Age-related MR characteristics in mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE).

BACKGROUND: Mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE) is a newly described, rare histopathologic entity detected in resected brain tissue of patients with refractory epilepsies. It shows a predominantly frontal localization causing a difficult-to-treat epilepsy with onset usually in early childhood. Histologically, MOGHE is characterized by blurred gray-white-matter boundaries with increased numbers of heterotopic neurons in the subcortical white matter and increased density of oligodendroglia. Little is known, to date, about radiologic features of MOGHE. Here, we report typical and age-related magnetic resonance (MR) characteristics of MOGHE. PATIENTS AND METHODS: Retrospective analysis of 40 preoperative MR images of 25 pediatric patients with MOGHE (m/f: 13/12) who underwent epilepsy surgery at a median age of 9.3 years at our center between 2003 and 2018. Median age at magnetic resonance imaging (MRI) was 5.2 years (1.5-20.7 years). RESULTS: Two MR subtypes were found: subtype I with an increased laminar T2 and fluid attenuated inversion recovery (FLAIR) signal at the corticomedullary junction and subtype II with reduced corticomedullary differentiation because of increased signal of the adjacent white matter. Distribution of subtypes was age-related, with subtype I occurring between 1.5 and 5.1 years (median 2.6 years) and subtype II between 3.4 and 20.7 years (median 14.1 years). In one patient, MRI at the age of 2.7 years showed subtype I but had converted to subtype II by the age of 16 years. Histology revealed that in addition to the above mentioned typical findings of MOGHE, patchy areas of reduced density of myelin in 6 of 7 patients presenting subtype I out of 14 patients in which retrospective analysis regarding myelination was accessible. CONCLUSION: Magnetic resonance characteristics in patients with MOGHE are age-related and seem to change from subtype I to subtype II probably because of maturational processes between 3 and 6 years. Patchy areas of hypomyelination in histology seem to disappear during brain maturation and may therefore represent the histologic correlate of laminar T2 and FLAIR hyperintensities in subtype I. This article is part of the Special Issue "Individualized Epilepsy Management: Medicines, Surgery and Beyond".

Limbic encephalitis in children and adolescents.

OBJECTIVE: Limbic encephalitis is rare in people <18 years of age and rarely given a formal diagnosis. DESIGN: Retrospective study on presentation and outcome of children and adolescents with the clinico-radiological syndrome of limbic encephalitis tested for specific neuronal autoantibodies (Abs) over 3.5 years. SETTING: Assessment, diagnosis, treatment and follow-up at 12 neuropaediatric and neurological departments in Europe, with Abs determined in Bonn, Germany and Oxford, UK. PATIENTS: Ten patients <18 years of age who presented with a disorder mainly affecting the limbic areas of <5 years' duration with MRI evidence of mediotemporal encephalitis (hyperintense T2/FLAIR signal, resolving over time). RESULTS: Median age at disease onset was 14 years (range 3-17). Eight patients had defined Abs: one each with Hu or Ma1/2 Abs, four with high titre glutamic acid decarboxylase (GAD) Abs, two of whom had low voltage-gated potassium channel (VGKC) Abs and two with only low titre VGKC Abs. A tumour was only found in the patient with Hu Abs (a neuroblastoma). After a median follow-up of 15 months with corticosteroid or intravenous immunoglobulin treatment, starting after a median of 4 months, two patients recovered, eight remained impaired and one died. CONCLUSIONS: Limbic encephalitis is a disease that can occur in childhood or adolescence with many of the hallmarks of the adult disorder, suggesting that both result from similar pathogenic processes. Since most of the cases were non-paraneoplastic, as now also recognised in adults, more systematic and aggressive immunotherapies should be evaluated in order to improve outcomes.

Levetiracetam as add-on therapy in different subgroups of "benign" idiopathic focal epilepsies in childhood.

Several recent studies have shown that levetiracetam (LEV) can be beneficial in the treatment of children with typical rolandic epilepsy (RE). Reports about the effectiveness of LEV in the treatment of children with the less benign variants in the spectrum of "benign" idiopathic focal epilepsies are still rare. Little is known about the effect of LEV on interictal epileptiform discharges in these syndromes. We report on LEV therapy in 32 children (mean age: 10.6 years, range: 4-14) with RE or variants like atypical benign idiopathic partial epilepsy of childhood (ABIPEC), Landau-Kleffner syndrome (LKS), and continuous spikes and waves during sleep (CSWS) and in children with benign idiopathic focal epileptiform discharges of childhood (BIFEDC). Cognitive and behavioral problems, not seizures, may be related to the pathological EEG. Patients with a reduction in seizure frequency >50% and/or reduction in BIFEDC >90% 3 months after having started LEV therapy were defined as responders. The average dose of LEV was 39 mg/kg body wt per day; LEV was given in monotherapy to 31.3% of the patients. Overall, 20 of 32 patients (62.5%) did benefit: 12 of 24 patients had a >50% reduction in seizure frequency; 2 of 24 patients (8.3%) were completely seizure free; 18 of 32 patients (56.3%) had a >90% reduction in BIFEDC (including CSWS); 6 of 32 (18.8%) had an EEG completely free of epileptiform discharges; and 17 of 32 (53.1%) showed improvement in cognition and/or language functions and/or behavior. Surprisingly, LEV tended to be more helpful in atypical rolandic epilepsies and other variants.

