Outcome of childhood-onset epilepsy from adolescence to adulthood: Transition issues.

This is the second of three papers that summarize the second symposium on Transition in Epilepsies held in Paris in June 2016. This paper addresses the outcome for some particularly challenging childhood-onset epileptic disorders with the goal of recommending the best approach to transition. We have grouped these disorders in five categories with a few examples for each. The first group includes disorders presenting in childhood that may have late- or adult-onset epilepsy (metabolic and mitochondrial disorders). The second group includes disorders with changing problems in adulthood (tuberous sclerosis complex, Rett syndrome, Dravet syndrome, and autism). A third group includes epilepsies that change with age (Childhood Absence Epilepsy, Juvenile Myoclonic Epilepsy, West Syndrome, and Lennox-Gastaut syndrome). A fourth group consists of epilepsies that vary in symptoms and severity depending on the age of onset (autoimmune encephalitis, Rasmussen's syndrome). A fifth group has epilepsy from structural causes that are less likely to evolve in adulthood. Finally we have included a discussion about the risk of later adulthood cerebrovascular disease and dementia following childhood-onset epilepsy. A detailed knowledge of each of these disorders should assist the process of transition to be certain that attention is paid to the most important age-related symptoms and concerns.

Early add-on immunoglobulin administration in Rasmussen encephalitis: the hypothesis of neuroimmunomodulation.

Rasmussen encephalitis (RE) is a chronic inflammatory disease leading to unilateral hemispheric atrophy, associated with progressive neurological dysfunction and intractable seizures. The best approach to RE is hemispherectomy. However long-term immunotherapy seems to prevent or slow down hemispheric tissue loss and the associated functional decline. We describe a girl with epilepsia partialis continua (EPC) and progressive neurological dysfunction compatible with RE. The brain MRI showed a lesion that was initially interpreted as focal cortical dysplasia. Combined antiepileptic and immunomodulation were administered for two years with initial beneficial effects. The follow-up MRI, 4 year later showed. atrophic change in right parietal region. The association of antiepileptic and immunomodulation therapies may inhibit pathogenetic mechanisms responsible for neuronal loss in RE, slowing down the progression of the disease.

Transporters in drug-refractory epilepsy: clinical significance.

Drug resistance remains an unmet challenge in a variety of neurological disorders, but epilepsy is probably the refractory disease that has received most experimental, preclinical, and therapeutic attention. Although resective surgery continues to improve our ability to provide seizure relief, new discoveries have potential as alternative therapeutic approaches to multiple drug resistance. As discussed here, the field is replete with controversies and false starts, in particular as it concerns the existence of genetic predisposition to inadequate pharmacological seizure control.

Joubert syndrome with bilateral polymicrogyria: clinical and neuropathological findings in two brothers.

Joubert syndrome (JS) is characterized by hypotonia, ataxia, developmental delay, and a typical neuroimaging finding, the so-called "molar tooth sign" (MTS). The association of MTS and polymicrogyria (PMG) has been reported as a distinct JS-related disorder (JSRD). So far, five patients have been reported with this phenotype, only two of them being siblings. We report on one additional family, describing a living child with JS and PMG, and the corresponding neuropathological picture in the aborted brother. No mutations were detected in the AHI1 gene, the only so far associated with the JS + PMG phenotype. Moreover, linkage analysis allowed excluding all known gene loci, suggesting further genetic heterogeneity.

Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement.

Rasmussen encephalitis (RE) is a rare but severe immune-mediated brain disorder leading to unilateral hemispheric atrophy, associated progressive neurological dysfunction and intractable seizures. Recent data on the pathogenesis of the disease, its clinical and paraclinical presentation, and therapeutic approaches are summarized. Based on these data, we propose formal diagnostic criteria and a therapeutic pathway for the management of RE patients.

Subcortical nodular heterotopia: a functional MRI and somatosensory evoked potentials study.

Subcortical nodular heterotopia (SNH) associated with refractory epilepsy may be surgically treated, and a positive outcome can be expected following the complete excision of the malformed tissue. Recent functional neuroimaging studies have suggested the possible functional relevance of cerebral malformations, and may make it possible to improve presurgical planning, thus allowing extended resections and minimising post-operative deficits. We here report the case of a 19-year-old man with epilepsy and a giant SNH associated with diffused abnormal gyrations of the right temporal-parietal regions. Cortical functional organisation was investigated by means of functional magnetic resonance imaging (MRI) during sensory and motor tasks, and somatosensory evoked potentials. The results revealed enlarged and displaced motor and sensory cortical areas with heterotopic tissue functional activation. The relevance of these findings is discussed in the light of the possible surgical treatment of drug-refractory epilepsy associated with cerebral malformations: surgical treatment based on conventional MRI studies alone, without taking the functional nature of dysplastic tissues into account, may lead to considerable side effects.

