient aplastic crisis, chronic red cell aplasia, 'gloves and socks syndrome,' and hydrops foetalis are other recognized conditions. Cardiac and neurological diseases are postulated to have a link to PVB19.1 PVB19 has been pointed as an infectious agent linked to encephalopathy and abnormal movements in children, probably by an immunomediated mechanism.2 We report a patient with acute encephalopathy and abnormal movements, with viral DNA detected in cerebrospinal fluid (CSF) and serological evidence of recent PVB19 infection. A 17-month-old Caucasian male was admitted to the Department of Neurology, Joana de Gusmão Children's Hospital, referred from another hospital. The first concerns had begun 15 days earlier with frequent vomiting and diarrhoea. Vomiting lasted 3 days and diarrhoea continued until 1 week after admission. Fever was not reported. The first neurological complaints started 8 days before admission when he could not recognize family members and did not obey even simple commands as he had before. Three days after these behavioural abnormalities, abnormal movements were first observed which continuously during waking, with self-injury. Seizures were not clearly reported but he had been treated with valproic acid and phenytoin. He was on aciclovir and haloperidol without any improvement. There were no remarkable pre- or perinatal antecedents. His development was previously normal. At admission, we observed abnormal and continuous choreiform movements involving four limbs. He did not display visual contact, voluntary grasp, nor head control. He was continuously irritable and, during sleep, movements disappeared. There were no significant feeding difficulties. Before referral, cranial computed tomography, blood count, hepatic enzymes, electrolytes, and renal function had been normal. Magnetic resonance imaging (MRI) performed a day before admission was normal. CSF examination showed less than 1 lymphocyte per millilitre, CSF glucose 4.2 mmol/L, and CSF protein 0.19g/L. Human PVB19 and cytomegalovirus (CMV) DNA was detected in CSF by polymerase chain reaction (PCR). PCR for other herpes group viruses, such as Epstein–Barr virus, Herpes 6, and Herpes simplex 1 and 2, were negative. Oligoclonal bands were detected in CSF. PVB19 specific IgM antibodies were detected by indirect immune-fluorescence assay in serum and IgG antibodies titres were normal 3 weeks after the first neurological manifestations. Serum CMV IgG antibodies were high with normal IgM antibodies. An electroencephalogram was diffusely slow without epileptiform discharges. Prednisolone was started at 1.5mg/kg/day and all other drugs, including aciclovir, were withdrawn. The patient was discharged a week after admission with discrete improvement of social contact and voluntary grasp and was readmitted 10 days later for a 5-day course of immunoglobulin (400mg/kg/day) as no significant improvement had been observed. Two weeks after the last immunoglobulin dose and about 6 weeks after the first neurological symptoms, clear improvement had been observed with recovering of head control and voluntary bilateral grasping. Twelve weeks after the first neurological complaints, full clinical recovery occurred. At this time, PVB19 specific IgM antibodies in blood were no longer detectable, and IgG antibodies were elevated by indirect immune-fluorescence assay. In 2002, Hartley et al. described four previously healthy females aged between 3 and 8 years with encephalopathy and prominent abnormal movements.3 The symptoms were self-limiting and oligoclonal bands were detected in CSF from all patients. They called this condition 'immune mediated chorea-encephalopathy'. In 2006, Fong and de Sousa reported a very similar case in an 8-year-old female. As this female also displayed sustained anaemia and lymphopenia, investigation for PVB19 was performed and they found viral DNA in CSF and serological evidence of PVB19 infection.2 Encephalopathy has also been associated to PVB19 infection in previously sick children.4,5 Our patient developed chorea-encephalopathy and serological evidence of acute PVB19 infection, without haematological abnormalities. Oligoclonal bands were present in CSF suggesting intrathecal antibody production. Viral DNA was detected in CSF, which has only been reported in one published case.2 The underlying mechanism by which PVB19 could lead to encephalopathy is not well understood and inappropriate immune responses directed against brain antigens have been considered as the mechanism of brain injury in previously healthy patients.2,3 A more direct mechanism has been proposed in previously sick children.4,5 The finding of CMV DNA in CSF by PCR is worthy of mentioning but the lack of serological evidence of recent infection could suggest that CMV is not involved in the pathogenesis. Although PCR for CMV is a highly sensitive and specific method, it could be a false-positive.6 In the present case, prominent abnormal movements suggest that the basal ganglia were particularly affected, although MRI was normal during the period of full clinical manifestations. Unremarkable cranial MRI findings are seen in ataxia–opsoclonus syndrome, Sydenham chorea, and encephalitis lethargica (three probably immunomediated encephalopathies with prominent extrapyramidal signs),7–9 suggesting a more functional and less structural abnormality. In the five reported cases of chorea-encephalopathy in previously healthy children, the initial MRI was normal.2,3 We think that the association between acute or subacute encephalopathy with severe abnormal movements and normal MRI could be suggestive of PVB19-related encephalopathy in children. Although behavioural abnormalities have been well reported both in Sydenham chorea and opsoclonus–myoclonus syndrome, the involvement of mental functions seems to be much more prominent in the present case and in previously reported cases of chorea-encephalopathy.2,3 This observation may be important in differential diagnosis in a child presenting acute or subacute encephalopathy and abnormal movements. Dale et al. also reported the association of abnormal movements, severe behavioural abnormalities, normal MRI, oligoclonal bands in CSF, and favourable outcome in individuals whom they described as suffering from contemporary encephalitis lethargica. Search for PVB19 is not mentioned in these reports.9 Favourable outcome with full recovery seems to be another distinctive feature of this and the other reported cases.2,3 Although a temporal relationship between intravenous immunoglobulin and rapid convalescence was observed, a similar outcome in the other reported cases without this treatment suggests a casual association.