Effectiveness of low dose of topiramate following rapid titration in multiply handicapped children and difficult-to-treat epilepsy.

This prospective, observational, single arm, monocentric study explored efficacy and tolerability outcomes of rapid oral initiation of topimarate in children with difficult to treat epilepsy. The study population consisted of 19 multiply handicapped children (mean age 4.4 years, range 0.6-15.3 years). The observation period was 12 weeks and included 7 visits. The mean initial dose of topiramate was 1.1 mg/kg body weight/d (range: 0.66-2.67 mg/kg/d) following rapid titration. The mean final dose was 3.3 mg/kg/d (range 0.5-6.7 mg/kg/d). An at least 50% reduction of seizure frequency compared to baseline was observed in 9 of 19 patients (47.4%). Six patients (31.6%) had a slight reduction of seizure frequency (<50%) and 4 patients (21.1%) experienced an increase of seizure frequency. A total number of 29 adverse events were documented in 17 of 19 patients. Most frequently captured were fatigue (26.3% of patients), decreased appetite (15.8%) and psychiatric disturbances (15.8%). No serious adverse events were reported. These data might suggest that in certain clinical circumstances rapid dose escalation with topiramate followed by a low maintenance dose might be a good therapeutic option for pediatric patients with difficult to treat epilepsy.

Clinical outcome of children presenting with a severe manifestation of acute disseminated encephalomyelitis.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is an acute, inflammatory-demyelinating disorder of the CNS with a favourable outcome in the majority of cases. OBJECTIVE: The aim of this study was to examine the long-term outcome of children with an initially severe form of ADEM. METHODS: Children with ADEM according to the criteria of the International Pediatric MS Study Group (IPMSSG) referred to the rehabilitation centre Vogtareuth were included. Neurological impairment was evaluated with a standardized telephone-based interview assessing the EDSS score. Neuropsychological outcome was assessed with review of the medical records and a standardized parental questionnaire (KOPKIJ). RESULTS: Twelve children (1 year 9 months to 13 years of age) were included. All children had focal-neurological signs and changes in mental status at presentation and an MRI of the brain showing a range of white and gray matter lesions. 11/12 patients with a mean follow-up of 6.2 years (2-13.6 years) had a monophasic course of the disease. One child had a multiphasic ADEM. Two children had an EDSS score of 0, three an EDSS of 2, five an EDSS between 3 and 5 and two children had an EDSS score of 6 and 9. Results of a standardized parental questionnaire (KOPKIJ) revealed that 7 children had deficits in the categories alertness, memory, school performance, visual-spatial skills and/or impulse control. CONCLUSION: The results of our study indicate that children with an initially severe manifestation of ADEM continue to have in the majority of cases neurological and neuropsychological handicaps.

Seizures, psychosis and coma: severe course of hashimoto encephalopathy in a six-year-old girl.

Hashimoto encephalopathy (HE) is a rare steroid-responsive encephalopathy associated with elevated antithyroid antibodies and is a well recognised complication of autoimmune thyroid disease. The clinical picture is pleomorphic, presenting with variable symptoms like coma, seizures, neuropsychiatric changes (impairment of cognitive functions, behavioural and mood disturbances, hallucinations) or focal neurological deficits. HE is mainly diagnosed in adults, but also a rare differential diagnosis of encephalopathy or epilepsy in children. The diagnosis is often overlooked at presentation but is crucial as it is a treatable disease. We report on the youngest patient described up to now presenting with progressive epilepsy resistant to anticonvulsive treatment and unclear encephalopathy related to Hashimoto thyroiditis.

Location and type of mutation in the LIS1 gene do not predict phenotypic severity.