Experience with immunomodulatory treatments in Rasmussen's encephalitis.

The authors investigated immunomodulatory treatments in 15 patients with Rasmussen encephalitis (RE) (14 with childhood and one with adolescent onset RE). Positive time-limited responses were obtained in 11 patients using variable combinations of corticosteroids, apheresis, and high-dose IV immunoglobulins. Although surgical exclusion of the affected hemisphere is the only treatment that halts disease progression, immunomodulation can be considered when early surgery is not feasible, in late-onset patients with slower disease progression, and in the few cases of bilateral disease.

Neuromuscular syndrome associated with the 3291T-->C mutation of mitochondrial DNA: a second case.

A mutation was found in an Italian child affecting the gene encoding the mitochondrial transfer RNA for leucine (codon UUR). This mutation (3291T-->C) had previously been reported in a single Japanese patient. In contrast with the original patient, who suffered from early-onset mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), our patient presented an apparently isolated mild myopathy. Mutational analysis in the proband and her family showed that the mutation was heteroplasmic, and that its relative amount was positively correlated with the severity of the phenotype. These findings lead to the definitive confirmation that the 3291T-->C is indeed pathogenic. As commonly found in mitochondrial-DNA related disorders, also for this mutation different clinical manifestations can be associated with the same genetic abnormality.

Congenital malformations due to antiepileptic drugs.

To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 microg/ml) in the treatment of epileptic women of childbearimg age.

Periventricular nodular heterotopia: epileptogenic findings.

PURPOSE: We studied 17 patients with periventricular nodular heterotopia (PNH) to further investigate the electroclinical pictures and semiology of the associated seizures. METHODS: PNH was diagnosed by means of magnetic resonance imaging (MRI). The patients' clinical and familial histories were carefully analyzed, and their electroclinical features and course of epilepsy followed for periods ranging from 10 months to 22 years. The electroclinical data were compared with those of previously reported PNH cases. RESULTS: The patients were subdivided into those with bilateral (7) and unilateral (10) PNH. The former were mainly characterized by structural abnormalities in the posterior cerebral fossa and multiple seizure types; the latter were characterized by the paratrigonal location of the malformation and, frequently, by elementary seizures with a visual or auditory onset. Focal seizures were drug resistant in most cases. The interictal EEG abnormalities were always focal and consistent with the location of the PNH. A previously unreported photic driving of posterior background activity was observed in all patients and was always consistent with the PNH location. CONCLUSIONS: Our present findings and previously reported data show that bilateral and unilateral PNH cases are different in their morphological and electroclinical features and may be determined by different etiologies. The female predominance, frequent familial occurrence, and positive family history for epilepsy suggest that genetic factors may be involved in the genesis of bilateral and symmetrical PNH, whereas the presence of prenatal risk factors and its location in the watershed paratrigonal area suggest that vascular mechanisms may determine unilateral PNH.

Neuronal migration disorders and epilepsy: a morphological analysis of three surgically treated patients.

Despite the increasing number of patients affected by neuronal migration disorders (NMDs) recently diagnosed in vivo by means of magnetic resonance imaging (MRI), few detailed data on the correlation between the neuroradiological and the anatomical features in the single NMD case are available. The present paper reports a combined cytoarchitectural and immunocytochemical analysis, by means of antisera recognizing specific neuronal and glial markers, of three MRI diagnosed NMD patients surgically treated for the relief of intractable seizures. The first case was a giant subcortical nodular heterotopia of morphologically normal neurons lacking any type of cortical lamination. The second case was a layered polymicrogyria with an abnormal amount of ectopic neurons in the underlying white matter. The third case was a focal cortical dysplasia characterized by a dramatic disruption of the normal cortical layering associated with marked cytological abnormalities. The present data demonstrate that the macroscopical and microscopical brain abnormalities can be markedly different in different NMD subtypes, and suggest that different anatomical substrates can underlie the intrinsic hyperexcitability of these brain malformations. The relevance of further prospective clinico-morphological studies for a better understanding of the mechanisms determining the development of these brain malformations is underlined.