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".

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.

Epileptic negative myoclonus. Subdural EEG recordings indicate a postcentral generator.

We report a patient with epileptic negative myoclonus (ENM) presenting as status epilepticus of the right arm. The etiology was a cortical malformation in the contralateral postcentral gyrus. Electrical stimulation of the right median nerve revealed giant surface somatosensory evoked potentials. Subdural recordings, performed to plan epilepsy surgery, demonstrated that the epileptogenic zone was in the left postcentral gyrus. Repetitive left postcentral spikes were consistently followed by an EMG silent period in the right arm with a latency of about 20 to 30 msec. The silent period in the EMG reflected the negative myoclonus and lasted 30 to 340 msec, mostly between 100 and 200 msec. Spikes in other regions of the cortex did not elicit ENM. The amplitude and duration of the spikes correlated with the EMG silent period: the more cortex involved in the spike generation, the longer the duration of the silent period. This suggests that epileptic activation of postcentral cortex leads to an inhibition of tonic activity of motor neurons. Focal ENM may be related to a hyperexcitability of the postcentral cortex.

Amnesia of the epileptic aura.

In a prospective study lasting 6 months, we recorded on video 108 seizures with aura of 23 patients in an attempt to evaluate the mechanisms involved in the encoding of memories. In 88 of those seizures, we also recorded an EEG. The percentage of auras remembered decreased significantly with increasing severity of the seizures. The recollection of auras was also significantly dependent on the ictal EEG changes during the aura. Ninety-seven percent of the auras without EEG changes, 94% of the auras with unilateral EEG changes, and 73% of the auras with bilateral EEG changes during the aura were remembered. The spread of the ictal EEG pattern during the aura also showed a significant correlation with the severity of the ensuing seizure. Three patients with bitemporal epilepsy made up a considerable proportion of those who never remembered their aura before secondary generalized tonic-clonic seizures (2 of 3) and of those who had a transient postictal amnesia of their aura (2 of 3). The only patient who failed to remember a previously documented isolated aura also suffered from bitemporal epilepsy. During the second part of the study, we questioned whether information provided during the history could be helpful in defining the type of epilepsy syndrome or localizing the EEG seizure pattern of the 80 patients who had been admitted for presurgical epilepsy diagnosis. Localized (regional, unilateral, and independent left and right lateral) EEG seizure patterns occurred in 82% of the 51 patients with auras in their history as compared with 24% of the 17 patients who did not have auras in their history (p < 0.01).

Ictal motor signs and interictal regional cerebral hypometabolism.

Early motor manifestations are the main components of focal seizures involving the frontal lobe. We examined the relationship between the initial ictal motor manifestations and interictal abnormalities of cerebral glucose consumption (rCMRGlc) as assessed by PET in 48 consecutive patients with focal seizures of neocortical origin. Group data analysis revealed that patients with predominantly unilateral clonic seizures had a significant contralateral perirolandic hypometabolism and to a lesser degree a contralateral frontomesial hypometabolism. Patients with predominantly focal tonic manifestations showed a hypometabolism within the frontomesial and perirolandic regions that was unilateral in all patients with lateralized tonic seizures. Patients with versive seizures had mainly contralateral metabolic depressions without a consistent regional pattern. Patients with hypermotor seizures had metabolic depressions involving frontomesial, anterior cingulate, perirolandic, and anterior insular/frontal operculum areas. In all patient groups, bilateral and symmetric hypometabolism of the thalamus and cerebellum was observed. We propose that this pattern of distinctly abnormal metabolic brain regions demonstrates not only possible epileptogenic zones but also symptomatogenic brain regions as shown by the associations between clinical manifestations and sets of abnormal brain regions, particularly if epileptogenic zones are in a clinically silent neocortical brain region. The detection and possible differentiation of symptomatogenic and epileptogenic zones might improve the effectiveness of presurgical noninvasive studies.

Individual prediction of change in delayed recall of prose passages after left-sided anterior temporal lobectomy.

Prognostic variables for individual memory outcome after left anterior temporal lobectomy (ATL) were studied in 27 patients with refractory temporal lobe epilepsy. The difference between pre- and postoperative performance in the delayed recall of two prose passages (Story A and B) from the Wechsler Memory Scale served as measure of postoperative memory change. Fifteen independent clinical, neuropsychological, and electrophysiological variables were submitted to a multiple linear regression analysis. Preoperative immediate and delayed recall of story content and right hemisphere Wada memory performance for pictorial and verbal items explained very well postoperative memory changes in recall of Story B. Delayed recall of Story B, but not of Story A, had high concurrent validity to other measures of memory. Patients who became seizure-free did not differ in memory change from patients who continued to have seizures after ATL. The variables age at epilepsy onset and probable age at temporal lobe damage provided complementary information for individual prediction but with less effectiveness than Wada test data. Our model confirmed that good preoperative memory functioning and impaired right hemispheric Wada memory performance for pictorial items predict a high risk of memory loss after left ATL. The analyses demonstrate that the combination of independent measures delivers more information than Wada test performance or any other variable alone. The suggested function can be used routinely to estimate the individual severity of verbal episodic memory impairment that might occur after left-sided ATL and offers a rational basis for the counseling of patients.

Reorganization of memory functions after human temporal lobe damage.

Hemispheric (re-)organization of episodic memory functions after temporal lobe damage (TLD) was investigated by the intracarotid amobarbital procedure in patients suffering temporal lobe epilepsy. Memory of the speech-dominant left hemisphere was intact after right-sided TLD independent of the age at manifestation. In contrast, the right hemisphere mediated memory well only after early left-sided TLD. These findings suggest a predisposition of the speech-dominant left hemisphere for the encoding of episodic memory, and indicate that for left-sided TLD the right hemisphere may compensate memory encoding sufficiently only if the damage occurred within a critical period in childhood.

The genetics of localization-related symptomatic epilepsy: risk of a family history with seizures in patients who have undergone surgery.

A family history of epileptic seizures including febrile convulsions was found in 15 of 103 patients (15%) with localization related epilepsy with partial seizures with and without secondary generalization, who were operated on because of drug resistance. This rate was significantly higher than that of the cumulative incidence in the general population (4%). The localization of the brain damage did not play a role (temporal lobe resection left: 15%, right: 17%, extra-temporal lesion excision: 20%, hemispherectomy: 11%). Various family members were involved. Some patients had more than one relative with seizures. Thus, 21 relatives suffered from seizures. Eleven of them had generalized tonic-clonic seizures (one grand mal on awakening), 7 had febrile convulsions (4 complicated), and in 1 patient the grand mal seizures on awakening were preceded by absences; 1 had generalized tonic-clonic and complex partial seizures; 1 after complicated febrile seizures likewise had complex partial seizures; another mentally retarded patient suffered from generalized tonic-clonic, axial tonic and myoclonic-astatic seizures. The seizure type of 3 remote relatives was not known. The first seizure occurred in 16 family members during childhood, in 3 in adolescence and in only 1 in adulthood (1 unknown). Eight showed mental retardation of slight degree in most. It is interesting that only one-third of the patients with a family history with seizures were seizure-free after the operation; 5 still had seizures, mostly reduced in frequency, 3 had seizures and isolated auras and 2 had only isolated auras. On comparing the findings in patients with and without a family history with seizures, those with family members with epileptic seizures showed a lower rate of an intellectual deficit (7 vs 47%) and brain tumours (13 vs 44%). Our earlier findings with a different group of patients are thus confirmed: that genetics play a role in symptomatic epilepsies.

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.

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.

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.

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.

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.

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.