BACKGROUND: Lissencephaly is a neuronal migration disorder leading to absent or reduced gyration and a broadened but poorly organized cortex. The most common form of lissencephaly is isolated, referred as classic or type 1 lissencephaly. Type 1 lissencephaly is mostly associated with a heterozygous deletion of the entire LIS1 gene, whereas intragenic heterozygous LIS1 mutations or hemizygous DCX mutations in males are less common. METHODS: Eighteen unrelated patients with type 1 lissencephaly were clinically and genetically assessed. In addition, patients with subcortical band heterotopia (n = 1) or lissencephaly with cerebellar hypoplasia (n = 2) were included. RESULTS: Fourteen new and seven previously described LIS1 mutations were identified. We observed nine truncating mutations (nonsense, n = 2; frameshift, n = 7), six splice site mutations, five missense mutations, and one in-frame deletion. Somatic mosaicism was assumed in three patients with partial subcortical band heterotopia in the occipital-parietal lobes or mild pachygyria. We report three mutations in exon 11, including a frameshift which extends the LIS1 protein, leading to type 1 lissencephaly and illustrating the functional importance of the WD domains at the C terminus. Furthermore, we present two patients with novel LIS1 mutations in exon 10 associated with lissencephaly with cerebellar hypoplasia type a. CONCLUSION: In contrast to previous reports, our data suggest that neither type nor position of intragenic mutations in the LIS1 gene allows an unambiguous prediction of the phenotypic severity. Furthermore, patients presenting with mild cerebral malformations such as subcortical band heterotopia or cerebellar hypoplasia should be considered for genetic analysis of the LIS1 gene.

SCN1A mutation analysis in myoclonic astatic epilepsy and severe idiopathic generalized epilepsy of infancy with generalized tonic-clonic seizures.

Severe myoclonic epilepsy in infancy (SMEI), severe idiopathic generalized epilepsy of infancy (SIGEI) with generalized tonic clonic seizures (GTCS), and myoclonic astatic epilepsy (MAE) may show semiological overlaps. In GEFS+ families, all three phenotypes were found associated with mutations in the SCN1A gene. We analyzed the SCN1A gene in 20 patients with non-familial myoclonic astatic epilepsy -- including 12 probands of the original cohort used by Doose et al. in 1970 to delineate MAE. In addition, 18 patients with sporadic SIGEI -- mostly without myoclonic-astatic seizures -- were analyzed. Novel SCN1A mutations were found in 3 individuals. A frame shift resulting in an early premature stop codon in a now 35-year-old woman with a borderline phenotype of MAE and SIGEI (L433fsX449) was identified. A splice site variant (IVS18 + 5 G --> C) and a missense mutation in the conserved pore region (40736 C --> A; R946 S) were detected each in a child with SIGEI. We conclude that, independent of precise syndromic delineation, myoclonic-astatic seizures are not predictive of SCN1A mutations in sporadic myoclonic epilepsies of infancy and early childhood.

Fatal propofol infusion syndrome in association with ketogenic diet.

Propofol is used for the treatment of refractory status epilepticus. When given as a long-term infusion propofol may cause a rare but frequently fatal complication, the propofol infusion syndrome. The hallmarks are metabolic acidosis, lipemia, rhabdomyolysis and myocardial failure. Propofol infusion syndrome is caused by impaired fatty acid oxidation. Beside anticonvulsants the ketogenic diet, a high-fat, low-carbohydrate, adequate-protein diet, is an effective treatment for difficult-to-control seizures. We report a 10-year-old boy with catastrophic epilepsy, who developed fatal propofol infusion syndrome when a ketogenic diet was initiated. Substances like propofol which impair fatty acid oxidation may pose an increased risk if combined with ketogenic diet.

Somatic mosaicism and variable penetrance in doublecortin-associated migration disorders.

X-linked isolated lissencephaly sequence (XLIS) and subcortical band heterotopia (SBH) are allelic disorders caused by mutations in the doublecortin (DCX) gene. This genetic analysis of seven families revealed four novel mutations in the DCX gene. The authors detected a high rate of somatic mosaicism in male and female patients with variable penetrance of bilateral SBH including nonpenetrance in a heterozygous woman. In addition, the authors implemented prenatal diagnosis in a family with SBH/XLIS.

Epilepsy surgery in children with focal cortical dysplasia (FCD): results of long-term seizure outcome.