Pontocerebellar hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or hypoplasia of the cerebellum, hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders.

The association of acute myelopathy and encephalopathy is reported in a 13-year-old boy. Signs and symptoms of infectious mononucleosis, presence of heterophile antibodies, anticapsid antibodies and Epstein-Barr virus DNA detected in cerebrospinal fluid, disclosed a primary or reactivated infection by Epstein-Barr virus. Outcome was rapid and benign with complete clinical recovery in 1 month, after pulse therapy with methylprednisolone. Epstein-Barr virus is a known agent related to acute disseminated encephalomyelitis, by immune mediated mechanisms. However, in this case, cortical involvement in magnetic resonance imaging, short time between infectious mononucleosis and central nervous system manifestations, and the presence of viral DNA in cerebrospinal fluid, raised the possibility of a direct action of the virus in central nervous system. Acute myelopathy associated to Epstein-Barr virus encephalitis has been rarely reported in children.

Interictal spike detection is a time-consuming, low-efficiency task, but is important to epilepsy diagnosis. Automated systems reported to date usually have their practical efficacy compromised by elevated rates of false-positive detections per minute, which are caused mainly by the influence of artifacts (such as noise activity and ocular movements) and by the adoption of single or simple approaches. This work describes the development of a hybrid system for automatic detection of spikes in long-term electroencephalogram (EEG), named System for Automatic Detection of Epileptiform Events in EEG (SADE(3)), which uses wavelet transform, neural networks and artificial intelligence procedures to recognize epileptic and to reject non-epileptic activity. The system's pre-processing stage filters the EEG epochs with the Coiflet wavelet function, which showed the closest correlation to epileptogenic (EPG) activity, in opposition to some other wavelet functions that did not correlate with these events. In contrast to current attempts using continuous wavelet transform, we chose to work with fast wavelet transform to reduce processing time and data volume. Detail components at appropriate decomposition levels were used to accentuate spikes, sharp waves, high-frequency noise activity and ocular artifacts. These four detailed components were used to train four specialized neural networks, designed to detect and classify the EPG and non-EPG events. An expert module analyzes the networks' outputs, together with multichannel and context information and concludes the detection. The system was evaluated with 126,000 EEG epochs, obtained from seven different patients during long-term monitoring, under diverse behavior and mental states. More than 6,721 spikes and sharp waves were previously identified by three experienced human electroencephalographers. In these tests, the SADE(3) system simultaneously achieved 70.9% sensitivity, 99.9% specificity and a rate of 0.13 false-positives per minute, indicating its usefulness and low vulnerability to artifact influence. After tests, the SADE(3) system showed itself to be able to process bipolar cortical EEG records, from long-term monitoring, up to 32 channels, without any data preparation or event positioning. At the same time, SADE(3) revealed a high capacity to reject non-epileptic paroxysms, robustness in relation to a variety of spike morphologies, flexibility in adjustment of performance rates and the capacity to actually save time during EEG reading. Furthermore, it can be adapted to other applications for pattern recognition, with simple adjustments.

A 5-year-old girl with distal renal tubular acidosis (RTA) and hypokalemic muscle paralysis is reported. RTA is a known cause of hypokalemia, but in spite of the presence of persistent hypokalemia muscular paralysis is uncommon, rarely described in children, and the onset of paralysis may initially be misinterpreted particularly if the patient is attended by a physician who is not a pediatric nephrologist. Therefore parents must be informed about this possibility. Still, as the clinical appearance of hypokalemic paralysis is quite similar to familial hypokalemic periodic paralysis, and because the emergent and prophylactic treatment of the two disorders are quite different, we discuss the diagnostic evaluation and the treatment for both of them.