The purpose of this study was to assess the effect of epilepsy surgery on seizure outcome in children and adolescents under 18 years with intractable epilepsy due to focal cortical dysplasia. We analysed clinical data, such as age at seizure onset, epilepsy course, localisation of focus from presurgical evaluation, MRI, tissue pathology and seizure outcome in 68 patients 6 months to 9 years after epilepsy surgery. Seizure outcome was classified according to the Engel classification. Mean age at seizure onset was 7 months, ranging from the first days of life to 7 years. All patients had medically intractable epilepsy. Localisation of the lesion was predominantly extratemporal: posterior (uni- or multilobar) 43 %, frontal without central region 26 %, multilobar involving central area 19 % and temporal in 12 %. MRI signs typically seen in cortical dysplasia (FCD) such as localised blurring of gray-white matter junction was found in 68 %, dysgyria in 62 %, thickening of the cortical ribbon in 46 % and T2 signal elongation of the subcortical white matter in 40 % of the patients' MRI. Age at surgery ranged from 5 months to 16 years; 14 patients were under 2 years when operated on. In 34 patients (6 patients under 3 years) subdural grid electrode evaluation was performed prior to surgery. Pathology revealed focal cortical dysplasia without balloon cells (type I) in 60 %, FCD of the balloon cell subtype (type II) in 40 % of the specimens. Postoperative complications were subdural hygroma in 5 and an increased motor deficit in 2 patients. Up to two years after epilepsy surgery 50 % of the children were seizure free (Engel class I), 10 % Engel class II, 33 % Engel class III and 7 % unchanged (Engel class IV). Long-term seizure outcome (> 3 years post surgery) in 32 patients showed similar results (class I 50 %, class II 19 %, class III 28 %, class IV 3 %). Complete resection of the dysplastic lesion was significantly correlated with favorable seizure outcome, whereas seizure outcome was not significantly different in patients with mild (type I) or balloon cell (type II) FCD. Children operated after 6 years of age had no better outcome than children operated in infancy or at preschool age. Epilepsy surgery resulted in good (class I and II) seizure control in 60 % of children with intractable epilepsy due to focal cortical dysplasia.

Functional MRI in a 6-year-old boy with unilateral cortical malformation: concordant representation of both hands in the unaffected hemisphere.

Functional magnetic resonance imaging (fMRI) was performed in a 6-year-old boy with a complex malformation of the right hemisphere who suffered from pharmaco-refractory epilepsy. Clinical examination revealed left-sided hemiparesis and marked mirror movements of the opposite hand both during paretic and non-paretic hand movements. Functional MRI of repetitive unimanual grasping demonstrated that the two hands share a common cortical representation located in the central motor region of the unaffected left hemisphere. The affected right hemisphere did not show any activation during either task. This case study demonstrates the feasibility and usefulness of motor fMRI in young children before they undergo epilepsy surgery.

The long-term use of vigabatrin and lamotrigine in patients with severe childhood onset epilepsy.

Our purpose was to compare the initial efficacy and retention at 5 years of lamotrigine (LTG) and vigabatrin (VGB) in patients with severe childhood-onset epilepsies, especially with regard to loss of efficacy. Add-on therapy in 95 young patients with severe epilepsies in a neuropaediatric department was prospectively followed in open label studies for up to 5 years. VGB group: 56 patients (mean age: 11.1 years). LTG group: 39 patients (mean age: 13.6 years). Definition of initial responders: more than 50% reduction in seizure-frequency after 6 weeks of VGB treatment or after 4 months of LTG treatment. Definition of retention at 5 years: percentage of patients still taking LTG or VGB after 5 years. Definition of loss of efficacy: return to the baseline seizure frequency. The results were: VGB group: after 6 weeks 18 of 56 patients (32%) were initial responders. The retention at 5 years was five of 56 patients (8.9%). One patient (1.8%) was still seizure free. A loss of efficacy occurred in 10 of the 18 initial responders, usually within the first 9 months after the initial response. In the LTG group, after 4 months, 11 of 39 patients (28%) were initial responders. The retention at 5 years was 10 of 39 patients (25.6%). Five patients (12.8%) were still seizure free. The rate of adverse events was equal in both groups (41%). All but one occurred within the first 6 months of treatment. Our study in patients with difficult to treat childhood epilepsies suggests that in clinical practice patients were less likely to be discontinued from LTG than from VGB within 5 years, after similiar initial efficacy. This was mainly due to a loss of efficacy in VGB treatment early after initial response.

Heterotopic ossification in childhood and adolescence.

Heterotopic ossification, or myositis ossificans, denotes true bone in an abnormal place. The pathogenic mechanism is still unclear. A total of 643 patients (mean age, 9.1 years) admitted for neuropediatric rehabilitation were analyzed retrospectively with respect to the existence of neurogenic heterotopic ossification. The purpose of this study was to obtain information about incidence, etiology, clinical aspect, and consequences for diagnosis and therapy of this condition in childhood and adolescence. Heterotopic ossification was diagnosed in 32 patients (mean age, 14.8 years) with average time of onset of 4 months after traumatic brain injury, near drowning, strangulation, cerebral hemorrhage, hydrocephalus, or spinal cord injury. The sex ratio was not significant. In contrast to what has been found in adult studies, serum alkaline phosphatase was not elevated during heterotopic ossification formation. A persistent vegetative state for longer than 30 days proved to be a significant risk factor for heterotopic ossification. The incidence of neurogenic heterotopic ossification in children seems to be lower than in adults. A genetic predisposition to heterotopic ossification is suspected but not proven. As a prophylactic regimen against heterotopic ossification we use salicylates for those patients in a coma or persistent vegetative state with warm and painful swelling of a joint and consider continuous intrathecal baclofen infusion and botulinum toxin injection for those patients with severe spasticity. We prefer to wait at least 1 year after trauma before excision of heterotopic ossification.

Temporal lobe epilepsy with sensory aura: interictal glucose hypometabolism.

Patients with mesial temporal lobe epilepsy (mTLE) exhibit marked depressions of the regional cerebral glucose metabolism (rCMRGlu) in the mesiotemporal region. We hypothesised that patients with temporal lobe epilepsy (TLE) who have a bilateral somatosensory or acoustic ( = temporolateral/SII-) aura can be differentiated from mTLE by rCMRGlu depressions primarily involving temporo-perisylvian locations. We therefore used this ictal semiology as a clinical criterion to define a subgroup of such patients and measured the rCMRGlu in 16 patients with TLE as evident from interictal and ictal EEG-video monitoring. Clinically, they presented with medically refractory complex partial seizures and were subjected to presurgical evaluation. The pattern of the interictal rCMRGlu in the TLE patients was different from that observed in patients with mTLE and showed significant depressions ipsilateral to the epileptic focus in mesial temporal and lateral temporal regions but spared the thalamus. The neocortical metabolic depressions were spatially more extended in right than in left TLE patients. Magnetic resonance images (MRI) were either normal (n = 5) or revealed unilateral or bilateral hippocampal atrophy/sclerosis (n = 7), or temporal or extratemporal focal cortical dysplasia (n = 4). The selected TLE patients presented here comprise a heterogeneous group showing most pronounced metabolic depressions in the lateral temporal cortex. Thus, our data suggest that non-invasive metabolic imaging can assist in identifying the neocortical symptomatogenic zone in putative temporo-perisylvian lobe epilepsy.

Evaluation with subdural plates in children and adolescents.

Noninvasive EEG examination is not always adequate for the determination of the epileptogenic area. In such cases invasive methods are required. The authors report on their experience with the implantation of subdural plates for the precise ictal and inter-ictal determination of the epileptogenic areal and the stimulation of the eloquent cortex. From December 1992 to December 1997, 97 patients were evaluated in the Bethel epilepsy center using subdural plates. Of these patients, 44 were children or adolescents, who underwent 45 resections. In order to be able to draw differentiated conclusions on the use of subdural plates in children and adolescents, these patients were divided into three age groups: Group 1, 0-5 years (n = 12); Group 2, 6-11 years (n = 13 + 1 repeat evaluation and resection); Group 3, 12-18 years (n = 19). In the groups of children and adolescents examined there were no complications or progress impediments which might give reason to assume that the application of these techniques involves risks or hazards. This has been verified by the results, in which 75% of age Groups 1 and 3 were categorized as 1 a/b or 2d according to the Engel classification.

Benign epileptic discharges in patients with lesional partial epilepsies.

Case reports of four patients with therapy-resistant lesional partial epilepsies and additional foci of benign epileptic discharges of childhood, in addition to the usual electroencephalogram (EEG) changes, are presented. A family history of epileptic or febrile seizures in childhood was reported in all four patients. A distant relative of one patient, not manifesting seizures, demonstrated rolandic spikes on EEG. An abnormal pregnancy (polyhydramnion, premature pains, induced labor because of an abnormal CTG , placenta insufficiency) was reported in one patient, risk factors during birth (birth 14 days after term, placenta insufficiency) were reported in one, and bacterial meningitis at 4 weeks of age was reported in one. All patients manifested a retarded, partly severe, unfavorable infantile psychomotor development. An early seizure onset was observed in all patients (in three patients during the first year of life and in one patient during the second year). A hemifacial seizure symptomatology was seen, in addition to other symptoms, in two patients, possibly indicating the seizure pattern indicative of benign partial seizures; seizures occurred exclusively in sleep in one patient. The benign focus was never located in the lesional area. It was recorded over the same hemisphere in two patients and over the other hemisphere in the other two.